metformin and Hyperglycemia studies

Metformin: A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289)
metformin : A member of the class of guanidines that is biguanide the carrying two methyl substituents at position 1.

Research Excerpts

Excerpt	Relevance	Reference
"To assess metformin's prophylactic effectiveness of prednisone-induced hyperglycemia among hematological cancer patients."	9.34	Metformin's effectiveness in preventing prednisone-induced hyperglycemia in hematological cancers. ( Guantai, EM; Nyamu, DG; Ochola, LA; Weru, IW, 2020)
"Metformin prevents weight gain in patients with type 2 diabetes (T2D)."	9.27	Metformin-associated prevention of weight gain in insulin-treated type 2 diabetic patients cannot be explained by decreased energy intake: A post hoc analysis of a randomized placebo-controlled 4.3-year trial. ( Jager-Wittenaar, H; Kooy, A; Krijnen, W; Lehert, P; Miedema, I; Out, M; Stehouwer, C; van der Schans, C, 2018)
"Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men."	9.27	High-Dose, Diazoxide-Mediated Insulin Suppression Boosts Weight Loss Induced by Lifestyle Intervention. ( Brandon, T; de Boer, H; Filius, M; Hermus, A; Loves, S; Mekking, M; Tack, CJ; van Groningen, L, 2018)
"Metformin has been used in pregnancy since the 1970s."	9.22	Metformin for pregnancy and beyond: the pros and cons. ( Dunne, FP; Newman, C, 2022)
"Linagliptin/metformin combination in newly diagnosed T2D patients with marked hyperglycemia was well tolerated and elicited substantial improvements in glycemic control regardless of baseline HbA1c, age, BMI, renal function, or race."	9.22	Linagliptin plus metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycemia. ( Bailes, Z; Caballero, AE; Del Prato, S; Gallwitz, B; Lewis-D'Agostino, D; Patel, S; Ross, SA; Thiemann, S; von Eynatten, M; Woerle, HJ, 2016)
"The percentage of patients experiencing any hypoglycemia event (ie, symptomatic event or event of plasma glucose concentration <54 mg/dL regardless of symptoms) was lower with saxagliptin compared with glimepiride (5."	9.22	Effects of Glimepiride versus Saxagliptin on β-Cell Function and Hypoglycemia: A Post Hoc Analysis in Older Patients with Type 2 Diabetes Inadequately Controlled with Metformin. ( Cook, W; Hirshberg, B; Ohman, P; Perl, S; Wei, C, 2016)
"Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers."	9.19	Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. ( Breitschaft, A; Darstein, C; Golor, G; Hermosillo Reséndiz, K; Hu, K, 2014)
"To evaluate the effects of vildagliptin compared to glimepiride on glycemic control, insulin resistance and post-prandial lipemia."	9.19	Vildagliptin compared to glimepiride on post-prandial lipemia and on insulin resistance in type 2 diabetic patients. ( Bianchi, L; Bonaventura, A; D'Angelo, A; Derosa, G; Fogari, E; Maffioli, P; Romano, D, 2014)
"Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on beta-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin."	9.14	Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. ( DeFronzo, RA; Glass, LC; Lewis, MS; Maggs, D; Qu, Y; Triplitt, C, 2010)
"To measure the vascularization and ovarian volume with three-dimensional sonography in patients diagnosed of polycystic ovary syndrome with stimulated ovulation treatment, and to analyse the differences between the patients treated with clomiphen citrate versus clomiphen citrate and metformin."	9.14	[Sonographic ovarian vascularization and volume in women with polycystic ovary syndrome treated with clomiphene citrate and metformin]. ( Alvarez-Alvarez, P; Bajo-Arenas, JM; de la Fuente-Valero, J; Engels-Calvo, V; Orensanz-Fernández, I; Zapardiel-Gutiérrez, I, 2010)
"Metformin attenuates hyperglycemia and increases muscle protein synthesis in severely burned patients, thereby indicating a metabolic link between hyperglycemia and muscle loss following severe injury."	9.11	Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury. ( Gore, DC; Herndon, DN; Sanford, A; Wolf, SE; Wolfe, RR, 2005)
"Metformin was given in a double-blind, placebo-controlled fashion to 10 patients, all with burns > 60% body surface area (age, 36 +/- 4 years; weight, 92 +/- 3 kg; mean +/- SEM)."	9.10	Metformin blunts stress-induced hyperglycemia after thermal injury. ( Gore, DC; Herndon, DN; Wolf, SE; Wolfe, RR, 2003)
"The aim of this study was to review TZD and metformin as pharmacological treatments for insulin resistance associated with obesity and cancer."	9.05	Pharmacological Strategies for Insulin Sensitivity in Obesity and Cancer: Thiazolidinediones and Metformin. ( Biondo, LA; de O S Ferreira, KC; Neto, JCR; Teixeira, AAS, 2020)
"To recommend an approach to monitoring and treating hyperglycemia in pasireotide-treated patients with Cushing's disease, a severe clinical condition caused by a pituitary adenoma hypersecreting adrenocorticotropic hormone."	8.90	Managing hyperglycemia in patients with Cushing's disease treated with pasireotide: medical expert recommendations. ( Casanueva, FF; Colao, A; De Block, C; Gaztambide, MS; Kumar, S; Seufert, J, 2014)
" Antidiabetic biguanides such as metformin, which reduce hyperglycemia and hyperinsulinemia by decreasing insulin resistance, extend lifespan, and inhibit carcinogenesis in rodents."	8.89	Metformin: do we finally have an anti-aging drug? ( Anisimov, VN, 2013)
"Metformin can prevent hyperglycaemia-induced osteoporosis and decrease the bone fracture rate, but the mechanism has not been fully elucidated."	8.31	Metformin promotes osteogenic differentiation and prevents hyperglycaemia-induced osteoporosis by suppressing PPARγ expression. ( Lian, H; Shen, X; Wang, S; Xie, Y; Yan, S; Zheng, L, 2023)
" Don for potential anti-diabetic activity in the in vivo mouse model of alloxan-induced hyperglycemia."	8.12	Detailed approach toward the anti-hyperglycemic potential of Sterculia diversifolia G. Don against alloxan-induced in vivo hyperglycemia model. ( Achyut, A; Amir, Z; Amna, N; Fazle, R; Irfan, U; Shafiq Ur, R, 2022)
"This study aimed at comparing the effects of metformin on tubulointerstitial fibrosis (TIF) in different stages of diabetic nephropathy (DN) in vivo and evaluating the mechanism in high glucose (HG)-treated renal tubular epithelial cells (RTECs) in vitro."	8.02	Metformin attenuates renal tubulointerstitial fibrosis via upgrading autophagy in the early stage of diabetic nephropathy. ( Shi, K; Sun, D; Sun, H; Wang, F; Zhang, C; Zhang, X; Zuo, B, 2021)
"Methods based on atomic force microscopy (AFM) were used to directly evaluate the influence of metformin on the nanomechanical and adhesive properties of endothelial and cancer cells in chronic hyperglycemia."	7.96	Metformin attenuates adhesion between cancer and endothelial cells in chronic hyperglycemia by recovery of the endothelial glycocalyx barrier. ( Grochot-Przeczek, A; Kloska, D; Malek-Zietek, KE; Rajfur, Z; Stepien, EŁ; Szymonski, M; Targosz-Korecka, M, 2020)
"Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease."	7.96	Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. ( Avolio, T; Bachman, TN; Bai, Y; Baust, JJ; Bonetto, A; Considine, RV; Cook, T; Fisher, A; Gladwin, MT; Goncharov, DA; Goncharova, EA; Halliday, G; Hu, J; Huot, JR; Lai, YC; Machado, RF; McTiernan, CF; Mora, AL; Satoh, T; Sebastiani, A; Tan, J; Vanderpool, RR; Wang, L, 2020)
"The present study aimed to investigate the effect of metformin on diabetes-accelerated atherosclerosis and whether Nod-like receptor protein 3 (NLRP3) inflammasome is a target for metformin."	7.91	Metformin inhibited Nod-like receptor protein 3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE ( Chen, Y; Duan, F; Hu, J; Li, H; Li, W; Tan, H; Tang, G; Wang, Y; Zeng, C; Zhang, X, 2019)
"Metformin beneficially impacts several aspects of metabolic syndrome including dysglycemia, obesity, and liver dysfunction, thus making it a widely used frontline treatment for early-stage type 2 diabetes, which is associated with these disorders."	7.91	Amelioration of metabolic syndrome by metformin associates with reduced indices of low-grade inflammation independently of the gut microbiota. ( Adeshirlarijaney, A; Chassaing, B; Gewirtz, AT; Tran, HQ; Zou, J, 2019)
"Metformin was found to protect against hyperglycemia-induced injury in osteoblasts, but the cellular mechanisms involved remain unclear."	7.91	Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway. ( Shen, X; Xie, Y; Yan, S; Ye, J; Zheng, L, 2019)
"To determine the impact of hyperglycemia and metformin use on relevant B vitamin biomarkers and cognitive outcomes in older adults."	7.91	Hyperglycemia and Metformin Use Are Associated With B Vitamin Deficiency and Cognitive Dysfunction in Older Adults. ( Casey, MC; Cunningham, C; Gallagher, AM; Hoey, L; Hughes, CF; Laird, E; McCann, A; McCarroll, K; McNulty, H; Molloy, AM; O'Kane, M; Porter, KM; Strain, S; Tracey, F; Ward, M, 2019)
"Metformin treatment did not affect food intake, body weight, and casual blood glucose levels within each mouse line during the 20-week feeding period."	7.91	Metformin Attenuates Early-Stage Atherosclerosis in Mildly Hyperglycemic Oikawa-Nagao Mice. ( Asai, A; Kawahara, M; Miyazawa, T; Nagao, M; Oikawa, S; Shuto, Y; Sugihara, H, 2019)
" The aim of present study was to investigate the therapeutic potentials of resveratrol (RSV) alone and/or in combination with vitamin-E (Vit-E) against hyperglycemia-induced modulations using experimentally alloxan-induced diabetic animal model."	7.88	Resveratrol regulates hyperglycemia-induced modulations in experimental diabetic animal model. ( Akash, MSH; Munawar, SM; Rehman, K; Saeed, K, 2018)
" In this study, we investigated the molecular crosstalk between miR-34a, the protein product of SIRT1 (sirtuin1), and the antidiabetic drug, metformin, in hyperglycemia-mediated impaired angiogenesis in mouse microvascular endothelial cells (MMECs)."	7.83	Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin. ( Arunachalam, G; Ding, H; Lakshmanan, AP; Samuel, SM; Triggle, CR, 2016)
"Metformin increased in vitro angiogenesis under hyperglycemia-hypoxia and augmented the expression of VEGFA."	7.83	Metformin improves the angiogenic potential of human CD34⁺ cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction. ( Abuzenadah, AM; Ahmed, F; Ahmed, FW; Al-Malki, AL; Alqahtani, MH; Bakhashab, S; Bashir, A; Chaudhary, AG; Gari, MA; Karim, S; Lary, S; Schulten, HJ; Weaver, JU, 2016)
" Interestingly, our findings showed an association of metformin therapy and prolonged progression-free survival in glioblastoma patients with diabetes and therefore serve as a foundation for further preclinical and clinical investigations."	7.81	Metformin influences progression in diabetic glioblastoma patients. ( Adeberg, S; Ben Harrabi, S; Bernhardt, D; Bostel, T; Debus, J; Diehl, C; Koelsche, C; Mohr, A; Rieken, S, 2015)
"We aimed to evaluate the effects of aerobic exercise training (4 days) and metformin exposure on acute glucose intolerance after dexamethasone treatment in rats."	7.81	Effects of exercise and metformin on the prevention of glucose intolerance: a comparative study. ( Bersani-Amado, CA; Cuman, RK; Ferraro, ZM; Hintze, LJ; Molena-Fernandes, C; Nardo, N, 2015)
"In an experimental model of obesity and hyperglycemia in Drosophila melanogaster we studied the effect of diet modification and administration of metformin on systemic infection with Rhizopus, a common cause of mucormycosis in diabetic patients."	7.80	Diet modification and metformin have a beneficial effect in a fly model of obesity and mucormycosis. ( Albert, N; Do, KA; Farmakiotis, D; Kim-Anh, D; Kontoyiannis, DP; Shirazi, F; Yan, Y, 2014)
"We reviewed patients with acute lymphoblastic leukemia treated with corticosteroids and asparaginase who received metformin for control of hyperglycemia."	7.79	Safety and efficacy of metformin for therapy-induced hyperglycemia in children with acute lymphoblastic leukemia. ( Bostrom, B; Chu, J; Gandrud, L; McEvoy, R; Messinger, Y; Uppal, P, 2013)
"This is the first study to show that metformin can improve immunosuppressant-induced hyperglycemia, when administered concurrently, and reduces exocrine apoptosis (reducing the impact on potential islet progenitor cells)."	7.79	Metformin improves immunosuppressant induced hyperglycemia and exocrine apoptosis in rats. ( Bennett, RG; Clure, CC; Hamel, FG; Larsen, JL; Shivaswamy, V, 2013)
"Metformin (an insulin sensitizer) and spironolactone (an antiandrogen) are both used for treatment of polycystic ovary syndrome."	7.78	Effect of metformin and spironolactone therapy on OGTT in patients with polycystic ovarian syndrome - a retrospective analysis. ( Ammini, AC; Ganie, MA; Gupta, N; Kulshreshtha, B, 2012)
" We investigated potential lipid-related mechanisms of metformin (Met) and/or exercise for blunting the progression of hyperglycemia/hyperinsulinemia and skeletal muscle insulin resistance in female Zucker diabetic fatty rats (ZDF), a high-fat (HF) diet-induced model of diabetes."	7.74	Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia. ( Bonen, A; Chabowski, A; Dyck, DJ; Junkin, KA; Mullen, KL; Nickerson, J; Smith, AC, 2007)
"Taking metformin with a meal has been shown to decrease bioavailability of metformin."	6.82	Postprandial hyperglycemia was ameliorated by taking metformin 30 min before a meal than taking metformin with a meal; a randomized, open-label, crossover pilot study. ( Asano, M; Fukuda, T; Fukuda, Y; Fukui, M; Hamaguchi, M; Hasegawa, G; Hashimoto, Y; Kimura, T; Kitagawa, N; Majima, S; Mistuhashi, K; Nakamura, N; Oda, Y; Okada, H; Senmaru, T; Tanaka, M; Tanaka, Y; Yamada, S; Yamazaki, M, 2016)
"Dyslipidemia in patients with type 2 diabetes is characterized by elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and a predominance of small dense low-density lipoprotein (LDL) particles."	6.76	PIOfix-study: effects of pioglitazone/metformin fixed combination in comparison with a combination of metformin with glimepiride on diabetic dyslipidemia. ( Forst, T; Fuchs, W; Lehmann, U; Lobmann, R; Merke, J; Müller, J; Pfützner, A; Schöndorf, T; Tschöpe, D, 2011)
"Metformin is a first-line oral anti-diabetic agent that has been used clinically to treat patients with type 2 diabetes for over 60 years."	6.53	Current understanding of metformin effect on the control of hyperglycemia in diabetes. ( An, H; He, L, 2016)
"Metformin is an oral hypoglycemic agent which is most widely used as first-line therapy for type 2 diabetes."	6.52	Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect. ( Saisho, Y, 2015)
"Hyperglycemia is a known exacerbating factor in ischemic stroke."	6.47	[Effectiveness of metformin in prevention of development of hyperglycemia and neuronal damage caused by ischemic stress]. ( Fujita-Hamabe, W; Harada, S; Tokuyama, S, 2011)
"Furthermore metformin seems to decrease cancer risk in diabetic patients."	6.46	Metformin for aging and cancer prevention. ( Anisimov, VN, 2010)
"Metformin alone reduced hyperinsulinemia and circulating c-reactive protein, but exacerbated nephropathy."	5.72	Rapamycin/metformin co-treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice. ( Calcutt, NA; Doty, R; Flurkey, K; Harrison, DE; Koza, RA; Reifsnyder, PC, 2022)
"Metformin was used as the standard antidiabetic drug."	5.62	Vanillin exerts therapeutic effects against hyperglycemia-altered glucose metabolism and purinergic activities in testicular tissues of diabetic rats. ( Erukainure, OL; Islam, MS; Olofinsan, KA; Salau, VF, 2021)
"This study evaluated the influence of type 2 diabetes mellitus on bone loss, bone repair and cytokine production in hyperglycemic rats, treated or not with metformin."	5.56	Impact of hyperglycemia and treatment with metformin on ligature-induced bone loss, bone repair and expression of bone metabolism transcription factors. ( Azarias, JS; Bastos, MF; Garcia, RP; Malta, FS; Miranda, TS; Ribeiro, GKDR; Shibli, JA, 2020)
"Metformin was demonstrated to evoke metabolic stress and induce cancer cell death."	5.48	Hyperglycemia-Associated Dysregulation of O-GlcNAcylation and HIF1A Reduces Anticancer Action of Metformin in Ovarian Cancer Cells (SKOV-3). ( Bryś, M; Forma, E; Marczak, A; Rogalska, A; Śliwińska, A, 2018)
"Chronic oral nitrite treatment improved hyperglycemia in obese ZSF1 rats by a process that requires skeletal muscle SIRT3-AMPK-GLUT4 signaling."	5.43	SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. ( Dube, JJ; Garcia-Ocaña, A; Gladwin, MT; Goncharov, DA; Goncharova, EA; Hughan, KS; Lai, YC; Mora, AL; St Croix, CM; Tabima, DM; Tofovic, SP; Vanderpool, RR, 2016)
"Metformin is a first-line drug for the management of type 2 diabetes."	5.43	Metformin Protects H9C2 Cardiomyocytes from High-Glucose and Hypoxia/Reoxygenation Injury via Inhibition of Reactive Oxygen Species Generation and Inflammatory Responses: Role of AMPK and JNK. ( Chen, M; Hu, M; Liao, H; Yang, F; Ye, P, 2016)
"In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs."	5.42	Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer. ( Eckert, MA; Johnson, A; Lengyel, E; Litchfield, LM; Mills, KA; Mukherjee, A; Pan, S; Romero, IL; Shridhar, V, 2015)
"Metformin treatment also improved hyperleptinemia, whereas pioglitazone was ineffective."	5.36	Metformin reduces body weight gain and improves glucose intolerance in high-fat diet-fed C57BL/6J mice. ( Hirasawa, Y; Ito, M; Kyuki, K; Matsui, Y; Sugiura, T; Toyoshi, T, 2010)
"To assess metformin's prophylactic effectiveness of prednisone-induced hyperglycemia among hematological cancer patients."	5.34	Metformin's effectiveness in preventing prednisone-induced hyperglycemia in hematological cancers. ( Guantai, EM; Nyamu, DG; Ochola, LA; Weru, IW, 2020)
"To determine the separated and combined effects of metformin and exercise on insulin sensitivity and free-living glycemic control in overweight individuals with prediabetes/type 2 diabetes (T2DM)."	5.34	Exercise improves metformin 72-h glucose control by reducing the frequency of hyperglycemic peaks. ( Mora-Rodríguez, R; Morales-Palomo, F; Moreno-Cabañas, A; Ortega, JF; Ramirez-Jimenez, M, 2020)
"Metformin vs placebo treatment of diabetic pigs (twice 1."	5.33	Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs: effects of metformin at isoenergetic feeding in a type 2-like diabetic pig model. ( Ackermans, M; Corbijn, H; Dekker, R; Koopmans, SJ; Mroz, Z; Sauerwein, H, 2006)
"Metformin-treated rats gained significantly less weight."	5.29	Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone. ( Burant, CF; Polonsky, KS; Pugh, W; Sreenan, S; Sturis, J, 1996)
"Metformin prevents weight gain in patients with type 2 diabetes (T2D)."	5.27	Metformin-associated prevention of weight gain in insulin-treated type 2 diabetic patients cannot be explained by decreased energy intake: A post hoc analysis of a randomized placebo-controlled 4.3-year trial. ( Jager-Wittenaar, H; Kooy, A; Krijnen, W; Lehert, P; Miedema, I; Out, M; Stehouwer, C; van der Schans, C, 2018)
"Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men."	5.27	High-Dose, Diazoxide-Mediated Insulin Suppression Boosts Weight Loss Induced by Lifestyle Intervention. ( Brandon, T; de Boer, H; Filius, M; Hermus, A; Loves, S; Mekking, M; Tack, CJ; van Groningen, L, 2018)
"Metformin has been used in pregnancy since the 1970s."	5.22	Metformin for pregnancy and beyond: the pros and cons. ( Dunne, FP; Newman, C, 2022)
"Linagliptin/metformin combination in newly diagnosed T2D patients with marked hyperglycemia was well tolerated and elicited substantial improvements in glycemic control regardless of baseline HbA1c, age, BMI, renal function, or race."	5.22	Linagliptin plus metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycemia. ( Bailes, Z; Caballero, AE; Del Prato, S; Gallwitz, B; Lewis-D'Agostino, D; Patel, S; Ross, SA; Thiemann, S; von Eynatten, M; Woerle, HJ, 2016)
"The percentage of patients experiencing any hypoglycemia event (ie, symptomatic event or event of plasma glucose concentration <54 mg/dL regardless of symptoms) was lower with saxagliptin compared with glimepiride (5."	5.22	Effects of Glimepiride versus Saxagliptin on β-Cell Function and Hypoglycemia: A Post Hoc Analysis in Older Patients with Type 2 Diabetes Inadequately Controlled with Metformin. ( Cook, W; Hirshberg, B; Ohman, P; Perl, S; Wei, C, 2016)
" We present a protocol for a study to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high birthweight babies and other pregnancy complications."	5.20	Efficacy of metformin in pregnant obese women: a randomised controlled trial. ( Chiswick, CA; Denison, FC; Drake, AJ; Forbes, S; Murray, GD; Newby, DE; Norman, JE; Quenby, S; Reynolds, RM; Walker, BR; Whyte, SA; Wray, S, 2015)
"Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia."	5.19	Restoring Insulin Secretion (RISE): design of studies of β-cell preservation in prediabetes and early type 2 diabetes across the life span. ( , 2014)
"Adding metformin to insulin therapy in women with insulin-resistant diabetes mellitus with pregnancy seems to be effective in proper glycemic control in a considerable proportion of women, along with benefits of reduced hospital stay, reduced frequency of maternal hypoglycemia as well as reduced frequency of neonatal hypoglycemia, NICU admission and neonatal respiratory distress syndrome."	5.19	The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial. ( Anwar, M; Faris, M; Hamdy, A; Ibrahim, MI; Shafik, A; Taha, S, 2014)
"Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers."	5.19	Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. ( Breitschaft, A; Darstein, C; Golor, G; Hermosillo Reséndiz, K; Hu, K, 2014)
"To evaluate the effects of vildagliptin compared to glimepiride on glycemic control, insulin resistance and post-prandial lipemia."	5.19	Vildagliptin compared to glimepiride on post-prandial lipemia and on insulin resistance in type 2 diabetic patients. ( Bianchi, L; Bonaventura, A; D'Angelo, A; Derosa, G; Fogari, E; Maffioli, P; Romano, D, 2014)
"Alogliptin monotherapy maintained glycaemic control comparable to that of glipizide in elderly patients with T2DM over 1 year of treatment, with substantially lower risk of hypoglycaemia and without weight gain."	5.17	Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. ( Fleck, P; Rosenstock, J; Wilson, C, 2013)
" Effective improvement of postprandial hyperglycemia was demonstrated by a meal-loading test in all three interventions but serum insulin concentration was not increased by miglitol."	5.17	Concomitant use of miglitol and mitiglinide as initial combination therapy in type 2 diabetes mellitus. ( Anno, T; Hashiramoto, M; Hirukawa, H; Kaku, K; Kanda-Kimura, Y; Kawasaki, F; Kimura, T; Matsuki, M; Mune, T; Shimoda, M; Tatsumi, F; Tawaramoto, K, 2013)
" However, vildagliptin induced better circadian glycaemic control than sitagliptin with a significant decrease on overall hyperglycemia, mainly driven by reduction on basal hyperglycaemia."	5.16	Continuous glucose profiles with vildagliptin versus sitagliptin in add-on to metformin: results from the randomized Optima study. ( Colette, C; Dejager, S; Guerci, B; Huet, D; Monnier, L; Petit, C; Quéré, S; Raccah, D; Serusclat, P; Valensi, P, 2012)
" The neonates of metformin group had less rate of birth weight centile >90 than insulin group (RR: 0."	5.16	Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial. ( Akbari, S; Alavi, A; Amjadi, N; Moosavi, S; Niromanesh, S; Sharbaf, FR, 2012)
"Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia."	5.14	Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. ( Fiedorek, FT; List, JF; Morales, E; Tang, W; Woo, V, 2009)
"Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on beta-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin."	5.14	Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. ( DeFronzo, RA; Glass, LC; Lewis, MS; Maggs, D; Qu, Y; Triplitt, C, 2010)
" The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes."	5.14	Exenatide versus glibenclamide in patients with diabetes. ( Ciccarelli, L; Cicero, AF; D'Angelo, A; Derosa, G; Ferrari, I; Franzetti, IG; Gadaleta, G; Maffioli, P; Piccinni, MN; Querci, F; Ragonesi, PD; Salvadeo, SA, 2010)
"To measure the vascularization and ovarian volume with three-dimensional sonography in patients diagnosed of polycystic ovary syndrome with stimulated ovulation treatment, and to analyse the differences between the patients treated with clomiphen citrate versus clomiphen citrate and metformin."	5.14	[Sonographic ovarian vascularization and volume in women with polycystic ovary syndrome treated with clomiphene citrate and metformin]. ( Alvarez-Alvarez, P; Bajo-Arenas, JM; de la Fuente-Valero, J; Engels-Calvo, V; Orensanz-Fernández, I; Zapardiel-Gutiérrez, I, 2010)
" If insufficient in monotherapy, it can preferably be used in combination with metformin, which targets insulin resistance, and also in combination with sodium-glucose cotransporter 2 inhibition, thiazolidinediones and insulin, which target other mechanisms."	5.12	Glucose-lowering action through targeting islet dysfunction in type 2 diabetes: Focus on dipeptidyl peptidase-4 inhibition. ( Ahrén, B, 2021)
" However, body weight, waist circumference, fasting serum levels of insulin and C-peptide were lower and less number of patients experienced hypoglycaemia during treatment with metformin vs."	5.12	Targeting hyperglycaemia with either metformin or repaglinide in non-obese patients with type 2 diabetes: results from a randomized crossover trial. ( Frandsen, M; Lund, SS; Parving, HH; Pedersen, O; Schalkwijk, CG; Smidt, UM; Stehouwer, CD; Tarnow, L; Vaag, A, 2007)
"Metformin attenuates hyperglycemia and increases muscle protein synthesis in severely burned patients, thereby indicating a metabolic link between hyperglycemia and muscle loss following severe injury."	5.11	Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury. ( Gore, DC; Herndon, DN; Sanford, A; Wolf, SE; Wolfe, RR, 2005)
"Metformin was given in a double-blind, placebo-controlled fashion to 10 patients, all with burns > 60% body surface area (age, 36 +/- 4 years; weight, 92 +/- 3 kg; mean +/- SEM)."	5.10	Metformin blunts stress-induced hyperglycemia after thermal injury. ( Gore, DC; Herndon, DN; Wolf, SE; Wolfe, RR, 2003)
"The aim of this study was to review TZD and metformin as pharmacological treatments for insulin resistance associated with obesity and cancer."	5.05	Pharmacological Strategies for Insulin Sensitivity in Obesity and Cancer: Thiazolidinediones and Metformin. ( Biondo, LA; de O S Ferreira, KC; Neto, JCR; Teixeira, AAS, 2020)
"Metformin can improve patients' hyperglycemia through significant suppression of hepatic glucose production."	5.05	Metformin and Systemic Metabolism. ( He, L, 2020)
"Metformin is the most widely prescribed treatment of hyperglycemia and type II diabetes since 1970s."	5.01	Mitochondrial targets of metformin-Are they physiologically relevant? ( Brázdová, A; Drahota, Z; Houštěk, J; Mráček, T; Pecinová, A, 2019)
"Metformin is the most commonly prescibed drug for type 2 diabetes mellitus as it is inexpensive, safe, and efficient in ameliorating hyperglycemia and hyperinsulinemia."	4.91	[Advances of the anti-tumor research of metformin]. ( Liu, KX; Xue, CJ, 2015)
"To recommend an approach to monitoring and treating hyperglycemia in pasireotide-treated patients with Cushing's disease, a severe clinical condition caused by a pituitary adenoma hypersecreting adrenocorticotropic hormone."	4.90	Managing hyperglycemia in patients with Cushing's disease treated with pasireotide: medical expert recommendations. ( Casanueva, FF; Colao, A; De Block, C; Gaztambide, MS; Kumar, S; Seufert, J, 2014)
"The effect of acarbose on weight loss seems to be more pronounced in Eastern than in Western populations with hyperglycaemia, and is superior to that of placebo, nateglinide and metformin across both ethnicities."	4.90	Acarbose monotherapy and weight loss in Eastern and Western populations with hyperglycaemia: an ethnicity-specific meta-analysis. ( Huang, L; Li, Y; Tong, N; Tong, Y; Wu, T; Zhang, Y, 2014)
" The traditional approach involves: i) metformin, acting mainly on fasting blood glucose; ii) sulphonylureas, that have shown a number of drawbacks, including the high risk of hypoglycemia; iii) pioglitazone, with a substantial effect on fasting and postprandial glucose and a low risk of hypoglycaemia; iv) insulin, that can be utilized with the basal or prandial approach."	4.89	What are the preferred strategies for control of glycaemic variability in patients with type 2 diabetes mellitus? ( Marangoni, A; Zenari, L, 2013)
" Antidiabetic biguanides such as metformin, which reduce hyperglycemia and hyperinsulinemia by decreasing insulin resistance, extend lifespan, and inhibit carcinogenesis in rodents."	4.89	Metformin: do we finally have an anti-aging drug? ( Anisimov, VN, 2013)
" Metformin and empagliflozin are two commonly prescribed anti-diabetes drugs which reduce hyperglycemia, however their direct effects on macrophage inflammatory responses alone or in combination are unreported."	4.31	Metformin, Empagliflozin, and Their Combination Modulate Ex-Vivo Macrophage Inflammatory Gene Expression. ( Arefin, A; Gage, MC, 2023)
"Metformin can prevent hyperglycaemia-induced osteoporosis and decrease the bone fracture rate, but the mechanism has not been fully elucidated."	4.31	Metformin promotes osteogenic differentiation and prevents hyperglycaemia-induced osteoporosis by suppressing PPARγ expression. ( Lian, H; Shen, X; Wang, S; Xie, Y; Yan, S; Zheng, L, 2023)
" leprosum (CLF-1) on sucrose-induced hyperglycemia in adult zebrafish (Danio rerio) was evaluated."	4.12	Hypoglycemic effect on adult zebrafish (Danio rerio) of the 3β-6β-16β-trihydroxylup-20(29)-ene triterpene isolated from Combretum leprosum leaves in vivo and in silico approach. ( Coutinho, MR; da Silva, AW; de Lima Rebouças, E; de Menezes, JESA; Dos Santos, HS; Ferreira, MKA; Marinho, EM; Marinho, ES; Marinho, MM; Mendes, FRS; Teixeira, AMR; Teixeira, EH, 2022)
" Don for potential anti-diabetic activity in the in vivo mouse model of alloxan-induced hyperglycemia."	4.12	Detailed approach toward the anti-hyperglycemic potential of Sterculia diversifolia G. Don against alloxan-induced in vivo hyperglycemia model. ( Achyut, A; Amir, Z; Amna, N; Fazle, R; Irfan, U; Shafiq Ur, R, 2022)
" The moderate hyperglycaemia seen in prediabetes can be treated using a combination of metformin and lifestyle interventions (low-calorie diets and exercising)."	4.12	Ameliorative Effects of a Rhenium (V) Compound with Uracil-Derived Ligand Markers Associated with Hyperglycaemia-Induced Renal Dysfunction in Diet-Induced Prediabetic Rats. ( Akinnuga, AM; Booysen, IN; Ismail, MB; Khathi, A; Khumalo, B; Ngubane, P; Sibiya, NH; Siboto, A, 2022)
"Treatment with the polyherbal mixture extract was more effective than the standard drugs (insulin and metformin) in the amelioration of hyperglycemia, hyperlipidemia, and histopathological changes of the pancreas, kidney and liver tissue."	4.02	Polyherbal mixture ameliorates hyperglycemia, hyperlipidemia and histopathological changes of pancreas, kidney and liver in a rat model of type 1 diabetes. ( Djordjević, L; Jugović, D; Jušković, M; Madić, V; Petrović, A; Stojanović, G; Vasiljević, P, 2021)
"To investigate the therapeutic effect of methyl-3β-hydroxylanosta-9,24-dien-21-oate (RA3), in the absence or presence of the anti-diabetic drug, metformin (MET), against hyperglycemia-induced cardiac injury using an in vitro H9c2 cell model."	4.02	The triterpene, methyl-3β-hydroxylanosta-9,24-dien-21-oate (RA3), attenuates high glucose-induced oxidative damage and apoptosis by improving energy metabolism. ( Dludla, PV; Johnson, R; Kappo, AP; Mosa, RA; Muller, CJF; Opoku, AR; Sangweni, NF, 2021)
"This study aimed at comparing the effects of metformin on tubulointerstitial fibrosis (TIF) in different stages of diabetic nephropathy (DN) in vivo and evaluating the mechanism in high glucose (HG)-treated renal tubular epithelial cells (RTECs) in vitro."	4.02	Metformin attenuates renal tubulointerstitial fibrosis via upgrading autophagy in the early stage of diabetic nephropathy. ( Shi, K; Sun, D; Sun, H; Wang, F; Zhang, C; Zhang, X; Zuo, B, 2021)
"Methods based on atomic force microscopy (AFM) were used to directly evaluate the influence of metformin on the nanomechanical and adhesive properties of endothelial and cancer cells in chronic hyperglycemia."	3.96	Metformin attenuates adhesion between cancer and endothelial cells in chronic hyperglycemia by recovery of the endothelial glycocalyx barrier. ( Grochot-Przeczek, A; Kloska, D; Malek-Zietek, KE; Rajfur, Z; Stepien, EŁ; Szymonski, M; Targosz-Korecka, M, 2020)
"Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease."	3.96	Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. ( Avolio, T; Bachman, TN; Bai, Y; Baust, JJ; Bonetto, A; Considine, RV; Cook, T; Fisher, A; Gladwin, MT; Goncharov, DA; Goncharova, EA; Halliday, G; Hu, J; Huot, JR; Lai, YC; Machado, RF; McTiernan, CF; Mora, AL; Satoh, T; Sebastiani, A; Tan, J; Vanderpool, RR; Wang, L, 2020)
"The present study aimed to investigate the effect of metformin on diabetes-accelerated atherosclerosis and whether Nod-like receptor protein 3 (NLRP3) inflammasome is a target for metformin."	3.91	Metformin inhibited Nod-like receptor protein 3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE ( Chen, Y; Duan, F; Hu, J; Li, H; Li, W; Tan, H; Tang, G; Wang, Y; Zeng, C; Zhang, X, 2019)
"Metformin beneficially impacts several aspects of metabolic syndrome including dysglycemia, obesity, and liver dysfunction, thus making it a widely used frontline treatment for early-stage type 2 diabetes, which is associated with these disorders."	3.91	Amelioration of metabolic syndrome by metformin associates with reduced indices of low-grade inflammation independently of the gut microbiota. ( Adeshirlarijaney, A; Chassaing, B; Gewirtz, AT; Tran, HQ; Zou, J, 2019)
" Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance."	3.91	Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK. ( An, H; Guo, S; He, L; Hussain, M; Liu, T; Maheshwari, A; O'Rourke, B; Qin, C; Radovick, S; Sesaki, H; Wang, Y; Wondisford, FE, 2019)
"Metformin was found to protect against hyperglycemia-induced injury in osteoblasts, but the cellular mechanisms involved remain unclear."	3.91	Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway. ( Shen, X; Xie, Y; Yan, S; Ye, J; Zheng, L, 2019)
"To determine the impact of hyperglycemia and metformin use on relevant B vitamin biomarkers and cognitive outcomes in older adults."	3.91	Hyperglycemia and Metformin Use Are Associated With B Vitamin Deficiency and Cognitive Dysfunction in Older Adults. ( Casey, MC; Cunningham, C; Gallagher, AM; Hoey, L; Hughes, CF; Laird, E; McCann, A; McCarroll, K; McNulty, H; Molloy, AM; O'Kane, M; Porter, KM; Strain, S; Tracey, F; Ward, M, 2019)
"Metformin treatment did not affect food intake, body weight, and casual blood glucose levels within each mouse line during the 20-week feeding period."	3.91	Metformin Attenuates Early-Stage Atherosclerosis in Mildly Hyperglycemic Oikawa-Nagao Mice. ( Asai, A; Kawahara, M; Miyazawa, T; Nagao, M; Oikawa, S; Shuto, Y; Sugihara, H, 2019)
" The aim of present study was to investigate the therapeutic potentials of resveratrol (RSV) alone and/or in combination with vitamin-E (Vit-E) against hyperglycemia-induced modulations using experimentally alloxan-induced diabetic animal model."	3.88	Resveratrol regulates hyperglycemia-induced modulations in experimental diabetic animal model. ( Akash, MSH; Munawar, SM; Rehman, K; Saeed, K, 2018)
" Metformin, an insulin-sensitizing biguanide, is used in the therapy of diabetic pregnancy."	3.88	Anti-inflammatory Action of Metformin with Respect to CX3CL1/CX3CR1 Signaling in Human Placental Circulation in Normal-Glucose Versus High-Glucose Environments. ( Alkhalayla, H; Bachanek, M; Pyzlak, M; Stangret, A; Szewczyk, G; Szukiewicz, D; Trojanowski, S; Wejman, J, 2018)
" Compared with vehicle-treated mice, borapetoside E markedly improved hyperglycemia, insulin resistance, hepatic steatosis, hyperlipidemia, and oxygen consumption in obese mice, and the effects were comparable to or better than the drug metformin."	3.85	Borapetoside E, a Clerodane Diterpenoid Extracted from Tinospora crispa, Improves Hyperglycemia and Hyperlipidemia in High-Fat-Diet-Induced Type 2 Diabetes Mice. ( Gao, Y; Hu, J; Liu, J; Lu, Y; Niu, Y; Peng, L; Qin, W; Wang, F; Xiong, W; Xu, Y, 2017)
" Metformin improves hyperglycemia, increases insulin sensitivity and attenuates the activation of the NF-κB pathway in T2DM."	3.85	The Effect of Metformin on the Expression of GPR109A, NF-κB and IL-1β in Peripheral Blood Leukocytes from Patients with Type 2 Diabetes Mellitus. ( Chen, Y; Fu, Y; Li, X; Lin, S; Ma, S; Wang, C; Wei, C; Xu, W; Xu, X, 2017)
" In this study, we investigated the molecular crosstalk between miR-34a, the protein product of SIRT1 (sirtuin1), and the antidiabetic drug, metformin, in hyperglycemia-mediated impaired angiogenesis in mouse microvascular endothelial cells (MMECs)."	3.83	Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin. ( Arunachalam, G; Ding, H; Lakshmanan, AP; Samuel, SM; Triggle, CR, 2016)
" Thus, in patients with diabetes-associated chronic kidney disease, the glucose lowering therapy has to account for renal function to avoid hypoglycemic episodes and other side effects such as lactic acidosis due to metformin."	3.83	[New aspects in prevention and therapy of diabetic nephropathy]. ( Böger, CA; Büttner, R; Rheinberger, M, 2016)
"Metformin increased in vitro angiogenesis under hyperglycemia-hypoxia and augmented the expression of VEGFA."	3.83	Metformin improves the angiogenic potential of human CD34⁺ cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction. ( Abuzenadah, AM; Ahmed, F; Ahmed, FW; Al-Malki, AL; Alqahtani, MH; Bakhashab, S; Bashir, A; Chaudhary, AG; Gari, MA; Karim, S; Lary, S; Schulten, HJ; Weaver, JU, 2016)
"The guideline for the management of new-onset diabetes after transplantation recommends metformin (MET) as a first-line drug, and addition of a second-line drug is needed to better control of hyperglycemia."	3.83	Effects of addition of a dipeptidyl peptidase IV inhibitor to metformin on sirolimus-induced diabetes mellitus. ( Chung, BH; Jin, J; Jin, L; Lim, SW; Yang, CW, 2016)
"Neither diabetes mellitus nor preadmission insulin or metformin use are associated with altered disease presentation, outcome or host response in patients with sepsis requiring intensive care."	3.83	Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients. ( Bonten, MM; Cremer, OL; Hoogendijk, AJ; Horn, J; Klein Klouwenberg, PM; Nürnberg, P; Schultz, MJ; Scicluna, BP; van der Poll, T; van Vught, LA; Wiewel, MA, 2016)
"Empagliflozin is a new medicine used to reduce hyperglycemia in patients with type 2 diabetes."	3.81	[Empagliflozin - the new representative of SGLT2 transporter inhibitors for the treatment of patients with diabetes 2 type]. ( Prázný, M; Slíva, J, 2015)
" Interestingly, our findings showed an association of metformin therapy and prolonged progression-free survival in glioblastoma patients with diabetes and therefore serve as a foundation for further preclinical and clinical investigations."	3.81	Metformin influences progression in diabetic glioblastoma patients. ( Adeberg, S; Ben Harrabi, S; Bernhardt, D; Bostel, T; Debus, J; Diehl, C; Koelsche, C; Mohr, A; Rieken, S, 2015)
"We aimed to evaluate the effects of aerobic exercise training (4 days) and metformin exposure on acute glucose intolerance after dexamethasone treatment in rats."	3.81	Effects of exercise and metformin on the prevention of glucose intolerance: a comparative study. ( Bersani-Amado, CA; Cuman, RK; Ferraro, ZM; Hintze, LJ; Molena-Fernandes, C; Nardo, N, 2015)
" Hyperglycemia was determined without any clinical sign and metformin was started for steroid-induced insulin resistance."	3.80	Metformin-induced hemolytic anemia. ( Arman Bilir, O; Kirkiz, S; Tunc, B; Yarali, N, 2014)
"Our primary objective was to determine whether administering the viscous and fermentable polysaccharide PolyGlycopleX (PGX) with metformin (MET) or sitagliptin/metformin (S/MET) reduces hyperglycemia in Zucker diabetic fatty (ZDF) rats more so than monotherapy of each."	3.80	Combining sitagliptin/metformin with a functional fiber delays diabetes progression in Zucker rats. ( Gahler, RJ; Grover, GJ; Koetzner, L; Lyon, MR; Reimer, RA; Wood, S, 2014)
"A 74-year-old female patient with a locally recurrent breast cancer developed hyperglycaemia, which started 2 weeks after the initiation of treatment with everolimus 10 mg once daily."	3.80	[Hyperglycaemia during treatment with everolimus]. ( Beijnen, JH; Huitema, AD; Opdam, FL; Schellens, JH, 2014)
"In an experimental model of obesity and hyperglycemia in Drosophila melanogaster we studied the effect of diet modification and administration of metformin on systemic infection with Rhizopus, a common cause of mucormycosis in diabetic patients."	3.80	Diet modification and metformin have a beneficial effect in a fly model of obesity and mucormycosis. ( Albert, N; Do, KA; Farmakiotis, D; Kim-Anh, D; Kontoyiannis, DP; Shirazi, F; Yan, Y, 2014)
"We reviewed patients with acute lymphoblastic leukemia treated with corticosteroids and asparaginase who received metformin for control of hyperglycemia."	3.79	Safety and efficacy of metformin for therapy-induced hyperglycemia in children with acute lymphoblastic leukemia. ( Bostrom, B; Chu, J; Gandrud, L; McEvoy, R; Messinger, Y; Uppal, P, 2013)
"This is the first study to show that metformin can improve immunosuppressant-induced hyperglycemia, when administered concurrently, and reduces exocrine apoptosis (reducing the impact on potential islet progenitor cells)."	3.79	Metformin improves immunosuppressant induced hyperglycemia and exocrine apoptosis in rats. ( Bennett, RG; Clure, CC; Hamel, FG; Larsen, JL; Shivaswamy, V, 2013)
"Metformin (an insulin sensitizer) and spironolactone (an antiandrogen) are both used for treatment of polycystic ovary syndrome."	3.78	Effect of metformin and spironolactone therapy on OGTT in patients with polycystic ovarian syndrome - a retrospective analysis. ( Ammini, AC; Ganie, MA; Gupta, N; Kulshreshtha, B, 2012)
"Baicalin was an efficient antioxidant in reducing hyperglycemia-induced oxidative stress through the increased expression of antioxidant enzyme activities."	3.77	Baicalin upregulates the genetic expression of antioxidant enzymes in Type-2 diabetic Goto-Kakizaki rats. ( Hsu, A; Huang, D; Siu, SY; Tan, BK; Waisundara, VY, 2011)
"An increase in the rate of gluconeogenesis is largely responsible for the hyperglycemia in individuals with type 2 diabetes, with the antidiabetes action of metformin being thought to be achieved at least in part through suppression of gluconeogenesis."	3.76	Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action. ( Emi, A; Hayashi, K; Hiramatsu, R; Inoue, H; Kasuga, M; Kinoshita, S; Matsuki, Y; Ogawa, W; Okamoto, Y; Sakaue, H; Senga, Y; Takashima, M; Watanabe, E; Wataoka, Y, 2010)
"Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes."	3.76	Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. ( Andreelli, F; Foretz, M; Hébrard, S; Leclerc, J; Mithieux, G; Sakamoto, K; Soty, M; Viollet, B; Zarrinpashneh, E, 2010)
" This study was undertaken to test for a hypothesized effect of hyperglycemia and the antihyperglycemic drug metformin on hepatic selenoprotein P biosynthesis."	3.75	Attenuation of hepatic expression and secretion of selenoprotein P by metformin. ( Sies, H; Speckmann, B; Steinbrenner, H, 2009)
"Baicalin had reduced the hyperglycemia-induced mitochondrial membrane damage, as well as enhanced the effects of metformin, as was observed in the results from the metformin and baicalin treated groups."	3.75	Baicalin reduces mitochondrial damage in streptozotocin-induced diabetic Wistar rats. ( Hsu, A; Huang, D; Tan, BK; Waisundara, VY, 2009)
" We investigated potential lipid-related mechanisms of metformin (Met) and/or exercise for blunting the progression of hyperglycemia/hyperinsulinemia and skeletal muscle insulin resistance in female Zucker diabetic fatty rats (ZDF), a high-fat (HF) diet-induced model of diabetes."	3.74	Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia. ( Bonen, A; Chabowski, A; Dyck, DJ; Junkin, KA; Mullen, KL; Nickerson, J; Smith, AC, 2007)
"When oral agents alone can no longer provide adequate glycemic control, the combination of a single bedtime injection of insulin with two daily doses of metformin will often normalize blood glucoses levels without the weight gain and hypoglycemia that may occur with other combined regimens."	3.70	A simple therapeutic combination for type 2 diabetes. ( Yki-Järvinen, H, 2000)
"During the 1970s two biguanide drugs, phenformin and metformin, were used to control hyperglycemia."	3.66	The status of metformin in Canada. ( Lucis, OJ, 1983)
"The ability to prevent or delay type 2 diabetes mellitus (T2DM) by modifying some of its risk factors has been hypothesized for decades."	3.01	Pharmacological approaches to the prevention of type 2 diabetes mellitus. ( Edem, D; Hamdy, O; Lozada Orquera, FA; Majety, P, 2023)
"Even normal pregnancy is characterized by relative insulin resistance and glucose intolerance."	3.01	Prophylactic metformin after antenatal corticosteroids (PROMAC): a double blind randomized controlled trial. ( Hong, JGS; Kamarudin, M; Omar, SZ; Tan, PC, 2021)
"insulin aspart in people with Type 2 diabetes receiving high doses of bolus insulin."	2.90	Mealtime fast-acting insulin aspart versus insulin aspart for controlling postprandial hyperglycaemia in people with insulin-resistant Type 2 diabetes. ( Bode, BW; Bowering, K; Harvey, J; Kolaczynski, JW; Snyder, JW, 2019)
"In patients with uncontrolled type 2 diabetes while using metformin, co-administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents."	2.87	Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. ( Eldor, R; Engel, SS; Golm, G; Huyck, SB; Johnson, J; Lauring, B; Mancuso, JP; Pratley, RE; Qiu, Y; Raji, A; Sunga, S; Terra, SG, 2018)
"Elderly subjects with metformin-treated type 2 diabetes have lower glucagon levels at 3."	2.87	Effects on the glucagon response to hypoglycaemia during DPP-4 inhibition in elderly subjects with type 2 diabetes: A randomized, placebo-controlled study. ( Ahrén, B; Farngren, J; Persson, M, 2018)
" In general, both treatments were well tolerated, with incidences and types of adverse events comparable between the two groups."	2.84	Efficacy and safety of adding evogliptin versus sitagliptin for metformin-treated patients with type 2 diabetes: A 24-week randomized, controlled trial with open label extension. ( Chung, CH; Han, KA; Hong, SM; Hwang, DM; Lee, CB; Mok, JO; Park, CY; Park, KS; Park, SW; Yoon, KH, 2017)
" The most common adverse events with exenatide QWS-AI were gastrointestinal events and injection-site reactions."	2.84	Efficacy and safety of autoinjected exenatide once-weekly suspension versus sitagliptin or placebo with metformin in patients with type 2 diabetes: The DURATION-NEO-2 randomized clinical study. ( Gadde, KM; Hardy, E; Iqbal, N; Öhman, P; Vetter, ML, 2017)
"Metformin is a widely used drug for the treatment of type 2 diabetes mellitus with a known ability to lower blood glucose levels."	2.82	The effect of metformin on glucose metabolism in patients receiving glucocorticoids. ( Fernandez, F; Landis, D; Nugent, K; Sutter, A, 2022)
"Normoglycaemia, prediabetes and type 2 diabetes appear to be part of a continuum of increased risk of adverse outcomes."	2.82	Vascular complications in prediabetes and type 2 diabetes: a continuous process arising from a common pathology. ( Gottwald-Hostalek, U; Gwilt, M, 2022)
" Adverse events occurred in similar proportions in the linagliptin and placebo patients (27."	2.82	Efficacy and safety of linagliptin in Asian patients with type 2 diabetes mellitus inadequately controlled by metformin: A multinational 24-week, randomized clinical trial. ( Gong, Y; Izumoto, T; Ning, G; Patel, S; Wang, W; Yang, G; Yang, J; Zhang, C, 2016)
" Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediate-release metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers."	2.82	The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies. ( Baron, A; Burns, C; Buse, JB; DeFronzo, RA; Fineman, M; Kim, T; Rosenstock, J; Skare, S, 2016)
"Taking metformin with a meal has been shown to decrease bioavailability of metformin."	2.82	Postprandial hyperglycemia was ameliorated by taking metformin 30 min before a meal than taking metformin with a meal; a randomized, open-label, crossover pilot study. ( Asano, M; Fukuda, T; Fukuda, Y; Fukui, M; Hamaguchi, M; Hasegawa, G; Hashimoto, Y; Kimura, T; Kitagawa, N; Majima, S; Mistuhashi, K; Nakamura, N; Oda, Y; Okada, H; Senmaru, T; Tanaka, M; Tanaka, Y; Yamada, S; Yamazaki, M, 2016)
"Metformin was titrated to 1500 mg/day or maximum-tolerated dose."	2.80	Metformin decreases glycated albumin to glycated haemoglobin ratio in patients with newly diagnosed type 2 diabetes. ( Deguchi, R; Hirai, K; Kasayama, S; Koga, M; Miki, S; Morita, S; Mukai, K; Nakamura, H; Sato, B; Sumitani, S; Utsu, Y, 2015)
" The insulin dosing algorithm was not sufficient to equalize nocturnal hypoglycaemia between the two insulins."	2.80	Modulation of insulin dose titration using a hypoglycaemia-sensitive algorithm: insulin glargine versus neutral protamine Hagedorn insulin in insulin-naïve people with type 2 diabetes. ( Bolli, GB; Candelas, C; Dain, MP; Deerochanawong, C; Home, PD; Landgraf, W; Mathieu, C; Pilorget, V; Riddle, MC, 2015)
"To evaluate the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin or metformin in combination with sulphonylurea."	2.80	Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea. ( Dieu Van, NK; Han, P; Ji, L; Liu, Y; Meininger, G; Qiu, R; Vijapurkar, U; Yang, G, 2015)
"To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination."	2.80	Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial. ( Burgess, L; de Bruin, TW; Hamer-Maansson, JE; Hruba, V; Korányi, L; Schumm-Draeger, PM, 2015)
"A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8."	2.80	Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double-blind, active-controlled, parallel group, multinational clinical trial. ( Bailes, Z; Caballero, AE; Del Prato, S; Gallwitz, B; Lewis-D'Agostino, D; Patel, S; Ross, SA; Thiemann, S; von Eynatten, M; Woerle, HJ, 2015)
"In a south Indian population with gestational diabetes, metformin was associated with better neonatal outcomes than glibenclamide."	2.80	Comparison of neonatal outcomes in women with gestational diabetes with moderate hyperglycaemia on metformin or glibenclamide--a randomised controlled trial. ( Abraham, A; Antonisamy, B; Beck, M; Benjamin, SJ; George, A; Jana, AK; Mathews, JE; Sam, D; Thomas, N, 2015)
"The dapagliflozin treatment arm was associated with a mean incremental benefit of 0."	2.80	The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus. ( Bergenheim, K; Callan, L; Charokopou, M; Lister, S; McEwan, P; Postema, R; Roudaut, M; Tolley, K; Townsend, R, 2015)
"In people with Type 2 diabetes, empagliflozin 10 mg and 25 mg given as add-on to metformin for 76 weeks were well tolerated and led to sustained reductions in HbA1c , weight and systolic blood pressure."	2.80	Empagliflozin as add-on to metformin in people with Type 2 diabetes. ( Broedl, UC; Christiansen, AV; Häring, HU; Kim, G; Meinicke, T; Merker, L; Roux, F; Salsali, A; Woerle, HJ, 2015)
"Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose."	2.79	Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. ( Abdul-Ghani, MA; Daniele, G; DeFronzo, RA; Eldor, R; Fiorentino, TV; Merovci, A; Norton, L; Perez, Z; Solis-Herrera, C; Tripathy, D; Xiong, J, 2014)
"In Asian patients with type 2 diabetes mellitus insufficiently controlled on metformin ± sulfonylurea, lixisenatide significantly improved glycaemic control and was well tolerated during the 24-week study."	2.79	Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia). ( Feng, P; Han, P; Jin Kui, Y; Liu, X; Lv, X; Niemoeller, E; Shang, S; Su, B; Tian, H; Yan, S; Yu Pan, C; Zhou, Z, 2014)
"At the time of diagnosis, almost 80% of pancreatic cancer patients present with new-onset type 2 diabetes (T2D) or impaired glucose tolerance."	2.79	Tumour-educated macrophages display a mixed polarisation and enhance pancreatic cancer cell invasion. ( Andersson, R; Karnevi, E; Rosendahl, AH, 2014)
"Both repaglinide and metformin were effective in glycaemic control in new onset patients with type 2 diabetes in China."	2.79	Comparison of metformin and repaglinide monotherapy in the treatment of new onset type 2 diabetes mellitus in China. ( Liao, Y; Liu, LY; Liu, W; Ma, J; Tao, T; Wu, PH, 2014)
"Approximately 2000 people with Type 2 diabetes mellitus who were drug-naive or who were treated with metformin for less than 1 month, and who have HbA1c of 48-58 mmol/mol (6."	2.79	Study to determine the durability of glycaemic control with early treatment with a vildagliptin-metformin combination regimen vs. standard-of-care metformin monotherapy-the VERIFY trial: a randomized double-blind trial. ( Del Prato, S; Foley, JE; Kothny, W; Kozlovski, P; Matthews, DR; Paldánius, PM; Stumvoll, M, 2014)
" Rates of serious adverse events in the albiglutide group were similar to comparison groups."	2.79	HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. ( Ahrén, B; Cirkel, DT; Feinglos, MN; Johnson, SL; Perry, C; Stewart, M; Yang, F, 2014)
"Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting."	2.78	A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes. ( Checklin, HL; Horowitz, M; Jones, KL; Ma, J; Meyer, JH; Rayner, CK; Stevens, JE; Wishart, JM, 2013)
" Overall, lixisenatide once daily was well tolerated, with a similar proportion of treatment-emergent adverse events (TEAEs) and serious TEAEs between groups (lixisenatide: 72."	2.78	Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). ( Aronson, R; Goldenberg, R; Guo, H; Muehlen-Bartmer, I; Niemoeller, E; Pinget, M, 2013)
" Frequency of adverse events was generally similar with empagliflozin (29."	2.78	Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. ( Hach, T; Hantel, S; Jelaska, A; Pinnetti, S; Rosenstock, J; Seman, LJ; Woerle, HJ, 2013)
"Diabetes mellitus type 2 with dyslipidemia is a common disease."	2.77	Anti-hyperglycemic and anti-hypercholesterolemic effects of Aloe vera leaf gel in hyperlipidemic type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial. ( Dabaghian, FH; Hajiaghaee, R; Huseini, HF; Kianbakht, S, 2012)
"With type 2 diabetes increasing, the effect of this traditional diet pattern on glycemic response has not been studied fully."	2.77	Bean and rice meals reduce postprandial glycemic response in adults with type 2 diabetes: a cross-over study. ( Hutchins, AM; Thompson, SV; Winham, DM, 2012)
"A total of 174 patients with Type 2 diabetes with poor glycaemic control were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to exenatide (5 μg twice a day for the first 4 weeks and forced titration to 10 μg twice a day thereafter) or placebo for 12 months."	2.77	Exenatide plus metformin compared with metformin alone on β-cell function in patients with Type 2 diabetes. ( Carbone, A; Ciccarelli, L; Derosa, G; Fogari, E; Franzetti, IG; Maffioli, P; Piccinni, MN; Querci, F, 2012)
"Dyslipidemia in patients with type 2 diabetes is characterized by elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and a predominance of small dense low-density lipoprotein (LDL) particles."	2.76	PIOfix-study: effects of pioglitazone/metformin fixed combination in comparison with a combination of metformin with glimepiride on diabetic dyslipidemia. ( Forst, T; Fuchs, W; Lehmann, U; Lobmann, R; Merke, J; Müller, J; Pfützner, A; Schöndorf, T; Tschöpe, D, 2011)
"Repaglinide was also associated with an increase in the AUC(60) and AUC(120) for insulin (+56%, +61%) and C-peptide (+41%, +36%)."	2.76	Effects of short-term therapy with glibenclamide and repaglinide on incretin hormones and oxidative damage associated with postprandial hyperglycaemia in people with type 2 diabetes mellitus. ( Bain, SC; Bodvarsdottir, TB; Bracken, RM; Deacon, CF; Dunseath, G; Holst, JJ; Lowe, GD; Luzio, S; Prior, SL; Rumley, A; Stephens, JW; Wareham, K, 2011)
"Perioperative hyperglycemia is common in patients with type 2 diabetes undergoing Coronary Artery Bypass Graft (CABG) surgery and there is a direct relation between postoperative hyperglycemia and mortality rate in these patients."	2.76	Metformin as an adjunct to insulin for glycemic control in patients with type 2 diabetes after CABG surgery: a randomized double blind clinical trial. ( Aarabi, M; Baradari, AG; Emami Zeydi, A; Ghafari, R, 2011)
"Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng x kg(-1) x min(-1)) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions."	2.74	Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. ( Carlson, OD; Charles, CP; Chia, CW; Egan, JM; Kim, HS; Kim, W; Melvin, DL; Shin, YK, 2009)
"To evaluate the efficacy and safety of two dosage strengths of a single-tablet metformin-glibenclamide (glyburide) combination, compared with the respective monotherapies, in patients with Type 2 diabetes mellitus (DM) inadequately controlled by metformin monotherapy."	2.70	Improved glycaemic control with metformin-glibenclamide combined tablet therapy (Glucovance) in Type 2 diabetic patients inadequately controlled on metformin. ( Allavoine, T; Howlett, H; Lehert, P; Marre, M, 2002)
" In study 2 (n = 14), subjects already established on adjunctive metformin/insulin therapy stopped the metformin component and received 12 weeks of metformin at their baseline dosage (range 1-2."	2.69	The effects of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. ( Burke, J; Elkeles, RS; Johnston, DG; Robinson, AC; Robinson, S, 1998)
" The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed."	2.68	Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus. ( Benet, LZ; Chiang, J; Goodman, AM; Karam, JH; Lin, ET; Liu, CY; O'Conner, M; Sambol, NC, 1996)
"026) was observed, at lower dosage (p = 0."	2.67	Antihyperglycaemic efficacy, response prediction and dose-response relations of treatment with metformin and sulphonylurea, alone and in primary combination. ( Hermann, LS; Melander, A; Scherstén, B, 1994)
"Metformin is an oral hypoglycemic agent extensively used as first-line therapy for type 2 diabetes."	2.66	Metformin: Up to Date. ( De Pergola, G; Giagulli, VA; Grimaldi, F; Guastamacchia, E; Iacoviello, M; Licchelli, B; Sciannimanico, S; Triggiani, V; Vescini, F, 2020)
"It is thought that it exerts its anti-cancer effect through the inhibition of the mammalian target of rapamycin (mTOR) signalling pathway."	2.61	The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth. ( Amin, S; Lux, A; O'Callaghan, F, 2019)
" The use of antenatal steroids in mothers at risk of preterm delivery complicates management of hyperglycaemia in the immediate antepartum period and requires appropriate dosing adjustments of insulin therapy."	2.58	Intra-partum management of women with diabetes. ( Jacob, JJ; Jewel, R, 2018)
"The diagnosis and treatment of gestational diabetes mellitus (GDM) have been in a state of flux since the World Health Organization accepted and endorsed the International Diabetes and Pregnancy Study Group's diagnostic pathway and criteria in 2013."	2.58	Changing environment of hyperglycemia in pregnancy: Gestational diabetes and diabetes mellitus in pregnancy. ( Cohen, N; Gray, SG; Little, PJ; Mcguire, TM; Ross, GP; Sweeting, AN, 2018)
"Choices for the treatment of type 2 diabetes mellitus (T2DM) have multiplied as our understanding of the underlying pathophysiologic defects has evolved."	2.55	Pharmacologic Management of Type 2 Diabetes Mellitus: Available Therapies. ( Thrasher, J, 2017)
"Metformin has also been reported to reverse resistance to epidermal growth factor receptor (EGFR)-inhibiting tyrosine kinase inhibitors."	2.55	Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity? ( Shah, RR, 2017)
"Metformin is a first-line oral anti-diabetic agent that has been used clinically to treat patients with type 2 diabetes for over 60 years."	2.53	Current understanding of metformin effect on the control of hyperglycemia in diabetes. ( An, H; He, L, 2016)
"Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets."	2.53	Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. ( Dejgaard, TF; Frandsen, CS; Madsbad, S, 2016)
"Maturity onset diabetes of the young (MODY), the most common monogenic form of diabetes, accounts for 1-2% of all diabetes diagnoses."	2.53	A review of maturity onset diabetes of the young (MODY) and challenges in the management of glucokinase-MODY. ( Bishay, RH; Greenfield, JR, 2016)
"Metformin is an oral hypoglycemic agent which is most widely used as first-line therapy for type 2 diabetes."	2.52	Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect. ( Saisho, Y, 2015)
"Dyslipidemia is manageable via statin treatment, while the anti-diabetic drug metformin would prevent hyperglycemia."	2.50	mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques. ( De Loof, H; De Meyer, GRY; Martinet, W, 2014)
"Diabetes may increase the risk of gastric cancer through shared risk factors including obesity, insulin resistance, hyperinsulinemia and smoking."	2.50	Diabetes and gastric cancer: the potential links. ( Tseng, CH; Tseng, FH, 2014)
"One of the medical treatments used in Cushing's disease is the somatostatin analogue pasireotide, which acts on adrenocorticotropic hormone (ACTH) secretion by the pituitary."	2.49	Management of hyperglycaemia in Cushing's disease: experts' proposals on the use of pasireotide. ( Bertherat, J; Bisot-Locard, S; Borson-Chazot, F; Brue, T; Chanson, P; Cortet-Rudelli, C; Delemer, B; Reznik, Y; Tabarin, A; Vergès, B, 2013)
"Hyperglycemia is a known exacerbating factor in ischemic stroke."	2.47	[Effectiveness of metformin in prevention of development of hyperglycemia and neuronal damage caused by ischemic stress]. ( Fujita-Hamabe, W; Harada, S; Tokuyama, S, 2011)
"In the pathophysiology of type 2 diabetes there are several biological processes, which may explain the higher cancer risk in type 2 diabetes."	2.47	[Diabetes and cancer risk: oncologic considerations]. ( Rosta, A, 2011)
"Metformin has recently gained much attention as it appears to reduce cancer incidence and improve prognosis of patients with diabetes."	2.47	Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. ( Gallagher, EJ; LeRoith, D, 2011)
"Hyperglycemia has been associated with an increased risk of morbidity and mortality in critically ill patients."	2.46	The role of hyperglycemia in burned patients: evidence-based studies. ( Al-Mousawi, AM; Gauglitz, GG; Herndon, DN; Jeschke, MG; Mecott, GA, 2010)
" The added efficacy of saxagliptin in combination with other OADs in improving glycemic parameters has resulted in a significant proportion of patients achieving an HbA1c <7% versus monotherapy or active comparator."	2.46	Reaching HbA1c goals with saxagliptin in combination with other oral antidiabetic drugs. ( LaSalle, JR, 2010)
"Furthermore metformin seems to decrease cancer risk in diabetic patients."	2.46	Metformin for aging and cancer prevention. ( Anisimov, VN, 2010)
"Overall, 7% of the US population has type 2 diabetes mellitus (T2DM), and among people aged 60 years or older, approximately 20% have T2DM, representing a significant health burden in this age group."	2.44	Initiating insulin in patients with type 2 diabetes. ( Aoki, TJ; White, RD, 2007)
"Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly."	2.44	[Non-alcoholic fatty liver disease--new view]. ( Lawniczak, M; Marlicz, W; Miezyńska-Kurtycz, J; Milkiewicz, P; Raszeja-Wyszomirska, J, 2008)
"Treatment of type 2 diabetes (T2DM) is based on lifestyle changes and oral antidiabetic agents or insulin."	2.44	[New therapies for type 2 diabetes: what place for incretin-based agents and rimonabant compared to the previous ones?]. ( Debaty, I; Halimi, S; Muller, M; Villaret, L, 2008)
"Metformin is a potent antihyperglycemic agent widely used in the management of type 2 diabetes whose main actions are the suppression of gluconeogenesis and the improvement of glucose uptake and insulin sensitivity."	2.44	Mechanisms of action of metformin in type 2 diabetes and associated complications: an overview. ( Carvalho, C; Correia, S; Moreira, PI; Oliveira, CR; Santos, MS; Seiça, R, 2008)
"In addition, as type 2 diabetes is a progressive disease, it is still questionable whether the effect corresponds to a prevention effect or only to a postponing of the development of the disease."	2.44	Antidiabetic agents in subjects with mild dysglycaemia: prevention or early treatment of type 2 diabetes? ( Scheen, AJ, 2007)
"However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes."	2.44	[Adjunctive therapies to glycaemic control of type 1 diabetes mellitus]. ( Gabbay, Mde A, 2008)
"Prediabetes is important to recognise because of at least 2 major implications: increased risk for future diabetes and for atherosclerotic cardiovascular diseases."	2.43	Drug therapy in prediabetes. ( Chowdhury, S; Mukhopadhyay, P, 2005)
"Patients with type 2 diabetes mellitus are associated with insulin resistance and/or impaired insulin secretion."	2.42	[Nateglinide and mitiglinide]. ( Odawara, M, 2003)
"Metformin is a mild inhibitor of respiratory chain complex 1; it activates AMPK in several models, apparently independently of changes in the AMP-to-ATP ratio; it activates G6PDH in a model of high-fat related insulin resistance; and it has antioxidant properties by a mechanism (s), which is (are) not completely elucidated as yet."	2.42	Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. ( Batandier, C; Chauvin, C; Detaille, D; Fontaine, E; Guigas, B; Koceir, EA; Leverve, XM; Wiernsperger, NF, 2003)
"The predicted global epidemic of type 2 diabetes highlights the importance of identifying the most effective ways to reduce the risk of long-term diabetic complications."	2.42	Metformin and vascular protection: a cardiologist's view. ( Libby, P, 2003)
"Insulin resistance is central to the pathogenesis of type 2 diabetes and may contribute to atherogenesis, either directly or through associated risk factors."	2.42	Peroxisome proliferator-activated receptor-gamma agonists in atherosclerosis: current evidence and future directions. ( Evans, M; Rees, A; Roberts, AW; Thomas, A, 2003)
"Insulin resistance is a condition in which the glycemic response to insulin is less than normal."	2.42	Treatment of insulin resistance in diabetes mellitus. ( Banerji, MA; Lebovitz, HE, 2004)
"Treatment with metformin was less effective than lifestyle modifications, resulting in an average reduction of risk of T2D of 31% compared with placebo."	2.41	Can reducing peaks prevent type 2 diabetes: implication from recent diabetes prevention trials. ( Haffner, SM, 2002)
"Metformin treatment improved fasting hyperglycemia in these patients through a reduction in hepatic glucose production, which could be attributed to a decrease in gluconeogenesis."	2.41	Nuclear magnetic resonance studies of hepatic glucose metabolism in humans. ( Petersen, KF; Roden, M; Shulman, GI, 2001)
"Nateglinide is a novel D-phenylalanine derivative that inhibits ATP-sensitive K+ channels in pancreatic beta-cells in the presence of glucose and thereby restores first phase insulin response in patients with Type 2 diabetes."	2.41	Nateglinide: a new rapid-acting insulinotropic agent. ( Hanif, W; Kumar, S, 2001)
"Metformin is an insulin-sensitizing agent with potent antihyperglycemic properties."	2.41	Metformin: an update. ( Kirpichnikov, D; McFarlane, SI; Sowers, JR, 2002)
"Metformin is an antihyperglycemic agent; it lowers the blood glucose concentration without causing hypoglycemia."	2.40	Metformin hydrochloride: an antihyperglycemic agent. ( Kelly, MW; Klepser, TB, 1997)
"Diabetes mellitus is associated with alterations in a number of key metabolic pathways."	2.40	Drug administration in patients with diabetes mellitus. Safety considerations. ( Cooper, ME; Gilbert, RE; Krum, H, 1998)
"Treatment with metformin reduced mortality due to cardiovascular disease in obese patients."	2.40	[Glycemic regulation and management of essential hypertension in diabetics with type 2 diabetes mellitus; the 'United Kingdom prospective diabetes study' of diabetic complications]. ( Heine, RJ; Wolffenbuttel, BH, 1999)
"NIDDM is the result of concomitant defects in both insulin secretion and insulin action."	2.39	What therapy do our NIDDM patients need? Insulin releasers. ( Crepaldi, G; Del Prato, S, 1995)
"Both hyperinsulinemia and hyperglycemia have been suggested as risk factors for accelerated atherogenesis in diabetes."	2.39	Does treatment of noninsulin-dependent diabetes mellitus reduce the risk of coronary heart disease? ( Giugliano, D, 1996)
"Metformin was started and increased to 1,000 mg twice daily."	1.91	Weekly Growth Hormone (Lonapegsomatropin) Causes Severe Transient Hyperglycemia in a Child with Obesity. ( Alkhatib, EH; Dauber, A; Estrada, DE; Majidi, S, 2023)
"Metformin was the most commonly used antidiabetic medication, followed by insulin, sodium-glucose transport protein 2 (SGLT2) inhibitors, and sulfonylurea."	1.72	Characterization, management, and risk factors of hyperglycemia during PI3K or AKT inhibitor treatment. ( Casas, A; Drilon, A; Flory, JH; Garcia, C; Goncalves, MD; Harding, JJ; Harnicar, S; Jhaveri, K; Liu, D; Sisk, AE; Weintraub, MA, 2022)
"Metformin alone reduced hyperinsulinemia and circulating c-reactive protein, but exacerbated nephropathy."	1.72	Rapamycin/metformin co-treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice. ( Calcutt, NA; Doty, R; Flurkey, K; Harrison, DE; Koza, RA; Reifsnyder, PC, 2022)
"Metformin was used as the standard antidiabetic drug."	1.62	Vanillin exerts therapeutic effects against hyperglycemia-altered glucose metabolism and purinergic activities in testicular tissues of diabetic rats. ( Erukainure, OL; Islam, MS; Olofinsan, KA; Salau, VF, 2021)
"Metformin (50 mg/kg bw) was used as a standard drug."	1.62	Swietenine potentiates the antihyperglycemic and antioxidant activity of Metformin in Streptozotocin induced diabetic rats. ( Balijepalli, MK; Chakravarthi, S; Mak, KK; Pichika, MR; Shiming, Z, 2021)
"Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes."	1.62	Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia. ( Boccalone, E; de Donato, A; Frullone, S; Gambardella, J; Martinelli, G; Matarese, A; Mone, P; Pansini, A; Santulli, G, 2021)
"EMTs facilitate bladder cancer (BC) metastasis development, but the mechanism by which high-glucose levels promote these EMTs in BC remains unclear."	1.56	Glucose promotes epithelial-mesenchymal transitions in bladder cancer by regulating the functions of YAP1 and TAZ. ( Chen, H; Li, S; Lin, Q; Xia, J; Xu, R; Zhang, F; Zhu, H, 2020)
"This study evaluated the influence of type 2 diabetes mellitus on bone loss, bone repair and cytokine production in hyperglycemic rats, treated or not with metformin."	1.56	Impact of hyperglycemia and treatment with metformin on ligature-induced bone loss, bone repair and expression of bone metabolism transcription factors. ( Azarias, JS; Bastos, MF; Garcia, RP; Malta, FS; Miranda, TS; Ribeiro, GKDR; Shibli, JA, 2020)
"Metformin has long been used for glycemic control in diabetic state."	1.51	Down-regulation of steroidogenesis-related genes and its accompanying fertility decline in streptozotocin-induced diabetic male rats: ameliorative effect of metformin. ( Ahmad, A; Bakar, ABA; Mohamed, M; Nna, VU, 2019)
"Metformin is an antidiabetic drug with a major impact on regulating blood glucose levels by decreasing hepatic gluconeogenesis, but also by affecting other pathways, including glucose transport and energy/lipid metabolism."	1.51	Metformin counteracts glucose-dependent lipogenesis and impairs transdeamination in the liver of gilthead sea bream ( Sparus aurata). ( Baanante, IV; Metón, I; Rashidpour, A; Seguí, L; Silva-Marrero, JI, 2019)
"Alendronate is a bisphosphonate widely used for the treatment of osteoporosis; however, one of its main adverse reactions is gastric ulcer."	1.51	Alendronate-induced gastric damage in normoglycemic and hyperglycemic rats is reversed by metformin. ( Alencar, MS; Alves, EHP; Araújo, AJ; Araújo, AR; Filho, JDBM; Iles, B; Leal, LKAM; Lopes, ALF; Medeiros, JVR; Nolêto, IRSG; Oliveira, AP; Pacheco, G; Sousa, FBM; Vasconcelos, DFP, 2019)
"Metformin was cost-effective relative to no intervention (£5224/QALY, £6842/QALY and £372/QALY in IGT, IFG and HbA1c, respectively), but was only cost-effective relative to other treatments in participants identified with HbA1c."	1.48	Economic evaluation of type 2 diabetes prevention programmes: Markov model of low- and high-intensity lifestyle programmes and metformin in participants with different categories of intermediate hyperglycaemia. ( Adler, A; Craig, D; Greenhalgh, T; McPherson, K; Roberts, S, 2018)
"Type 2 diabetes is an endocrine disorder characterized with hyperglycemia, hyperinsulinemia and insulin resistance."	1.48	Unusual shape and structure of lymphocyte nuclei is linked to hyperglycemia in type 2 diabetes patients. ( Bumbasirevic, V; Ciric, D; Despotovic, S; Djuricic, D; Kravic-Stevovic, T; Lalic, I; Lalic, K; Martinovic, T; Pantic, I; Rasulic, I, 2018)
"Metformin was demonstrated to evoke metabolic stress and induce cancer cell death."	1.48	Hyperglycemia-Associated Dysregulation of O-GlcNAcylation and HIF1A Reduces Anticancer Action of Metformin in Ovarian Cancer Cells (SKOV-3). ( Bryś, M; Forma, E; Marczak, A; Rogalska, A; Śliwińska, A, 2018)
"Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization."	1.48	Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma. ( Akkan, J; Benitz, S; Bruns, P; Ceyhan, GO; Cheng, T; Friess, H; Hofmann, T; Huang, P; Jäger, C; Jastroch, M; Jian, Z; Kleeff, J; Kleigrewe, K; Kong, B; Lamp, D; Maeritz, N; Michalski, CW; Nie, S; Raulefs, S; Shen, S; Shi, K; Steiger, K; Zhang, Z; Zou, X, 2018)
"Obesity is a major cause of type 2 diabetes mellitus (T2DM) in mammals."	1.46	Development of a Novel Zebrafish Model for Type 2 Diabetes Mellitus. ( Nishimura, N; Shimada, Y; Zang, L, 2017)
"Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway."	1.46	Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2. ( Bahl, A; Biernacka, KM; Gillatt, D; Holly, JM; Perks, CM; Persad, RA, 2017)
"Chronic oral nitrite treatment improved hyperglycemia in obese ZSF1 rats by a process that requires skeletal muscle SIRT3-AMPK-GLUT4 signaling."	1.43	SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. ( Dube, JJ; Garcia-Ocaña, A; Gladwin, MT; Goncharov, DA; Goncharova, EA; Hughan, KS; Lai, YC; Mora, AL; St Croix, CM; Tabima, DM; Tofovic, SP; Vanderpool, RR, 2016)
"These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise."	1.43	Practical considerations for the use of sodium-glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes. ( Chan, TM; Chow, CC; Kong, AP; Lam, KS; Lee, KK; Ma, RC; So, WY; Tan, KC; Tang, SC; Tomlinson, B; Tong, PC; Tsang, MW, 2016)
"Metformin is a first-line drug for the management of type 2 diabetes."	1.43	Metformin Protects H9C2 Cardiomyocytes from High-Glucose and Hypoxia/Reoxygenation Injury via Inhibition of Reactive Oxygen Species Generation and Inflammatory Responses: Role of AMPK and JNK. ( Chen, M; Hu, M; Liao, H; Yang, F; Ye, P, 2016)
"Metformin is a safe, well-tolerated, inexpensive treatment that can be given in addition to current standard-of-care therapies for prostate cancer."	1.43	Repurposing Metformin as Therapy for Prostate Cancer within the STAMPEDE Trial Platform. ( Adler, A; Clarke, N; Gillessen, S; Gilson, C; James, N; Sydes, MR, 2016)
"Comorbidity, young age, central obesity and poor baseline glycaemic control are important predictors of therapy one year after Type 2 diabetes mellitus debut."	1.42	Prescribing practices and clinical predictors of glucose-lowering therapy within the first year in people with newly diagnosed Type 2 diabetes. ( Beck-Nielsen, H; Berencsi, K; Brandslund, I; Christiansen, JS; Friborg, S; Mor, A; Nielsen, JS; Rungby, J; Svensson, E; Sørensen, HT; Thomsen, RW; Vaag, A, 2015)
"In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs."	1.42	Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer. ( Eckert, MA; Johnson, A; Lengyel, E; Litchfield, LM; Mills, KA; Mukherjee, A; Pan, S; Romero, IL; Shridhar, V, 2015)
"The strategy for the management ot type 2 diabetes, summarized by a group of European and American experts, has been updated early 2015."	1.42	[2015 updated position statement of the management of hyperglycaemia in type 2 diabetes]. ( Paquot, N; Scheen, AJ, 2015)
"Treatment with metformin attenuated the HG-induced reduction of SIRT1 expression, modulated the SIRT1 downstream targets FoxO-1 and p53/p21, and protected endothelial cells from HG-induced premature senescence."	1.40	Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. ( Arunachalam, G; Ding, H; Marei, I; Samuel, SM; Triggle, CR, 2014)
"Hyperglycemia is the main feature for the diagnosis of this disease."	1.40	Persistent impaired glucose metabolism in a zebrafish hyperglycemia model. ( Antonioli, R; Bogo, MR; Bonan, CD; Capiotti, KM; Da Silva, RS; Kist, LW, 2014)
"Hyperglycemia is associated with increased risk of all-site cancer that may be mediated through activation of the renin-angiotensin-system (RAS) and 3-hydroxy-3-methyl-glutaryl-coenzyme-A-reductase (HMGCR) pathways."	1.40	Additive effects of blood glucose lowering drugs, statins and renin-angiotensin system blockers on all-site cancer risk in patients with type 2 diabetes. ( Chan, JC; Cheung, KK; Chow, CC; Kong, AP; Lee, HM; Luk, A; Ma, RC; Ozaki, R; So, WY; Xu, G; Yang, X; Yu, L, 2014)
"Metformin is considered first-line treatment for type 2 diabetes mellitus."	1.40	Differing effects of metformin on glycemic control by race-ethnicity. ( Ahmedani, BK; González Burchard, E; Lanfear, DE; Padhukasahasram, B; Peterson, EL; Wells, KE; Williams, LK, 2014)
"The treatment for patients with type 2 diabetes mellitus (T2DM) follows a stepwise progression."	1.40	The evaluation of clinical and cost outcomes associated with earlier initiation of insulin in patients with type 2 diabetes mellitus. ( Curtis, BH; Gahn, JC; Murphy, DR; Smolen, HJ; Yu, X, 2014)
"Type 2 diabetes is defined by chronic hyperglycaemia, decreased insulin secretion and increased insulin resistance and is often associated with overweight or obesity, hypertension and dyslipidaemia."	1.39	HbA1c targets in type 2 diabetes: guidelines and evidence. ( , 2013)
"However, in most patients with type II diabetes mellitus (T2DM), it was found that metformin alone is not enough to adequately control hyperglycemia."	1.39	Potential utility of sodium selenate as an adjunct to metformin in treating type II diabetes mellitus in rats: a perspective on protein tyrosine phosphatase. ( Elkoussi, AA; Khalifa, AE; Salama, RM; Schaalan, MF, 2013)
" A γ-conglutin dosage of 28 mg/kg body weight was daily administered to animals for 21 d."	1.38	Lupin seed γ-conglutin lowers blood glucose in hyperglycaemic rats and increases glucose consumption of HepG2 cells. ( Castiglioni, S; Duranti, M; Lovati, MR; Magni, C; Manzoni, C; Parolari, A, 2012)
"We studied 52 consecutive patients with type 2 diabetes who had poor glycemic control despite treatment with metformin and/or sulfonylurea."	1.38	Serum level of soluble CD26/dipeptidyl peptidase-4 (DPP-4) predicts the response to sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes controlled inadequately by metformin and/or sulfonylurea. ( Aso, Y; Hara, K; Haruki, K; Inukai, T; Morita, K; Naruse, R; Ozeki, N; Shibazaki, M; Suetsugu, M; Takebayashi, K; Terasawa, T, 2012)
"Metformin was added to their insulin therapy, and both hepatic glucose production and peripheral glucose uptake were assessed before and one week after metformin treatment, with the use of stable isotope [6,6-²H₂] glucose."	1.38	Effect of metformin on hepatic glucose production in Japanese patients with type 2 diabetes mellitus. ( Kaneto, H; Katakami, N; Matsuhisa, M; Shimomura, I; Takahara, M, 2012)
"Because pharmacotherapies in type 2 diabetes exert complex effects, we examined the different anti-diabetic strategies, especially the influence of insulin doses, on the activation of oxidative stress, a key player in atherosclerosis, ageing and the risk of cancer."	1.37	Insulin therapy has a complex relationship with measure of oxidative stress in type 2 diabetes: a case for further study. ( Colette, C; Cristol, JP; Michel, F; Monnier, L; Owens, DR, 2011)
"The study cohort consisted of type 2 diabetes mellitus patients (n = 80) on regular therapy with glibenclamide either alone or with concomitant metformin."	1.37	Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 diabetes mellitus patients. ( Adithan, C; Agrawal, A; Anichavezhi, D; Pradhan, SC; Rajan, S; Subrahmanyam, DK; Surendiran, A, 2011)
"Increases in the prevalence of type 2 diabetes will likely be greater in the Middle East and other developing countries than in most other regions during the coming two decades, placing a heavy burden on regional healthcare resources."	1.36	Optimising the medical management of hyperglycaemia in type 2 diabetes in the Middle East: pivotal role of metformin. ( Al-Arouj, M; Al-Maatouq, M; Alberti, KG; Assaad, SH; Assaad, SN; Azar, ST; Hassoun, AA; Jarrah, N; Zatari, S, 2010)
"Metformin treatment also improved hyperleptinemia, whereas pioglitazone was ineffective."	1.36	Metformin reduces body weight gain and improves glucose intolerance in high-fat diet-fed C57BL/6J mice. ( Hirasawa, Y; Ito, M; Kyuki, K; Matsui, Y; Sugiura, T; Toyoshi, T, 2010)
"Metformin HCl was used as standard drug."	1.35	Oral glucose tolerance test (OGTT) in normal control and glucose induced hyperglycemic rats with Coccinia cordifolia l. and Catharanthus roseus L. ( Ahmed, M; Akhtar, MA; Alam, AH; Amran, MS; Hossain, MS; Ibne-Wahed, MI; Islam, MA; Khan, MR; Rahman, BM, 2009)
" Biphasic insulin aspart 30 in combination with metformin administered twice a day may be recommended as a starting insulin treatment in obese diabetic persons whose glycaemic control remained poor while on oral metformin therapy alone."	1.34	Effect of biphasic insulin aspart 30 combined with metformin on glycaemic control in obese people with type 2 diabetes. ( Ascić-Buturović, B, 2007)
"Type 2 diabetes mellitus is a heterogeneous condition in which the clinical manifestation of hyperglycemia is a reflection of the impaired balance between insulin sensitivity and insulin secretion."	1.33	Type 2 diabetes mellitus in youth: the complete picture to date. ( Arslanian, S; Bacha, F; Gungor, N; Hannon, T; Libman, I, 2005)
"Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator-activated response-gamma coactivator-1alpha (PGC-1alpha) and manganese superoxide dismutase (MnSOD) mRNAs."	1.33	Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. ( Araki, E; Fujisawa, K; Imoto, K; Kukidome, D; Matsumura, T; Motoshima, H; Nishikawa, T; Sonoda, K; Taguchi, T; Yano, M, 2006)
"Metformin vs placebo treatment of diabetic pigs (twice 1."	1.33	Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs: effects of metformin at isoenergetic feeding in a type 2-like diabetic pig model. ( Ackermans, M; Corbijn, H; Dekker, R; Koopmans, SJ; Mroz, Z; Sauerwein, H, 2006)
"Type 2 diabetes mellitus is the consequence of both insulin resistance and impaired insulin secretion."	1.32	Optimal glycemic control in type 2 diabetes mellitus: fasting and postprandial glucose in context. ( Abrahamson, MJ, 2004)
"Metformin treatment almost normalized glycogen levels, whereas lactate declined concomitantly in the pellet."	1.29	Demonstration of defective glucose uptake and storage in erythrocytes from non-insulin dependent diabetic patients and effects of metformin. ( Belleville, I; Martinand, A; Rapin, JR; Wiernsperger, NF; Yoa, RG, 1993)
"Metformin-treated rats gained significantly less weight."	1.29	Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone. ( Burant, CF; Polonsky, KS; Pugh, W; Sreenan, S; Sturis, J, 1996)

Research

Studies (448)

Authors

Clinical Trials (83)

Trial Overview

Trial Outcomes

Change From Baseline in Body Weight

Timeframe	Studies, this research(%)	All Research%
pre-1990	7 (1.56)	18.7374
1990's	19 (4.24)	18.2507
2000's	84 (18.75)	29.6817
2010's	272 (60.71)	24.3611
2020's	66 (14.73)	2.80

Authors	Studies
Shukla, P	1
Singh, AB	3
Srivastava, AK	4
Pratap, R	1
Singh, FV	1
Chaurasia, S	1
Joshi, MD	1
Goel, A	1
Dwivedi, AP	1
Kumar, S	3
Varshney, V	1
Sahu, DP	1
Maurya, R	1
Xu, Y	4
Niu, Y	1
Gao, Y	1
Wang, F	2
Qin, W	1
Lu, Y	1
Hu, J	4
Peng, L	2
Liu, J	2
Xiong, W	1
Koufakis, T	2
Papazafiropoulou, A	1
Makrilakis, K	2
Kotsa, K	2
Newman, C	1
Dunne, FP	1
Zhang, X	7
Ogihara, T	1
Zhu, M	1
Gantumur, D	1
Li, Y	3
Mizoi, K	1
Kamioka, H	1
Tsushima, Y	1
Tian, JL	1
Si, X	1
Shu, C	1
Wang, YH	1
Tan, H	2
Zang, ZH	1
Zhang, WJ	1
Xie, X	1
Chen, Y	3
Li, B	1
Liu, D	1
Weintraub, MA	1
Garcia, C	1
Goncalves, MD	1
Sisk, AE	1
Casas, A	1
Harding, JJ	1
Harnicar, S	1
Drilon, A	1
Jhaveri, K	1
Flory, JH	1
Coutinho, MR	1
da Silva, AW	1
Ferreira, MKA	1
de Lima Rebouças, E	1
Mendes, FRS	1
Teixeira, EH	1
Marinho, EM	1
Marinho, MM	1
Marinho, ES	1
Teixeira, AMR	1
de Menezes, JESA	1
Dos Santos, HS	1
Fazle, R	1
Amir, Z	1
Amna, N	1
Achyut, A	1
Irfan, U	1
Shafiq Ur, R	1
Xie, D	1
Chen, F	1
Zhang, Y	3
Shi, B	2
Song, J	1
Chaudhari, K	1
Yang, SH	1
Zhang, GJ	1
Sun, X	1
Taylor, HS	1
Li, D	1
Huang, Y	1
Landis, D	1
Sutter, A	1
Fernandez, F	1
Nugent, K	1
Gottwald-Hostalek, U	1
Gwilt, M	1
Clark, GJ	1
Pandya, K	1
Lau-Cam, CA	1
Reifsnyder, PC	1
Flurkey, K	1
Doty, R	1
Calcutt, NA	1
Koza, RA	1
Harrison, DE	1
Zheng, S	1
Jiang, S	1
Chen, J	2
Zhu, X	1
Siboto, A	2
Akinnuga, AM	2
Khumalo, B	2
Ismail, MB	2
Booysen, IN	2
Sibiya, NH	2
Ngubane, P	2
Khathi, A	2
Albawardi, A	1
Saraswathiamma, D	1
Sharma, C	1
Elomami, A	1
Souid, AK	1
Almarzooqi, S	1
Sithara, S	1
Crowley, T	1
Walder, K	1
Aston-Mourney, K	1
Arefin, A	1
Gage, MC	1
Zheng, L	2
Shen, X	2
Xie, Y	2
Lian, H	1
Yan, S	3
Wang, S	1
Majety, P	1
Lozada Orquera, FA	1
Edem, D	1
Hamdy, O	1
Alkhatib, EH	1
Dauber, A	1
Estrada, DE	1
Majidi, S	1
Corremans, R	1
Vervaet, BA	1
Dams, G	1
D'Haese, PC	1
Verhulst, A	1
Chen, H	3
Lyu, N	1
Chan, W	1
De La Cruz, A	1
Calarge, C	1
Giordo, R	1
Posadino, AM	1
Mangoni, AA	1
Pintus, G	1
Zhu, W	1
Xu, D	1
Mei, J	1
Lu, B	1
Wang, Q	3
Zhu, C	1
Wang, L	2
Zhang, Z	3
Ochola, LA	1
Nyamu, DG	1
Guantai, EM	1
Weru, IW	1
Tang, G	1
Duan, F	1
Li, W	1
Wang, Y	2
Zeng, C	1
Li, H	2
Zaidun, NH	1
Sahema, ZCT	1
Mardiana, AA	1
Santhana, RL	1
Latiff, AA	1
Syed Ahmad Fuad, SB	1
Adeshirlarijaney, A	1
Zou, J	1
Tran, HQ	1
Chassaing, B	1
Gewirtz, AT	1
Hedrington, MS	1
Davis, SN	1
Sciannimanico, S	1
Grimaldi, F	1
Vescini, F	1
De Pergola, G	1
Iacoviello, M	1
Licchelli, B	1
Guastamacchia, E	1
Giagulli, VA	1
Triggiani, V	1
An, H	2
Liu, T	1
Qin, C	1
Sesaki, H	1
Guo, S	1
Radovick, S	1
Hussain, M	1
Maheshwari, A	1
Wondisford, FE	1
O'Rourke, B	1
He, L	3
Johnson, R	2
Sangweni, NF	2
Mabhida, SE	1
Dludla, PV	3
Mabasa, L	1
Riedel, S	1
Chapman, C	1
Mosa, RA	2
Kappo, AP	2
Louw, J	1
Muller, CJF	2
He, X	1
Yang, Y	2
Yao, MW	1
Ren, TT	1
Guo, W	1
Li, L	2
Xu, X	2
Tousian, H	1
Razavi, BM	1
Hosseinzadeh, H	1
Sivalingam, VN	1
Latif, A	1
Kitson, S	1
McVey, R	1
Finegan, KG	1
Marshall, K	1
Lisanti, MP	1
Sotgia, F	1
Stratford, IJ	1
Crosbie, EJ	1
Targosz-Korecka, M	1
Malek-Zietek, KE	1
Kloska, D	1
Rajfur, Z	1
Stepien, EŁ	1
Grochot-Przeczek, A	1
Szymonski, M	1
Biondo, LA	1
Teixeira, AAS	1
de O S Ferreira, KC	1
Neto, JCR	1
Mohamad, HE	1
Asker, ME	1
Keshawy, MM	1
Abdel Aal, SM	1
Mahmoud, YK	1
Ortega, JF	1
Morales-Palomo, F	1
Ramirez-Jimenez, M	1
Moreno-Cabañas, A	1
Mora-Rodríguez, R	1
Udler, MS	1
Powe, CE	1
Austin-Tse, CA	1
Jindal, S	1
Kalra, S	2
Halliday, G	1
Huot, JR	1
Satoh, T	1
Baust, JJ	1
Fisher, A	1
Cook, T	1
Avolio, T	1
Goncharov, DA	2
Bai, Y	1
Vanderpool, RR	2
Considine, RV	1
Bonetto, A	1
Tan, J	1
Bachman, TN	1
Sebastiani, A	1
McTiernan, CF	1
Mora, AL	2
Machado, RF	1
Goncharova, EA	2
Gladwin, MT	3
Lai, YC	3
Gabriel, R	1
Boukichou Abdelkader, N	1
Acosta, T	1
Gilis-Januszewska, A	1
Gómez-Huelgas, R	1
Kamenov, Z	1
Paulweber, B	1
Satman, I	1
Djordjevic, P	1
Alkandari, A	1
Mitrakou, A	1
Lalic, N	1
Colagiuri, S	1
Lindström, J	1
Egido, J	1
Natali, A	1
Pastor, JC	1
Teuschl, Y	1
Lind, M	1
Silva, L	1
López-Ridaura, R	1
Tuomilehto, J	1
Mustafa, OG	1
Zebekakis, P	1
Li, S	2
Zhu, H	1
Xia, J	2
Zhang, F	1
Xu, R	1
Lin, Q	1
Tao, T	2
Hu, Z	1
Madić, V	1
Petrović, A	1
Jušković, M	1
Jugović, D	1
Djordjević, L	1
Stojanović, G	1
Vasiljević, P	1
Malta, FS	1
Garcia, RP	1
Azarias, JS	1
Ribeiro, GKDR	1
Miranda, TS	1
Shibli, JA	1
Bastos, MF	1
Wang, D	1
Mao, Y	1
Wang, T	1
Xiong, T	1
Yang, X	2
de Oliveira, AM	1
de Freitas, AFS	1
Costa, MDS	1
Torres, MKDS	1
Castro, YAA	1
Almeida, AMR	1
Paiva, PMG	1
Carvalho, BM	1
Napoleão, TH	1
Komamura, K	1
Nahar, N	1
Mohamed, S	2
Mustapha, NM	1
Lau, S	1
Ishak, NIM	1
Umran, NS	1
Hasan, SS	1
Kow, CS	1
Bain, A	1
Kavanagh, S	1
Merchant, HA	1
Hadi, MA	1
Liu, XD	1
Li, YG	1
Wang, GY	1
Bi, YG	1
Zhao, Y	2
Yan, ML	1
Liu, X	2
Wei, M	2
Wan, LL	1
Zhang, QY	1
Machado, IF	1
Teodoro, JS	1
Castela, AC	1
Palmeira, CM	1
Rolo, AP	1
Sang, J	1
Dhakal, S	1
Lee, Y	1
Hong, JGS	1
Tan, PC	1
Kamarudin, M	1
Omar, SZ	1
Liu, Q	1
You, N	1
Pan, H	1
Shen, Y	2
Lu, P	1
Wang, J	1
Lu, W	1
Zhu, L	1
Martinez, L	1
Opoku, AR	1
Salau, VF	1
Erukainure, OL	1
Olofinsan, KA	1
Islam, MS	2
Shiming, Z	1
Mak, KK	1
Balijepalli, MK	1
Chakravarthi, S	1
Pichika, MR	1
Ahrén, B	3
Yeh, KC	1
Yeh, TK	1
Huang, CY	1
Hu, CB	1
Wang, MH	1
Huang, YW	1
Chou, LH	1
Ho, HH	1
Song, JS	1
Hsu, T	1
Jiaang, WT	1
Chao, YS	1
Chen, CT	1
Nie, L	1
Zhao, P	1
Yue, Z	1
Zhang, P	1
Ji, N	1
Chen, Q	1
Nguyen, H	1
Koh, JY	1
Islas-Robles, A	1
Meda Venkata, SP	1
Wang, JM	1
Monks, TJ	1
Zhuang, Y	1
Qin, T	1
Chang, M	1
Ji, X	1
Wang, N	1
Zhou, H	1
Li, JZ	1
Tseng, CH	2
Sun, H	1
Zuo, B	1
Shi, K	2
Zhang, C	5
Sun, D	1
Mone, P	1
Gambardella, J	1
Pansini, A	1
de Donato, A	1
Martinelli, G	1
Boccalone, E	1
Matarese, A	1
Frullone, S	1
Santulli, G	1
Venu, VKP	1
Saifeddine, M	1
Mihara, K	1
Faiza, M	1
Gorobets, E	1
Flewelling, AJ	1
Derksen, DJ	1
Hirota, SA	1
Marei, I	2
Al-Majid, D	1
Motahhary, M	1
Ding, H	4
Triggle, CR	4
Hollenberg, MD	1
Liang, H	1
Xu, W	2
Zhou, L	1
Yang, W	1
Weng, J	1
Di Biase, S	1
Shim, HS	1
Kim, KH	1
Vinciguerra, M	1
Rappa, F	1
Brandhorst, S	1
Cappello, F	1
Mirzaei, H	1
Lee, C	1
Longo, VD	1
Jain, RK	1
Schroeder, EB	1
Xu, S	2
Goodrich, GK	1
Nichols, GA	1
O'Connor, PJ	1
Steiner, JF	1
Zang, L	1
Shimada, Y	1
Nishimura, N	1
Nouhjah, S	1
Shahbazian, H	1
Shahbazian, N	1
Jahanshahi, A	1
Jahanfar, S	1
Cheraghian, B	1
Thrasher, J	1
Bajaj, HS	1
Ye, C	2
Jain, E	1
Venn, K	1
Stein, E	1
Aronson, R	2
Lingvay, I	1
Harris, S	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
Early Prevention of Diabetes Complications in People With Hyperglycaemia in Europe: e-PREDICE Study[NCT03222765]		1,000 participants (Anticipated)	Interventional	2015-03-15	Recruiting
A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide Versus Insulin Glargine in Subjects With Type 2 Diabetes Mellitus (DUAL™ V - Basal Insulin Switch)[NCT01952145]	Phase 3	557 participants (Actual)	Interventional	2013-09-20	Completed
Study of Metformin HCL in Patients With Type 2 Diabetes Intensively Treated With Insulin: a Treatment Strategy for Insulin Resistance in Type 2 Diabetes Mellitus: a Randomized Controlled Trial[NCT00375388]	Phase 3	400 participants	Interventional	1998-01-31	Completed
Efficacy, Safety & Tolerability of Combination of Ertugliflozin and Sitagliptin in Patients With Type II Diabetes Mellitus[NCT05556291]		190 participants (Anticipated)	Observational	2022-12-01	Recruiting
A Phase III, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of the Combination of Ertugliflozin (MK-8835/PF-04971729) With Sitagliptin Compared With Ertugliflozin Alone and Sitagliptin Alone, in the Treatment of Subjects W[NCT02099110]	Phase 3	1,233 participants (Actual)	Interventional	2014-04-22	Completed
Diazoxide-mediated Insulin Suppression in Hyperinsulinemic Obese Men, Part III[NCT00631033]	Phase 2	51 participants (Actual)	Interventional	2008-07-31	Completed
Gut-Brain-axis: Targets for Improvement of Cognition in the Elderly[NCT04841668]		136 participants (Anticipated)	Observational	2021-04-10	Recruiting
Management of Intrapartum Glycemia in Gestational Diabetic Mothers: A Randomized Controlled Trial[NCT05647798]		120 participants (Anticipated)	Interventional	2023-05-22	Recruiting
Long-term Effects of Flash Glucose Monitoring System in Patients With Gestational Diabetes[NCT06031987]		100 participants (Anticipated)	Interventional	2022-01-26	Recruiting
Diagnostic Efficiency Analysis of Oral Glucose Tolerance Test and Prediction Model Establishment in the First Trimester for Gestational Diabetes Mellitus: a Prospective Cohort Study[NCT05487352]		781 participants (Actual)	Observational	2021-05-30	Active, not recruiting
A Randomized, Double-blind, Placebo-controlled, 2-arm Parallel-group, Multicenter Study With a 24-week Main Treatment Period and an Extension Assessing the Efficacy and Safety of AVE0010 on Top of Pioglitazone in Patients With Type 2 Diabetes Not Adequate[NCT00763815]	Phase 3	484 participants (Actual)	Interventional	2008-09-30	Completed
Effects of Lixisenatide on Gastric Emptying, Glycaemia and 'Postprandial' Blood Pressure in Type 2 Diabetes and Healthy Subjects.[NCT02308254]	Phase 1/Phase 2	30 participants (Anticipated)	Interventional	2013-11-30	Recruiting
Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Melanoma, breAst or Lung Cancer Patients With Brain Metastases: the Phase II OPTIMAL Study[NCT04001725]	Phase 2	110 participants (Anticipated)	Interventional	2019-10-15	Recruiting
Effect of Empagliflozin on Liver Fat Content in Patients With Type 2 Diabetes: A 12-week Randomized Clinical Study[NCT02686476]		100 participants (Actual)	Interventional	2016-03-31	Completed
Effect of Dapagliflozin vs Sitagliptin on Liver Fat Accumulation and Body Composition in Patients With Diabetes Mellitus and Liver Transplantation: a Randomized Controlled Trial[NCT05042505]		100 participants (Anticipated)	Interventional	2022-01-01	Recruiting
Beta Cell Restoration Through Fat Mitigation[NCT01763346]		88 participants (Actual)	Interventional	2013-06-30	Completed
Restoring Insulin Secretion Pediatric Medication Study[NCT01779375]	Phase 3	91 participants (Actual)	Interventional	2013-06-16	Completed
Restoring Insulin Secretion Adult Medication Study[NCT01779362]	Phase 3	267 participants (Actual)	Interventional	2013-04-30	Completed
Modulation of Gut Microbiota to Enhance Health and Immunity of Vulnerable Individuals During COVID-19 Pandemic[NCT04884776]		453 participants (Actual)	Interventional	2021-06-01	Active, not recruiting
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of Alogliptin Plus Metformin, Alogliptin Alone, or Metformin Alone in Subjects With Type 2 Diabetes[NCT01023581]	Phase 3	784 participants (Actual)	Interventional	2009-11-30	Completed
SGLT-2 Inhibitor Empagliflozin Effects on Appetite and Weight Regulation: A Randomised Double-blind Placebo-controlled Trial (The SEESAW Study)[NCT02798744]	Phase 4	68 participants (Actual)	Interventional	2016-12-31	Completed
Effect of Dapagliflozin Administration on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion[NCT02113241]	Phase 2/Phase 3	24 participants (Actual)	Interventional	2014-04-30	Completed
A 16-wk, Uni-center, Randomized, Double-blind, Parallel, Phase 3b Trial to Evaluate Efficacy of Saxagliptin + Dapagliflozin vs.Dapagliflozin With Regard to EGP in T2DM With Insufficient Glycemic Control on Metformin+/-Sulfonylurea Therapy[NCT02613897]		56 participants (Actual)	Interventional	2016-01-31	Completed
Effect of Saxagliptin in Addition to Dapagliflozin and Metformin on Insulin Resistance, Islet Cell Dysfunction, and Metabolic Control in Subjects With Type 2 Diabetes Mellitus on Previous Metformin Treatment[NCT02304081]	Phase 4	64 participants (Actual)	Interventional	2015-01-31	Completed
Efficacy and Safety of Lixisenatide in Patients With Type 2 Diabetes Mellitus Insufficiently Controlled by Metformin (With or Without Sulfonylurea): a Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Study With 24-week Treatment P[NCT01169779]	Phase 3	391 participants (Actual)	Interventional	2010-07-31	Completed
A Phase 2/3, Placebo-Controlled, Efficacy and Safety Study of Once-Weekly, Subcutaneous LY2189265 Compared to Sitagliptin in Patients With Type 2 Diabetes Mellitus on Metformin[NCT00734474]	Phase 2/Phase 3	1,202 participants (Actual)	Interventional	2008-08-31	Completed
Exercise Snacks and Glutamine to Improve Glucose Control in Adolescents With Type 1 Diabetes[NCT03199638]		14 participants (Actual)	Interventional	2016-04-01	Completed
Superiority of Insulin Glargine Lantus vs. NPH: Treat to Normoglycemia Concept.Effect of Insulin Glargine in Comparison to Insulin NPH in Insulin-nave People With Type 2 Diabetes Mellitus Treated With at Least One OAD and Not Adequately Controlled[NCT00949442]	Phase 4	708 participants (Actual)	Interventional	2009-07-31	Completed
A Randomized Trial Comparing Two Therapies: Basal Insulin/Glargine, Exenatide and Metformin Therapy (BET) or Basal Insulin/Glargine, Bolus Insulin Lispro and Metformin Therapy (BBT) in Subjects With Type 2 Diabetes Who Were Previously Treated by Basal Ins[NCT00960661]	Phase 3	1,036 participants (Actual)	Interventional	2009-09-30	Completed
Is the Stepping-down Approach a Better Option Than Multiple Daily Injections in Patients With Chronic Poorly-controlled Diabetes on Advanced Insulin Therapy?[NCT02846233]		22 participants (Actual)	Interventional	2016-08-31	Completed
Variability of Glucose Assessed in a Randomized Trial Comparing the Initiation of A Treatment Approach With Biosimilar Basal Insulin Analog Or a Titratable iGlarLixi combinatioN in Type 2 Diabetes Among South Asian Subjects (VARIATION 2 SA Trial)[NCT03819790]	Phase 4	119 participants (Actual)	Interventional	2018-10-02	Completed
A 16-week, Multicentre, Randomised, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Safety and Efficacy of Dapagliflozin 2.5 mg BID, 5 mg BID and 10 mg QD Versus Placebo in Patients With Type 2 Diabetes Who Are Inadequately Controlled on [NCT01217892]	Phase 3	400 participants (Actual)	Interventional	2010-11-30	Completed
Phase 3, Double Blinded, Placebo Controlled Study of the Effects of 12 Weeks DPP-IV Inhibitor Treatment on Secretion and Action of the Incretin Hormones in Patients With Type 2 Diabetes[NCT00411411]	Phase 3	49 participants (Actual)	Interventional	2007-02-28	Completed
Effect of Cassia Cinnamon on Arterial Stiffness Parameters in Patients With Type 2 Diabetes Mellitus[NCT04259606]		30 participants (Anticipated)	Interventional	2018-08-17	Recruiting
Efficacy and Safety of American Ginseng (Penax Quinquefolius) Extract on Glycemic Control in Individuals With Type 2 Diabetes: A Double-blind, Randomized, Crossover Clinical Trial[NCT02923453]	Phase 2	23 participants (Actual)	Interventional	1998-03-31	Completed
Effect of Cinnamomum Cassia as an Enhancer of the Insulin Response of the Insulin-Like Growth Factor-1 and Metabolic Control in Patients With Type 2 Diabetes Mellitus Treated With Metformin Without Glycemic Control[NCT03610412]	Phase 3	28 participants (Actual)	Interventional	2019-08-01	Completed
Effect of the Antidiabetic Drug DAPAgliflozin on the Coronary Macrovascular and MICROvascular Function in Type 2 Diabetic Patients[NCT05392959]	Phase 4	100 participants (Anticipated)	Interventional	2022-06-06	Recruiting
Comparison of Metformin and Pioglitazone Effects on Serum YKL-40 Concentrations in Patients With Newly Diagnosed Type 2 Diabetes[NCT01963663]		84 participants (Actual)	Interventional	2012-11-30	Completed
Metformin Administration Effect Over Systemic Inflammation Serum Markers in HIV Positive Prediabetic Patients[NCT03774108]	Phase 4	40 participants (Actual)	Interventional	2018-12-15	Active, not recruiting
Interactions Between Exogenous Insulin Aspart, Endogenous Insulin and Plasma Glucose in Type 2 Diabetes Mellitus Patients[NCT01510093]	Phase 2	10 participants (Actual)	Interventional	2012-05-31	Completed
Metformin Gastrointestinal Intolerance: Measurement of Mitochondrial Complex I[NCT03445702]	Early Phase 1	15 participants (Actual)	Interventional	2018-10-15	Completed
A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Delayed-Release Metformin in Subjects With Type 2 Diabetes Mellitus[NCT01819272]	Phase 2	240 participants (Actual)	Interventional	2013-04-30	Completed
A Randomized, Crossover Study Assessing the Effect of EFB0027 on Plasma Glucose and Pharmacokinetics in Subjects With Type 2 Diabetes Mellitus[NCT01804842]	Phase 1/Phase 2	26 participants (Actual)	Interventional	2012-12-31	Completed
Comparison of Metformin Hydrochloride Sustained-release Tablet (DuLeNing) and Glucophage in Patients With Type 2 Diabetes[NCT03039075]	Phase 4	240 participants (Actual)	Interventional	2016-11-30	Completed
A Randomized, Crossover Study Assessing the Pharmacokinetics of EFB0027 Versus ETB0015 and ETB0014 in Healthy Subjects[NCT02291510]	Phase 1	20 participants (Actual)	Interventional	2012-10-31	Completed
Independent and Additive Effects Of Micronutrients With Metformin In Patients With PCOS:A Double Blind Randomized Placebo Controlled Trial[NCT05653895]		250 participants (Anticipated)	Interventional	2022-12-07	Recruiting
The Effects of Acetyl L--Carnitine and Myo/Chiro-Inositol on Improving Ovulation, Pregnancy Rate, Ovarian Function and Perceived Stress Response in Patients With PCOS[NCT05767515]		120 participants (Anticipated)	Interventional	2023-04-15	Not yet recruiting
A Dose Escalation Study to Evaluate the Effect of Inhaled Nitrite on Cardiopulmonary Hemodynamics in Subjects With Pulmonary Hypertension[NCT01431313]	Phase 2	48 participants (Actual)	Interventional	2012-06-30	Completed
STAMPEDE: Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial[NCT00268476]	Phase 2/Phase 3	11,992 participants (Actual)	Interventional	2005-07-08	Active, not recruiting
Ketosis-Prone Diabetes in African Americans: Predictive Markers, Underlying Mechanisms, and Treatment Outcomes: The Effects of Metformin vs. Sitagliptin on Beta-Cell Preservation in Obese Subjects With Ketosis-Prone Type 2 Diabetes Mellitus[NCT01099618]	Phase 4	48 participants (Actual)	Interventional	2010-03-31	Completed
A 24-week, Randomized, Double-blind, Active-controlled, Parallel Group Trial to Assess the Superiority of Oral Linagliptin and Metformin Compared to Linagliptin Monotherapy in Newly Diagnosed, Treatment-naïve, Uncontrolled Type 2 Diabetes Mellitus Patient[NCT01512979]	Phase 4	316 participants (Actual)	Interventional	2012-01-31	Completed
A 52-Week, Randomised, Double Blind, Active-Controlled, Multi-Centre Phase IIIb/IV Study to Evaluate the Efficacy and Tolerability of Saxagliptin Compared to Glimepiride in Elderly Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycaemic Contr[NCT01006603]	Phase 4	957 participants (Actual)	Interventional	2009-10-31	Completed
A Randomized, Long-Term, Open-Label, 3-Arm, Multicenter Study to Compare the Glycemic Effects, Safety, and Tolerability of Exenatide Once Weekly Suspension to Sitagliptin and Placebo in Subjects With Type 2 Diabetes Mellitus[NCT01652729]	Phase 3	365 participants (Actual)	Interventional	2013-02-28	Completed
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase 2 Trial to Evaluate the Safety and Efficacy of BMS-512148 as Monotherapy in Subjects With Type 2 Diabetes Mellitus Who Are Treatment Naive And Have Inadequate Glycemic Cont[NCT00263276]	Phase 2	389 participants (Actual)	Interventional	2005-12-31	Completed
Effectiveness and Tolerability of Novel, Initial Triple Combination Therapy With Xigduo (Dapagliflozin Plus Metformin) and Saxagliptin vs. Conventional Stepwise add-on Therapy in Drug-naïve Patients With Type 2 Diabetes[NCT02946632]	Phase 3	104 participants (Anticipated)	Interventional	2016-12-31	Not yet recruiting
Effectiveness of the Treatment With Dapagliflozin and Metformin Compared to Metformin Monotherapy for Weight Loss on Diabetic and Prediabetic Patients With Obesity Class III[NCT03968224]	Phase 2/Phase 3	90 participants (Anticipated)	Interventional	2018-07-07	Recruiting
Diabetes Prevention Program Outcomes Study[NCT00038727]	Phase 3	2,779 participants (Actual)	Interventional	2002-09-30	Active, not recruiting
An Evaluation of the Metabolic Effects of Exenatide, Rosiglitazone, and Exenatide Plus Rosiglitazone in Subjects With Type 2 Diabetes Mellitus Treated With Metformin[NCT00135330]	Phase 3	137 participants (Actual)	Interventional	2005-10-31	Completed
The Impact of Glucose Lowering Therapies Including Dipeptidyl Peptidase-4 Inhibitor on Circulating Endothelial Progenitor Cells (EPCs) and Its Mobilising Factor Stromal Derived Factor-1α (SDF-1α) in Patients With Type 2 Diabetes[NCT02694575]		241 participants (Actual)	Observational	2015-03-01	Completed
Acute Effect of a GLP-1-Analogue (Exenatide) and of a DPP-4-Inhibitor (Sitagliptin) in Subjects With Type 2 Diabetes Treated With Insulin Glargine Once Daily[NCT00971659]	Phase 1	48 participants (Actual)	Interventional	2008-01-31	Completed
Randomized Study to Evaluate the Safety and Efficacy of INCB013739 Plus Metformin Compared to Metformin Alone on Glycemic Control in Type 2 Diabetic Subjects[NCT00698230]	Phase 2	302 participants (Actual)	Interventional	2008-05-31	Completed
Adaptive Study for Efficacy and Safety of Metformin Glycinate for the Treatment of Patients With MS and DM2, Hospitalized With Severe Acute Respiratory Syndrome Secondary to SARS-CoV-2. Randomized, Double-Blind, Phase IIIb.[NCT04626089]	Phase 2	0 participants (Actual)	Interventional	2021-02-28	Withdrawn (stopped due to Administrative decision of the company)
Short and Long Term Effects of a Dypeptidil-peptidase-4 Versus Bedtime NPH Insulin as add-on Therapy in Patients With Type 2 Diabetes[NCT02607410]	Phase 4	40 participants (Actual)	Interventional	2010-01-31	Completed
Effects of a Pioglitazone/Metformin Fixed Combination in Comparison to Metformin in Combination With Glimepiride on Diabetic Dyslipidemia[NCT00770653]	Phase 3	305 participants (Actual)	Interventional	2007-04-30	Completed
The Effect of a Checklist on the Education of Simulated Patients During Insulin Initiation: a Randomized Controlled Trial[NCT02266303]		100 participants (Anticipated)	Interventional	2014-07-31	Recruiting
The Effect of a Checklist on the Quality of Education During Insulin Initiation by Trained Medical Students: a Randomized Controlled Trial[NCT02313805]		100 participants (Anticipated)	Interventional	2014-07-31	Recruiting
Glycemic Response of Bean-and-rice Meals in Persons With Type 2 Diabetes Mellitus[NCT01241253]	Phase 2	17 participants (Actual)	Interventional	2009-11-30	Completed
Effect of Tight Control of Blood Glucose During Hyper-CVAD Chemotherapy For Acute Lymphocytic Leukemia[NCT00500240]	Phase 3	52 participants (Actual)	Interventional	2004-04-30	Terminated (stopped due to Terminated early due to futility.)
Effect of Anti-diabetic Drugs on Glycemic Variability. A Comparison Between Gliclazide MR (Modified Release) and Dapagliflozin on Glycemic Variability Measured by Continuous Glucose Monitoring (CGM) in Patients With Uncontrolled Type 2 Diabetes[NCT02925559]	Phase 4	135 participants (Actual)	Interventional	2016-10-31	Completed
Prospective, Randomized, Open-label Study With Blinded Endpoint (PROBE Design) to Compare the 72 hr Glycemic Profiles Obtained by Continuous Subcutaneous Glucose Monitoring (CSGM) in Type 2 Diabetic Patients at Baseline With Metformin Monotherapy and Afte[NCT01193296]	Phase 4	36 participants (Actual)	Interventional	2010-06-30	Completed
Is the Co-administration of Metformine and CC as Compared to Placebo and CC Superior to Induce Ovulation in PCOS Patients With a Confirmed insulin-resistant-a Double Blind Randomized Clinical Trial[NCT02523898]	Phase 2	388 participants (Anticipated)	Interventional	2015-11-30	Enrolling by invitation
An Open-label, Randomized Two-arm Parallel Group Study to Compare the Effects of 4-week QD Treatment With Lixisenatide or Liraglutide on the Postprandial Plasma Glucose in Patients With Type 2 Diabetes Not Adequately Controlled With Metformin[NCT01175473]	Phase 2	148 participants (Actual)	Interventional	2010-08-31	Completed
Using Pharmacogenetics to Improve Treatment in Early-onset Diabetes[NCT01238380]		1,916 participants (Actual)	Observational	2010-12-31	Completed
Modulation of Insulin Secretion and Insulin Sensitivity in Bangladeshi Type 2 Diabetic Subjects by an Insulin Sensitizer Pioglitazone and T2DM Association With PPARG Gene Polymorphism.[NCT01589445]	Phase 4	77 participants (Actual)	Interventional	2008-11-30	Completed
Assessing Progression to Type-2 Diabetes (APT-2D): A Prospective Cohort Study Expanded From BRITE-SPOT (Bio-bank and Registry for StratIfication and Targeted intErventions in the Spectrum Of Type 2 Diabetes)[NCT02838693]		2,300 participants (Anticipated)	Observational	2016-03-31	Recruiting
A Phase 3, Randomized, Triple-Blind, Parallel-Group, Long-Term, Placebo-Controlled, Multicenter Study to Examine the Effect on Glucose Control (HbA1c) of AC2993 Given Twice Daily in Subjects With Type 2 Diabetes Mellitus Treated With Metformin and a Sulfo[NCT00035984]	Phase 3	734 participants (Actual)	Interventional	2002-05-31	Completed
A Phase 3, Randomized, Triple-Blind, Parallel-Group, Long-Term, Placebo-Controlled, Multicenter Study to Examine the Effect on Glucose Control (HbA1c) of AC2993 Given Two Times a Day in Subjects With Type 2 Diabetes Mellitus Treated With Metformin Alone[NCT00039013]	Phase 3	336 participants (Actual)	Interventional	2002-03-31	Completed
Observational Study of Interstitial Glucose Monitoring With Continuous Glucose Monitoring to Track Patients Treated With Exenatide[NCT00569907]		18 participants (Actual)	Observational	2007-01-31	Completed
Adaptive Study to Demonstrate Efficacy and Safety of Metformin Glycinate for the Treatment of Hospitalized Patients With Severe Acute Respiratory Syndrome Secondary to SARS-CoV-2. Randomized, Double-Blind, Phase IIIb[NCT04625985]	Phase 2	20 participants (Actual)	Interventional	2020-07-14	Completed
Effect of Metformin in Combination With Tyrosine Kinase Inhibitors (TKI) on Clinical, Biochemical and Nutritional in Patients With Non-Small Cell Lung Carcinoma (NSCLC): Randomized Clinical Trial[NCT03071705]		120 participants (Anticipated)	Interventional	2016-03-31	Recruiting
Efficacy and Safety of Metformin Glycinate Compared to Metformin Hydrochloride on the Progression of Type 2 Diabetes[NCT04943692]	Phase 3	500 participants (Anticipated)	Interventional	2021-08-31	Suspended (stopped due to Administrative decision of the investigation direction)
Safety and Efficacy of Metformin Glycinate vs Metformin Hydrochloride on Metabolic Control and Inflammatory Mediators in Type 2 Diabetes Patients[NCT01386671]	Phase 3	203 participants (Actual)	Interventional	2014-06-30	Completed
Effect of Myoinositol on Serum Asprosin Levels in PCOS Patients[NCT05951309]		30 participants (Actual)	Interventional	2021-09-01	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Change from baseline in body weight after 26 weeks of treatment (NCT01952145)
Timeframe: Week 0, week 26

Change From Baseline in HbA1c (Glycosylated Haemoglobin)

Intervention	Kg (Mean)
Insulin Degludec/Liraglutide (IDegLira)	-1.4
Insulin Glargine (IGlar)	1.8

Change from baseline in HbA1c after 26 weeks of treatment (NCT01952145)
Timeframe: Week 0, week 26

Number of Treatment Emergent Confirmed Hypoglycaemic Episodes

Intervention	Percentage (%) (Mean)
Insulin Degludec/Liraglutide (IDegLira)	-1.81
Insulin Glargine (IGlar)	-1.13

Confirmed hypoglycaemic episodes were defined as either: Severe (i.e., an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) or an episode biochemically confirmed by a plasma glucose value of <3.1 mmol/L (56 mg/dL), with or without symptoms consistent with hypoglycaemia. (NCT01952145)
Timeframe: During 26 weeks of treatment

Change From Baseline in A1C at Week 26: Excluding Rescue Approach

Intervention	Number of episodes (Number)
Insulin Degludec/Liraglutide (IDegLira)	289
Insulin Glargine (IGlar)	683

A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 26 A1C minus the Week 0 A1C. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. (NCT02099110)
Timeframe: Baseline and Week 26

Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach

Intervention	Percentage (Least Squares Mean)
Ertugliflozin 5 mg	-1.02
Ertugliflozin 15 mg	-1.08
Sitagliptin 100 mg	-1.05
Ertugliflozin 5 mg + Sitagliptin 100 mg	-1.49
Ertugliflozin 15 mg + Sitagliptin 100 mg	-1.52

This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. (NCT02099110)
Timeframe: Baseline and Week 26

Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach

Intervention	Kilograms (Least Squares Mean)
Ertugliflozin 5 mg	-2.69
Ertugliflozin 15 mg	-3.74
Sitagliptin 100 mg	-0.67
Ertugliflozin 5 mg + Sitagliptin 100 mg	-2.52
Ertugliflozin 15 mg + Sitagliptin 100 mg	-2.94

Blood glucose was measured on a fasting basis after at least a 10-hour fast. This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. (NCT02099110)
Timeframe: Baseline and Week 26

Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach

Intervention	mg/dL (Least Squares Mean)
Ertugliflozin 5 mg	-35.73
Ertugliflozin 15 mg	-36.91
Sitagliptin 100 mg	-25.56
Ertugliflozin 5 mg + Sitagliptin 100 mg	-43.96
Ertugliflozin 15 mg + Sitagliptin 100 mg	-48.70

This change from baseline reflects the Week 26 systolic blood pressure minus the Week 0 systolic blood pressure. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. (NCT02099110)
Timeframe: Baseline and Week 26

Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach

Intervention	mm Hg (Least Squares Mean)
Ertugliflozin 5 mg	-3.89
Ertugliflozin 15 mg	-3.69
Sitagliptin 100 mg	-0.66
Ertugliflozin 5 mg + Sitagliptin 100 mg	-3.42
Ertugliflozin 15 mg + Sitagliptin 100 mg	-3.67

Static beta-cell sensitivity to glucose index (SBCSGI) estimates the ratio of insulin secretion (expressed in pmol/min) related to above-basal glucose concentration (expressed in mmol/L * L) following a meal. Blood samples were collected before and after a standard meal and glucose, insulin, and C-peptide levels were analyzed. The C-peptides minimal model was used to estimate the insulin secretion rate (ISR). Analysis included both non-model-based [including insulinogenic index with C-peptide, glucose area under the curve (AUC)/insulin AUC] and model-based [beta cell function and insulin secretion rate at 9 mM glucose] testing. Analysis was performed with non-linear least squares using the Software Architecture Analysis Method (SAAM) II software. SBCSGI was expressed in units of 10^-9 min^-1. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. (NCT02099110)
Timeframe: 30 min. before and 0, 15, 30, 60, 90, 120, and 180 minutes following the start of the standard meal at Baseline and Week 26

Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach

Intervention	SBCSGI (10^-9min^-1) (Least Squares Mean)
Ertugliflozin 5 mg	8.62
Ertugliflozin 15 mg	9.71
Sitagliptin 100 mg	21.11
Ertugliflozin 5 mg + Sitagliptin 100 mg	16.24
Ertugliflozin 15 mg + Sitagliptin 100 mg	11.51

A1C is blood marker used to report average blood glucose levels over a prolonged periods of time and is reported as a percentage (%). Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. (NCT02099110)
Timeframe: Week 26

Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach

Intervention	Percentage of participants (Number)
Ertugliflozin 5 mg	26.4
Ertugliflozin 15 mg	31.9
Sitagliptin 100 mg	32.8
Ertugliflozin 5 mg + Sitagliptin 100 mg	52.3
Ertugliflozin 15 mg + Sitagliptin 100 mg	49.2

An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Including rescue approach data analysis included data following the initiation of rescue therapy. (NCT02099110)
Timeframe: Up to 52 weeks

Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach

Intervention	Percentage of participants (Number)
Ertugliflozin 5 mg	3.2
Ertugliflozin 15 mg	3.2
Sitagliptin 100 mg	2.8
Ertugliflozin 5 mg + Sitagliptin 100 mg	3.3
Ertugliflozin 15 mg + Sitagliptin 100 mg	3.7

Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24

Intervention	Percentage of participants (Number)
Ertugliflozin 5 mg	62.0
Ertugliflozin 15 mg	57.7
Sitagliptin 100 mg	57.5
Ertugliflozin 5 mg + Sitagliptin 100 mg	58.8
Ertugliflozin 15 mg + Sitagliptin 100 mg	55.7

Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. (NCT00763815)
Timeframe: Baseline, Week 24

Change From Baseline in Beta-cell Function Assessed by Homeostasis Model Assessment for Beta-cell Function (HOMA-beta) at Week 24

Intervention	percentage of hemoglobin (Least Squares Mean)
Placebo	-0.34
Lixisenatide	-0.90

Beta cell function was assessed by HOMA-beta. HOMA-beta (% of normal beta cells function) = (20 multiplied by fasting plasma insulin [micro unit per milliliter]) divided by (fasting plasma glucose [mmol/L] minus 3.5). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. (NCT00763815)
Timeframe: Baseline, Week 24

Change From Baseline in Body Weight at Week 24

Intervention	% of normal beta cells function (Least Squares Mean)
Placebo	6.98
Lixisenatide	6.72

Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. (NCT00763815)
Timeframe: Baseline, Week 24

Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24

Intervention	kilogram (Least Squares Mean)
Placebo	0.21
Lixisenatide	-0.21

Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. (NCT00763815)
Timeframe: Baseline, Week 24

Change From Baseline in Fasting Plasma Insulin (FPI) at Week 24

Intervention	mmol/L (Least Squares Mean)
Placebo	-0.32
Lixisenatide	-1.16

Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period

Intervention	pmol/L (Least Squares Mean)
Placebo	-1.01
Lixisenatide	-10.36

Routine fasting self-monitored plasma glucose (SMPG) and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG >270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8.5%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. (NCT00763815)
Timeframe: Baseline up to Week 24

Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24

Intervention	percentage of participants (Number)
Placebo	11.3
Lixisenatide	3.8

The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. (NCT00763815)
Timeframe: Baseline, Week 24

Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24

Intervention	percentage of participants (Number)
Placebo	5.1
Lixisenatide	9.2

The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required. (NCT00763815)
Timeframe: Week 24

Percentage of Patients With HbA1c Level Less Than or Equal to 6.5% at Week 24

Intervention	percentage of participants (Number)
Placebo	26.4
Lixisenatide	52.3

Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia

Intervention	percentage of participants (Number)
Placebo	10.1
Lixisenatide	28.9

Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available. (NCT00763815)
Timeframe: First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks

Glycemia

Steady State Beta Cell Compensation

Intervention	participants (Number)
	Symptomatic Hypoglycemia	Severe Symptomatic Hypoglycemia
Lixisenatide	23	0
Placebo	7	0

Intervention	percent of hemoglobin (Mean)
Metformin	5.84
Gastric Banding	5.73

mean plasma C-peptide concentration during clamp steady state, adjusted for mean clamp insulin sensitivity (NCT01763346)
Timeframe: 24 months

Glycemia

ACPRg

Intervention	(nmol/L) adjusted for M/I (Geometric Mean)
Metformin	3.01
Gastric Banding	3.19

Intervention	mmol/l (Mean)
	fasting glucose	2-hour glucose
Gastric Banding	5.85	9.92
Metformin	5.95	10.87

First phase response (NCT01779375)
Timeframe: 3-months after a medication washout

Clamp Measure of Insulin Sensitivity

Intervention	nmol/L (Mean)
Metformin Alone	1.11
Glargine Followed by Metformin	1.12

Participants had 12-months of active therapy. Secondary results at the end of active intervention. (NCT01779375)
Timeframe: End of active intervention (Month 12)

M/I

Intervention	x 10-5 mmol/kg/min per pmol/L (Mean)
Metformin Alone	1.52
Glargine Followed by Metformin	1.93

Clamp measure of insulin sensitivity (NCT01779375)
Timeframe: 3-months after a medication washout

ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12

Intervention	x 10-5 mmol/kg/min per pmol/L (Mean)
Metformin Alone	1.48
Glargine Followed by Metformin	1.70

Participants had 12-months of active therapy. Secondary results at the end of active intervention. (NCT01779375)
Timeframe: End of active intervention (Month 12).

ß-cell Response Measured by Hyperglycemic Clamp

Intervention	nmol/L (Mean)
	Steady State C-peptide	ACPRmax	ACPRg
Glargine Followed by Metformin	4.37	5.79	1.03
Metformin Alone	4.78	6.95	1.06

Clamp measures of ß-cell response, co-primary outcomes (NCT01779375)
Timeframe: 3-months after medication washout (Month 15)

ACPRg

Intervention	nmol/L (Mean)
	Steady State C-peptide	ACPRmax
Glargine Followed by Metformin	4.18	5.95
Metformin Alone	4.82	6.92

First phase response from the hyperglycemic clamp (NCT01779362)
Timeframe: 3-months after a medication washout

Insulin Sensitivity, M/I

Intervention	nmol/L (Geometric Mean)
Metformin Alone	1.68
Glargine Followed by Metformin	1.68
Placebo	1.68
Liraglutide + Metformin	1.68

Clamp measure of insulin sensitivity (NCT01779362)
Timeframe: 3-months after a medication washout

ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12

Intervention	x 10-5 mmol/kg/min per pmol/L (Geometric Mean)
Metformin Alone	3.53
Glargine Followed by Metformin	3.38
Placebo	3.63
Liraglutide + Metformin	3.49

Participants had 12-months of active therapy. Secondary results at the end of active intervention. (NCT01779362)
Timeframe: Secondary analysis was on all participants with a Month 12 visit.

ß-cell Response Measured by Hyperglycemic Clamp

Intervention	nmol/L (Geometric Mean)
	ACRPg	Steady State C-peptide	ACRPmax
Glargine Followed by Metformin	1.88	11.6	14.1
Liraglutide + Metformin	2.68	21.2	10.1
Metformin Alone	1.93	11.7	13.4
Placebo	1.69	10.8	13.6

Clamp measures of ß-cell response, co-primary outcomes (NCT01779362)
Timeframe: 3-months after medication washout (Month 15)

Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26

Intervention	nmol/L (Geometric Mean)
	Steady State C-peptide	ACPRmax
Glargine Followed by Metformin	3.58	4.32
Liraglutide + Metformin	3.73	4.58
Metformin Alone	3.65	4.61
Placebo	3.60	4.45

The change from Baseline to Week 26 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). (NCT01023581)
Timeframe: Baseline and Week 26.

Change From Baseline in Fasting Plasma Glucose Over Time

Intervention	percentage glycosylated hemoglobin (Least Squares Mean)
Placebo	0.15
Alogliptin 25 QD	-0.52
Alogliptin 12.5 BID	-0.56
Metformin 500 BID	-0.65
Metformin 1000 BID	-1.11
Alogliptin 12.5 BID + Metformin 500 BID	-1.22
Alogliptin 12.5 BID + Metformin 1000 BID	-1.55

The change from Baseline in fasting plasma glucose was assessed at Weeks 1, 2, 4, 8, 12, 16, 20 and 26. Least Squares Means were from an ANCOVA model with treatment and geographic region as fixed effects, and baseline fasting plasma glucose as a covariate. (NCT01023581)
Timeframe: Baseline and Weeks 1, 2, 4, 8, 12, 16, 20 and 26.

Change From Baseline in HbA1c Over Time

Intervention	mg/dL (Least Squares Mean)
	Week 1 (n=102, 103, 94, 95, 104, 101, 109)	Week 2 (n=105, 112, 105, 102, 108, 106, 111)	Week 4 (n=105, 112, 106, 106, 110, 106, 111)	Week 8 (n=105, 112, 106, 106, 110, 106, 112)	Week 12 (n=105, 112, 106, 106, 110, 106, 112)	Week 16 (n=105, 112, 106, 106, 110, 106, 112)	Week 20 (n=105, 112, 106, 106, 110, 106, 112)	Week 26 (n=105, 112, 106, 106, 110, 106, 112)
Alogliptin 12.5 BID	-11.9	-11.6	-16.6	-12.1	-14.7	-14.7	-12.3	-9.7
Alogliptin 12.5 BID + Metformin 1000 BID	-36.3	-43.6	-44.1	-43.8	-44.7	-47.7	-44.6	-45.9
Alogliptin 12.5 BID + Metformin 500 BID	-32.7	-34.5	-37.6	-32.9	-31.6	-35.9	-33.8	-31.7
Alogliptin 25 QD	-3.9	-7.4	-11.5	-10.9	-9.7	-7.1	-9.2	-6.1
Metformin 1000 BID	-23.1	-22.2	-29.0	-30.7	-30.7	-33.5	-35.1	-31.9
Metformin 500 BID	-12.6	-14.5	-16.9	-11.8	-14.0	-13.3	-10.9	-11.5
Placebo	5.7	4.6	7.2	7.1	11.6	10.1	8.7	12.4

"The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) was assessed at Weeks 4, 8, 12, 16 and 20.~Least squares means are from an analysis of covariance (ANCOVA) model with treatment and geographic region as fixed effects, and baseline HbA1c as a covariate." (NCT01023581)
Timeframe: Baseline and Weeks 4, 8, 12, 16, and 20.

Alanine Aminotransferase (ALT) at Week 12.

Intervention	percentage glycosylated hemoglobin (Least Squares Mean)
	Week 4 (n=95, 97, 89, 94, 102, 94, 101)	Week 8 (n=102, 104, 104, 103, 108, 102, 111)	Week 12 (n=102, 104, 104, 103, 108, 102, 111)	Week 16 (n=102, 104, 104, 103, 108, 102, 111)	Week 20 (n=102, 104, 104, 103, 108, 102, 111)
Alogliptin 12.5 BID	-0.42	-0.58	-0.62	-0.63	-0.59
Alogliptin 12.5 BID + Metformin 1000 BID	-0.75	-1.17	-1.40	-1.50	-1.54
Alogliptin 12.5 BID + Metformin 500 BID	-0.70	-1.08	-1.22	-1.26	-1.25
Alogliptin 25 QD	-0.34	-0.51	-0.53	-0.58	-0.57
Metformin 1000 BID	-0.58	-0.86	-1.02	-1.09	-1.14
Metformin 500 BID	-0.37	-0.59	-0.68	-0.72	-0.68
Placebo	0.09	0.08	0.12	0.13	0.12

The ALT hepatic transaminase levels are going to be measured at week 12 with standardized techniques. (NCT02113241)
Timeframe: Week 12.

Aspartate Aminotransferase (AST) at Week 12.

Intervention	U/L (Mean)
Dapagliflozin	32.1
Placebo	38.1

The hepatic transaminase AST will be evaluated with standardized methods at week 12 (NCT02113241)
Timeframe: Week 12

AUC of Glucose at Week 12.

Intervention	U/L (Mean)
Dapagliflozin	31.1
Placebo	29.5

The AUC of glucose will be calculated from the glucose values obtained from the minuted oral glucose tolerance curve at week 12 (NCT02113241)
Timeframe: Week 12

AUC of Insulin at Week 12.

Intervention	mmol*hr/L (Mean)
Dapagliflozin	1153
Placebo	1129

The AUC will be calculated from the insulin values obtained from the minuted oral glucose tolerance curve at week 12 (NCT02113241)
Timeframe: Week 12

Body Mass Index at Week 12

Intervention	pmol*h/L (Mean)
Dapagliflozin	45016
Placebo	119704

The Body Mass index it's going to be calculated at week 12 with the Quetelet index. (NCT02113241)
Timeframe: Week 12

Body Weight at Week 12.

Intervention	kg/m^2 (Mean)
Dapagliflozin	32.6
Placebo	32.1

The weight it's going to be measured at week 12 with a bioimpedance balance. (NCT02113241)
Timeframe: Week 12

Creatinine at Week 12.

Intervention	kilograms (Mean)
Dapagliflozin	81.2
Placebo	79.6

The creatinine levels are going to be measured at week 12 with standardized techniques. (NCT02113241)
Timeframe: Week 12.

Diastolic Blood Pressure at Week 12.

Intervention	mmol/L (Mean)
Dapagliflozin	0.07
Placebo	0.05

The diastolic blood pressure is going to be evaluated at week 12 with a digital sphygmomanometer. (NCT02113241)
Timeframe: Week 12

Fat Mass at Week 12.

Intervention	mmHg (Mean)
Dapagliflozin	76
Placebo	79

The fat mass is going to be evaluated at week 12 through bioimpedance. (NCT02113241)
Timeframe: Week 12

Glucose at Minute 120 at Week 12.

Intervention	kilograms (Mean)
Dapagliflozin	32.7
Placebo	34.4

The glucose at minute 120 is going to be evaluated at week 12 during a minuted oral glucose tolerance curve (NCT02113241)
Timeframe: Week 12

Glucose at Minute 30 at Week 12.

Intervention	mmol/L (Mean)
Dapagliflozin	8.5
Placebo	8.8

The glucose at minute 30 is going to be evaluated at week 12 during a minuted oral glucose tolerance curve (NCT02113241)
Timeframe: Week 12

Glucose at Minute 60 at Week 12.

The glucose at minute 60 is going to be evaluated at week 12 during a minuted oral glucose tolerance curve (NCT02113241)
Timeframe: Week 12

Glucose at Minute 90 at Week 12.

The glucose at minute 90 is going to be evaluated at week 12 during a minuted oral glucose tolerance curve (NCT02113241)
Timeframe: Week 12

Glucose Levels at Minute 0 at Week 12.

The fasting glucose (0') levels are going to be evaluated at week 12 with enzymatic/colorimetric techniques. (NCT02113241)
Timeframe: Week 12

High Density Lipoprotein (c-HDL) Levels at Week 12.

The c-HDL levels are going to be evaluated at week 12 with enzymatic/colorimetric techniques. (NCT02113241)
Timeframe: Week 12

Insulinogenic Index (Total Insulin Secretion) at Week 12.

"The insulinogenic index is a ratio that relates enhancement of circulating insulin to the magnitude of the corresponding glycemic stimulus.~Total insulin secretion was calculated with the insulinogenic index (ΔAUC insulin/ΔAUC glucose), the entered values reflect the total insulin secretion at week 12." (NCT02113241)
Timeframe: Week 12

Low Density Lipoproteins (c-LDL) at Week 12

The c-LDL levels are going to be measured at week 12 with standardized techniques. (NCT02113241)
Timeframe: Week 12

Matsuda Index (Total Insulin Sensitivity) at Week 12.

Matsuda Index value is used to indicate insulin resistance on diabetes. Insulin sensitivity was calculated with Matsuda index [10,000 / √glucose 0' x insulin 0') (mean glucose oral glucose tolerance test (OGTT) x mean insulin OGTT)]. The entered values reflect the insulin sensitivity at week 12. (NCT02113241)
Timeframe: Week 12

Stumvoll Index (First Phase of Insulin Secretion) at Week 12.

"Human studies support the critical physiologic role of the first-phase of insulin secretion in the maintenance of postmeal glucose homeostasis.~First phase of insulin secretion was estimated using the Stumvoll index (1283+ 1.829 x insulin 30' - 138.7 x glucose 30' + 3.772 x insulin 0'), the entered values reflect the frst phase of insulin secretion at week 12." (NCT02113241)
Timeframe: Week 12

Systolic Blood Pressure at Week 12.

The systolic blood pressure is going to be evaluated at week 12 with a digital sphygmomanometer. (NCT02113241)
Timeframe: Week 12

Total Cholesterol at Week 12

The total cholesterol will be estimated by standardized techniques at week 12. (NCT02113241)
Timeframe: Week 12

Triglycerides Levels at Week 12.

The triglycerides levels are going to be evaluated at week 12 with enzymatic-colorimetric techniques. (NCT02113241)
Timeframe: Week 12

Uric Acid at Week 12.

The uric acid levels are going to be measured at week 12 with standardized techniques. (NCT02113241)
Timeframe: Week 12.

Waist Circumference at Week 12.

The waist circumference is going to be evaluated at week 12 with a flexible tape with standardized techniques. (NCT02113241)
Timeframe: Week 12

Change in BMI

Change in BMI (body mass index) from study start to 16 weeks (NCT02613897)
Timeframe: Change from baseline to 16 weeks

Change in Body Weight

Change in body weight from baseline to 16 weeks (NCT02613897)
Timeframe: Baseline to 16 weeks

Change in Fasting Plasma Glucagon (FPG)

A measure of the change in fasting plasma glucagon from study start to 16 weeks (NCT02613897)
Timeframe: Change from baseline to 16 weeks

Change in Free Fatty Acids (FFA)

Measure of change in Free Fatty Acids from study start to 16 weeks (NCT02613897)
Timeframe: Change from baseline to 16 weeks

Change in Glucose Oxidation

Change in percentage of glucose oxidation from study start to 16 weeks (NCT02613897)
Timeframe: Change from baseline to 16 weeks

Change in Lipid Oxidation

Change in lipid oxidation percentage from baseline to 16 weeks (NCT02613897)
Timeframe: Change from baseline to 16 weeks

HBA1c

Change in blood glucose level measured over a 3 month period from study start to 16 weeks (NCT02613897)
Timeframe: Change from baseline to 16 weeks

Mean Oral Glucose Tolerance Test (OGTT)

Measure of change in OGTT from study start to 16 weeks (NCT02613897)
Timeframe: Change from baseline to 16 weeks

Change in Endogenous Glucose Production (EGP)

All subjects received a Double-Tracer Oral Glucose Tolerance Test (OGTT) with 75g of glucose containing 14C-glucose together with intravenous primed-continuous infusion of 3(3H)-glucose for 240 minutes, at baseline (prior to) and after 16 weeks of therapy. Blood and urine samples were obtained during the OGTT to determine EGP. (NCT02613897)
Timeframe: Baseline and 16 weeks

Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24

Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline on-treatment assessment for at least 1 efficacy variable, were required. (NCT01169779)
Timeframe: Baseline, Week 24

Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24

The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. (NCT01169779)
Timeframe: Baseline, Week 24

Change From Baseline in Body Weight at Week 24

Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline on-treatment assessment for at least 1 efficacy variable, were required. (NCT01169779)
Timeframe: Baseline, Week 24

Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24

Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline on-treatment assessment for at least 1 efficacy variable, were required. (NCT01169779)
Timeframe: Baseline, Week 24

Change From Baseline in Glucose Excursion at Week 24

Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest. (NCT01169779)
Timeframe: Baseline, Week 24

Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period

Routine fasting self-monitored plasma glucose (SMPG) and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG >250 milligram/deciliter (mg/dL) (13.9 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >220 mg/dL (12.2 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8.5%. For a patient to be included in mITT population, both baseline and at least 1 post baseline on-treatment assessment for at least 1 efficacy variable, were required. (NCT01169779)
Timeframe: Baseline up to Week 24

Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24

The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline on-treatment assessment for at least 1 efficacy variable, were required. (NCT01169779)
Timeframe: Baseline, Week 24

Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24

The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline on-treatment assessment for at least 1 efficacy variable, were required. (NCT01169779)
Timeframe: Week 24

Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24

The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline on-treatment assessment for at least 1 efficacy variable, were required. (NCT01169779)
Timeframe: Week 24

Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia

Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available. (NCT01169779)
Timeframe: First dose of study drug up to 3 days after the last dose administration

Antibodies to LY2189265

The number of participants with postbaseline detection of treatment-emergent antidrug LY2189265 antibodies (ADA) is summarized. (NCT00734474)
Timeframe: Baseline through 104 weeks

Change From Baseline in Body Weight at Dose Decision Point

Change from baseline in body weight was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks. (NCT00734474)
Timeframe: Baseline up to 27.4 weeks

Change From Baseline in Glycosylated Hemoglobin (HbA1c) at the Dose Decision Point

Change from baseline in HbA1c was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks. (NCT00734474)
Timeframe: Baseline up to 27.4 weeks

Change From Baseline in Pulse Rate at Dose Decision Point

Sitting pulse rate was measured at the time that the dose decision was made (dose decision point). Change from baseline in pulse rate was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks. (NCT00734474)
Timeframe: Baseline up to 27.4 weeks

Glycosylated Hemoglobin (HbA1c) Change From Baseline

Least squares (LS) means were calculated using analysis of covariance (ANCOVA) and last observation carried forward (LOCF) imputation with country and treatment as fixed effects and baseline HbA1c as a covariate. (NCT00734474)
Timeframe: Baseline, 52 weeks

Number of Participants With Adjudicated Pancreatitis at 104 Weeks

The number of participants with pancreatitis confirmed by adjudication is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. (NCT00734474)
Timeframe: Baseline through 104 weeks

Number of Participants With Treatment-emergent Adverse Events at 104 Weeks

A treatment-emergent adverse event (TEAE) was defined as an event that first occurs or worsens (increases in severity) after baseline regardless of causality or severity. The number of participants with 1 or more TEAEs is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. (NCT00734474)
Timeframe: Baseline through 104 weeks

Number of Participants With Treatment-emergent Adverse Events at 26 Weeks

Number of Participants With Treatment-emergent Adverse Events at 52 Weeks

Pharmacokinetics of LY2189265: Area Under the Concentration-Time Curve

Pharmacokinetic (PK) parameter estimates from LY2189265 concentration data were obtained using a 2-compartment population PK model with first order absorption. Area under the plasma-concentration curve from 0 to 168 hours, steady state (AUC0-168h, ss) of LY2189265 is summarized. (NCT00734474)
Timeframe: Baseline through 52 weeks

Beta Cell Function and Insulin Sensitivity (HOMA2)

The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-cell function. HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state beta cell function (%B) as a percentage of a normal reference population (normal young adults). HOMA2-%S is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin sensitivity (%S), as percentages of a normal reference population (normal young adults). The normal reference population for both HOMA2-%B and HOMA2-%S were set at 100%. Least squares (LS) means of change from baseline of C-peptide based HOMA2-%B and HOMA2-%S were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 26, 52, and 104 weeks

Body Weight Change From Baseline

Least squares (LS) means of change from baseline body weight were calculated using analysis of covariance (ANCOVA) and last observation carried forward (LOCF) imputation with country and treatment as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 26, 52, and 104 weeks

Change From Baseline in Blood Pressure

Sitting and standing systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Least squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 26 weeks, 104 weeks

Change From Baseline in Blood Pressure at Dose Decision Point

Sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at the dose decision point. Change from baseline in DBP was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the time of the decision point was 27.4 weeks. (NCT00734474)
Timeframe: Baseline up to 27.4 weeks

Change From Baseline in Electrocardiogram (ECG) Parameters, Fridericia-corrected QT (QTcF) and PR Interval

The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and was calculated from electrocardiogram (ECG) data using Fridericia's formula: QTc = QT/RR^0.33. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between two R waves. PR is the interval between the P wave and the QRS complex. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 26 weeks, 104 weeks

Change From Baseline in Pulse Rate

Sitting and standing pulse rate were measured. Least squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as covariate. (NCT00734474)
Timeframe: Baseline, 26 weeks, 104 weeks

Durability of Change From Baseline Body Weight

Durability of effect on body weight was assessed by comparing the differences in mean change from baseline in body weight at 1 time point versus an earlier time point. Least squares (LS) means of change from baseline body weight data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 13, 26, 52, and 104 weeks

Durability of Change From Baseline in Glycosylated Hemoglobin (HbA1c)

Durability of effect on HbA1c was assessed by comparing the differences in mean change from baseline in HbA1c at 1 time point versus an earlier time point. Least squares (LS) means of change from baseline HbA1c data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 13, 26, 52, and 104 weeks

Fasting Blood Glucose Change From Baseline

Least squares (LS) means of change from baseline were calculated using mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 26, 52, and 104 weeks

Fasting Insulin Change From Baseline

Least squares (LS) means of change from baseline fasting insulin data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 26, 52, and 104 weeks

Glycosylated Hemoglobin (HbA1c) Change From Baseline

Incidence of Hypoglycemic Episodes

Hypoglycemic episodes (HE) were classified as severe (defined as episodes requiring assistance from another person to actively administer resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia and has a plasma glucose level of ≤3.9 millimoles per liter [mmol/L]), asymptomatic (defined as episodes not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of ≤3.9 mmol/L), nocturnal (defined as any episode that occurred between bedtime and waking), or probable symptomatic (defined as episodes during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The number of participants with self-reported hypoglycemic events is summarized cumulatively. (NCT00734474)
Timeframe: Baseline through 26 and 104 weeks

Number of Participants With Adjudicated Cardiovascular Events at 104 Weeks

Data on any new cardiovascular (CV) event was prospectively collected using a CV event electronic case report form. At prespecified visits, participants were asked about any new CV event. Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by a committee of physicians with cardiology expertise external to the Sponsor. The nonfatal cardiovascular AEs to be adjudicated include myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, coronary interventions (such as coronary artery bypass graft or percutaneous coronary intervention), and cerebrovascular events including cerebrovascular accident (stroke) and transient ischemic attack. The number of participants with adjudicated CV events is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. (NCT00734474)
Timeframe: Baseline through 104 weeks

Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 104 Weeks

The number of participants with treatment-emergent abnormal laboratory results (defined as abnormalities that first occur after baseline) was summarized cumulatively for alkaline phosphatase, alanine aminotransferase or serum glutamic pyruvic transaminase (ALT/SGPT), amylase (pancreatic and total), aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT), basophils, bilirubin (direct and total), calcitonin, chloride, creatine phosphokinase (CPK), creatinine, creatinine clearance, eosinophils, erythrocytes, gamma glutamyltransferase (GGT), hematocrit, hemoglobin, leukocytes, lipase, lymphocytes, mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), monocytes, neutrophils, platelets, potassium, sodium, urea nitrogen, and urine microalbumin-to-creatinine ratio (UMCR). (NCT00734474)
Timeframe: Baseline through 104 weeks

Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 26 Weeks

Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 52 Weeks

The number of participants with treatment-emergent abnormal laboratory results (defined as abnormalities that first occur after baseline) was summarized cumulatively for alkaline phosphatase, alanine aminotransferase or serum glutamic pyruvic transaminase (ALT/SGPT), amylase (pancreatic and total), aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT), basophils, bilirubin (direct and total), calcitonin, chloride, creatine phosphokinase (CPK), creatinine, creatinine clearance, eosinophils, erythrocytes, gamma glutamyltransferase (GGT), hematocrit, hemoglobin, leukocytes, lipase, lymphocytes, mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), monocytes, neutrophils, platelets, potassium, sodium, urea nitrogen, and urine microalbumin-to-creatinine ratio (UMCR) . (NCT00734474)
Timeframe: Baseline through 52 weeks

Number of Participants With Treatment-emergent Abnormal Lipid Tests

The number of participants with treatment-emergent abnormal lipid test (cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C], and triglycerides [TG]) results (defined as lipid test abnormalities that first occurred after baseline) is summarized cumulatively. (NCT00734474)
Timeframe: Baseline through 26 and 104 weeks

Participant-reported Outcomes, EQ-5D

The EQ-5D questionnaire is a generic, multidimensional, health-related, quality-of-life instrument. It consists of 2 parts. The first part allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a three level scale of 1-3 (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). The second part of the questionnaire consists of a 100-millimeter visual analog scale (VAS) on which the participants rated their perceived health state on that day from 0 (worst imaginable health state) to 100 (best imaginable health state). (NCT00734474)
Timeframe: Baseline, 52 weeks, and 104 weeks

Participant-reported Outcomes, Impact of Weight on Quality of Life-Lite (IWQoL-Lite)

"The Impact of Weight on Quality of Life-Lite (IWQoL-Lite questionnaire) is an obesity-specific, 31-item questionnaire designed to measure the impact of weight on participants' quality of life. Items are scored on a 5-point numeric rating scale where 5 = always true and 1 = never true. Items are summed into 6 scales (physical function [11 items], self-esteem [7 items], sexual life [4 items], public distress [5 items], work [4 items], and total score [31 items]) based on the average for the valid responses on that scale multiplied by the number of items on that scale (rounded to the nearest whole integer). Higher scores indicate lower levels of functioning (negative effects). Scores are linearly transformed to a 0 to 100 scale." (NCT00734474)
Timeframe: Baseline, 52 weeks, and 104 weeks

Percentage of Participants Who Achieve Glycosylated Hemoglobin (HbA1c) <7% or ≤6.5%

The percentage of participants achieving HbA1c levels <7.0% and ≤6.5% was analyzed using a logistic regression model and last observation carried forward (LOCF) imputation with baseline, country, and treatment as factors included in the model. (NCT00734474)
Timeframe: Baseline, 26, 52, and 104 weeks

Rate of Hypoglycemic Episodes

Hypoglycemic episodes (HE) were classified as severe (defined as episodes requiring assistance from another person to actively administer resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia and has a plasma glucose level of ≤3.9 millimoles per liter [mmol/L]), asymptomatic (defined as episodes not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of ≤3.9 mmol/L), nocturnal (defined as any episode that occurred between bedtime and waking), or probable symptomatic (defined as episodes during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The 1-year adjusted rate of HE is summarized cumulatively. (NCT00734474)
Timeframe: Baseline through 26 and 104 weeks

Resource Utilization

The number of visits to the emergency room (ER) is summarized cumulatively. (NCT00734474)
Timeframe: Baseline through 52 and 104 weeks

Waist Circumference Change From Baseline

Least squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. (NCT00734474)
Timeframe: Baseline, 26, 52, and 104 weeks

Change in Percent of Blood Glucose (BG) Within Target

Percent of BG between 70 and 180 mg/dL, as measured using Continuous Glucose Monitor (CGM) (NCT03199638)
Timeframe: baseline vs. at 3 months

Change in the Mean Amplitude of Glycemic Excursions (MAGE)

MAGE describes the average amplitude of glycemic variations measured using continuous glucose monitoring (CGM) (NCT03199638)
Timeframe: before vs. at 3 months

HbA1c, Glycated Hemoglobin

Insulin Dose

Change in insulin dose (Units/kg/day) used at home (NCT03199638)
Timeframe: baseline vs. at 3 months

Insulin Sensitivity Score (ISS)

Change in insulin sensitivity score, determined using SEARCH ISS model published equation: logeIS = 4.64725 - 0.02032 × (waist, cm) - 0.09779 × (HbA1c, %) - 0.00235 × (Triglycerides, mg/dL). The range of ISS scores is between 1-15. Higher scores imply a better insulin sensistivity. (NCT03199638)
Timeframe: baseline vs. at 3 months

Percent Blood Glucose (BG) >180

Change in Percent of BG above 180 mg, as determined using Continuous Glucose Monitor (CGM) (NCT03199638)
Timeframe: baseline vs. at 3 months

Percent of BG <70 mg/dL

Change in Percent of BG below 70 mg/dL, as determined by Continuous Glucose Monitor (CGM) (NCT03199638)
Timeframe: baseline vs. at 3 months

Change in Body Weight From Baseline to Week 30.

Change in body weight from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects. (NCT00960661)
Timeframe: baseline, week 30

Change in Diastolic Blood Pressure (DBP) From Baseline to Week 30

Change in Diastolic Blood Pressure (DBP) from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects. (NCT00960661)
Timeframe: baseline, Week 30

Change in Fasting Blood Glucose (FBG) From Baseline to Week 30.

Change in fasting blood glucose (FBG) from Baseline to Week 30 using MMRM model. The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects. (NCT00960661)
Timeframe: Baseline, Week 30

Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 30

Change in HbA1c from baseline following 30 weeks of therapy (i.e. HbA1c at week 30 minus HbA1c at baseline). (NCT00960661)
Timeframe: Baseline, 30 weeks

Change in High Density Lipoprotein (HDL) From Baseline to Week 30

Change in High Density Lipoprotein (HDL) from baseline to Week 30 using ANCOVA model.The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate. (NCT00960661)
Timeframe: Baseline, week 30

Change in Low Density Lipoprotein (LDL) From Baseline to Week 30

Change in Low Density Lipoprotein (LDL) from baseline to week 30 using ANCOVA model.The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate. (NCT00960661)
Timeframe: Baseline, Week 30

Change in Systolic Blood Pressure (SBP) From Baseline to Week 30

Change in Systolic Blood Pressure (SBP) from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects. (NCT00960661)
Timeframe: Baseline, Week 30

Change in Total Cholesterol From Baseline to Week 30

Change in total cholesterol from baseline to Week 30 using ANCOVA model. The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate. (NCT00960661)
Timeframe: Baseline, week 30

Major Hypoglycemia Rate Per Year

Mean (standard deviation) of major hyperglycemia episodes experienced per year. Rates per year were calculated for each individual as the number of episodes divided by the total number of days in the study (from randomization to last visit date), then multiplied by 365.25. Major hypoglycemia was defined as any symptoms consistent with hypoglycemia resulting in loss of consciousness or seizure that shows prompt recovery in response to administration of glucagon or glucose OR documented hypoglycemia (blood glucose <3.0 mmol/L [54 mg/dL]) and requiring the assistance of another person because of severe impairment in consciousness or behavior. (NCT00960661)
Timeframe: 30 weeks

Minor Hypoglycemia Rate Per Year

Mean (standard deviation) of minor hyperglycemia episodes experienced per year. Rates per year were calculated for each individual as the number of episodes divided by the total number of days in the study (from randomization to last visit date), then multiplied by 365.25. Minor hypoglycemia was defined as any time a participant feels that he or she is experiencing a sign or symptom associated with hypoglycemia that is either self-treated by the participant or resolves on its own AND has a concurrent finger stick blood glucose <3.0 mmol/L (54 mg/dL) (NCT00960661)
Timeframe: 30 weeks

Percent of Participants Achieving HbA1c ≤ 6.5%.

Percent of participants achieving HbA1c ≤ 6.5%. (NCT00960661)
Timeframe: Week 30

Percentage of Participants Achieving HbA1C < 7.0%

Percentage of participants achieving HbA1C < 7.0% (NCT00960661)
Timeframe: Week 30

Daily Insulin Glargine Dose at Baseline and at Week 30

Daily Insulin Glargine Dose at baseline and at Week 30 (NCT00960661)
Timeframe: Baseline, week 30

Change in A1c at the End of Study Period

change in A1c (%) from baseline to end of study at 16 weeks (NCT02846233)
Timeframe: 16 weeks (from baseline to end of study at 16 weeks)

Changes in Blood Pressure

change (mmHg) of systolic BP from baseline to the end of study at 16 weeks (NCT02846233)
Timeframe: 16 weeks (from baseline to end of study at 16 weeks)

Changes in Heart Rate

change (beats/min) from baseline to the end of study at 16 weeks (NCT02846233)
Timeframe: 16 weeks

Changes in LDL

change (mg/dL) from baseline to the end of study at 16 weeks (NCT02846233)
Timeframe: 16 weeks (from baseline to end of study at 16 weeks)

Changes in Serum Creatinine

change (mg/dL) from baseline to the end of study at 16 weeks (NCT02846233)
Timeframe: 16 weeks (from baseline to end of study at 16 weeks)

Changes in Total Cholesterol

change (mg/dL) from baseline to the end of study at 16 weeks (NCT02846233)
Timeframe: 16 weeks (from baseline to end of study at 16 weeks)

Changes in Treatment Satisfaction Scores (DM-SAT Total Score)

"Patient satisfaction with treatment in both groups will be measured by the validated the Diabetes Medications Satisfaction Tool (DM-SAT). Response options range from 0=not at all satisfied to 10=extremely satisfied and a total score is calculated ranging from 0 to 100, with higher scores indicating more diabetes medication satisfaction." (NCT02846233)
Timeframe: 16 weeks (from baseline to end of study at 16 weeks)

Changes in Weight

change (in pounds) from baseline to the end of study at 16 weeks (NCT02846233)
Timeframe: 16 weeks (from baseline to end of study at 16 weeks)

Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 1

To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 1 week of double-blind treatment. (NCT01217892)
Timeframe: Baseline to Week 1

Adjusted Mean Change in Fasting Plasma Glucose (FPG) From Baseline to Week 16

To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. (NCT01217892)
Timeframe: Baseline to Week 16

Adjusted Mean Change in HbA1c Levels

To compare the change from baseline in HbA1c achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. (NCT01217892)
Timeframe: Baseline to Week 16

Adjusted Percent Change in Body Weight

To compare the percent change from baseline in body weight achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID, and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment. (NCT01217892)
Timeframe: Baseline to Week 16

Proportion of Participants With HbA1c<7.0% at Week 16, in Participants Who Had HbA1c ≥7.0% at Baseline.

To compare the adjusted proportions controlling for baseline HbA1c [acc. to Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu] of participants with HbA1c <7.0% achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment, in patients who had HbA1c ≥7.0% at baseline. (NCT01217892)
Timeframe: Baseline to Week 16

the Relative Increase in Meal-induced Total GLP-1 Secretion

Patients will be followed for 12 weeks with three meal test examinations; before treatment, after 1 week of treatment and after 12 weeks of treatment. Primary outcome is AUC GLP-1 (pM x 120 as stated). (NCT00411411)
Timeframe: 12 weeks

Restoration of the Insulinotropic Effect of GIP

Restoration of the insulinotropic effect of GIP measured as the relative increase in GIP induced amplification of the late phase insulin secretion (AUC) response to glucose. Patients will be followed for 12 weeks with examinations after 1 and after 12 weeks of treatment. (NCT00411411)
Timeframe: 12 weeks

AUC4-12wk of Change in Fasting Plasma Glucose (mg/dL*Week) Concentrations From Baseline to 12 Weeks

(NCT01819272)
Timeframe: Baseline and 4 to 12 weeks after the first dose of study medication

Change in Fasting Plasma Glucose (mg/dL) at 4 Weeks

(NCT01819272)
Timeframe: Baseline and 4 weeks after the first dose of study medication

Change in HbA1c (%) at 12 Weeks

(NCT01819272)
Timeframe: Baseline and 12 weeks after the first dose of study medication

AUC (0-24) of Plasma Metformin

AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. (NCT01804842)
Timeframe: Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

Cmax of Plasma Metformin

Cmax = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. (NCT01804842)
Timeframe: Times points to determine Cmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

AUC (0-24) of Plasma Glucose

AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. (NCT01804842)
Timeframe: Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the time of the standardized dinner.

Rmax (0-24) of Plasma Glucose

Rmax (0-24) = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. (NCT01804842)
Timeframe: Times points to determine Rmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

AUC (0-t) of Plasma Metformin

AUC (0-t) = Area under the curve from the time of dosing (0 h) to the time of the last quantifiable concentration after the standardized dinner. Doses were administered 1 min prior to 0 h (standardized dinner) for once daily in the evening (qPM) and twice daily (BID) dosing and 1 min prior to 12 h (standardized breakfast) for once daily in the morning (qAM) and BID dosing. (NCT02291510)
Timeframe: Time points to create AUC (0-t) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

Cmax of Plasma Metformin

Cmax = Maximum concentration from the first dose of study medication administration (0 h) to the time of the last quantifiable concentration following dose administration. Doses were administered 1 min prior to 0 h (standardized dinner) for qPM and BID dosing and 1 min prior to 12 h (standardized breakfast) for qAM and BID dosing. (NCT02291510)
Timeframe: Time points to create Cmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

Change in Mitochondrial Oxygen Consumption Compared to Baseline After Each Dose of Nitrite

Basal platelet oxygen consumption measured in isolated platelets by extracellular flux analysis (XF24, Seahorse Biosciences, Billerica, MA). (NCT01431313)
Timeframe: Maximal effect at 15 minutes post 45mg or 90mg inhalation vs Pre dose

Change in Plasma Nitrite Concentrations in Mixed Venous Blood

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of plasma nitrite concentrations in mixed venous blood over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. (NCT01431313)
Timeframe: Pre-dose, 15 minutes post 45mg and 90mg inhalation

Change in Pulmonary Artery Occlusion (Capillary) Pullback Nitrite

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of pulmonary artery occlusion (capillary) pullback nitrite concentration over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. (NCT01431313)
Timeframe: Pre-dose, 15 minutes post 45mg and 90mg inhalation

Change in Pulmonary Vascular Impedance / Wave Intensity

Characteristic impedance (Zc) which may be related to compliance effects in the large, conduit arteries. (NCT01431313)
Timeframe: Pre dose and 60 minutes post last dosage inhaled

Change in Pulmonary Vascular Resistance (PVR)

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since pulmonary vascular resistance (PVR) was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of PVR over all subsequent times and doses (beta from the mixed effects model, converted back from natural log to Woods units), and is reported as the mean and 95% confidence interval. (NCT01431313)
Timeframe: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

Change in Systemic Blood Pressure (Mean Arterial Pressure, MAP)

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of MAP over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. (NCT01431313)
Timeframe: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

Change in Systemic Vascular Resistance (SVR)

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since systemic vascular resistance was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of SVR over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval. (NCT01431313)
Timeframe: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

Time to Maximum Pulmonary Vascular Resistance (PVR) Decrease

Time in minutes to maximum PVR decrease. During study procedure, hemodynamics were measured at 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose. The time point at which each patient's maximal decrease in PVR occurred was recorded and reported as the mean and standard deviation in each cohort. (NCT01431313)
Timeframe: 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose

Length of Remission

For those patients that are able to discontinue insulin therapy at or <12 weeks, how long were they able to well controlled with an A1c <7% on the agent that they were randomized to. (NCT01099618)
Timeframe: 3 years

Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks of Treatment

The change from baseline is the FPG after 24 weeks minus the baseline FPG. Means are adjusted for treatment, continuous baseline HbA1c and continuous baseline fasting plasma glucose. (NCT01512979)
Timeframe: Baseline and 24 weeks

Change From Baseline in HbA1c After 24 Weeks

HbA1c is measured as a percentage. The change from baseline is the Week 24 HbA1c minus the baseline HbA1c. Means are adjusted for treatment and continuous baseline HbA1c (NCT01512979)
Timeframe: Baseline and 24 weeks

Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 0.5% After 24 Weeks of Treatment)

The proportion of patients who achieved HbA1c lowering by at least 0.5% after 24 weeks of treatment.The model includes treatment, and continuous baseline HbA1c. (NCT01512979)
Timeframe: Baseline and 24 weeks

Occurrence of Relative Efficacy Response (HbA1c Lowering by at Least 1.0% After 24 Weeks of Treatment)

The proportion of patients who achieved HbA1c lowering by at least 1.0% after 24 weeks of treatment. The model includes treatment, and continuous baseline HbA1c. (NCT01512979)
Timeframe: Baseline and 24 weeks

Occurrence of Treat to Target Efficacy Response (HbA1c <7.0%) After 24 Weeks of Treatment

The proportion of patients who achieved HbA1c below 7.0% after 24 weeks of treatment. The model includes treatment, and continuous baseline HbA1c. (NCT01512979)
Timeframe: Baseline and 24 weeks

Change From Baseline in FPG by Visit Over Time

The change from baseline is the FPG over time minus the baseline FPG. Means are adjusted for treatment, continuous baseline HbA1c, continuous baseline FPG in addition to week repeated within patient, week by baseline FPG interaction and week by treatment interaction. (NCT01512979)
Timeframe: Baseline, 6, 12, 18 and 24 weeks

Change From Baseline in HbA1c by Visit Over Time

HbA1c is measured as a percentage. The change from baseline is the HbA1c over time minus the baseline HbA1c. The model includes treatment, continuous baseline HbA1c in addition to week repeated within patient, week by baseline HbA1c interaction and week by treatment interaction. (NCT01512979)
Timeframe: Baseline, 6, 12, 18 and 24 weeks

Change From Baseline to Week 52 in Fasting Plasma Glucose (FPG)

Measured as the difference between the last on-treatment value (defined as obtained before or on the first day after the last dosing date)and the last pre-randomisation fasting plasma glucose value, as determined by central laboratory. Full analysis set. (NCT01006603)
Timeframe: From week 0 to week 52

Change From Baseline to Week 52 in HbA1c.

Measured as the difference between the last on-treatment value (defined as obtained before or on the 8th day after the last dosing date), and the last pre-randomisation HbA1c value, as determined by central laboratory. Full analysis set. (NCT01006603)
Timeframe: From week 0 to week 52.

Change From Baseline to Week 52 in Insulin

Measured as the difference between the last on-treatment value (defined as obtained before or on the first day after the last dosing date) and the last pre-randomisation fasting plasma insulin value, as determined by central laboratory. Full analysis set. (NCT01006603)
Timeframe: From week 0 to week 52

Change From Baseline to Week 52 in β-cell Function (as Measured by Homeostasis Model Assessment-β [HOMA-β]

β-cell function as estimated by the homeostasis model assessment (HOMA) model. Value is derived from FPG and fasting insulin; fasting insulin values below 2.074 μU/mL or above 57.595 μU/mL and FPG values below 3 mmol/L or above 25 mmol/L are excluded (as restricted by the calculation method used). Full analysis set. (NCT01006603)
Timeframe: From week 0 to week 52

Proportion of Patients Achieving a Therapeutic Glycaemic Response at Week 52 Defined as HbA1c <7.0%

Proportion of patients with their last on-treatment value (defined as obtained before or on the 8th day after the last dosing date), as determined by central laboratory, below the specified limits. Full analysis set. (NCT01006603)
Timeframe: From week 0 to week 52

Proportion of Patients Having Experienced at Least One Hypoglycaemic Event (Confirmed or Severe) Over the 52-week Double-blind Treatment Period.

"Hypoglyceamic event defined as, Confirmed hypoglycaemia: any event defined as either a symptomatic event with blood glucose level <3 mmol/L (<54 mg/dL) and no need for external assistance, or an asymptomatic blood glucose measurement <3 mmol/L (<54 mg/dL).~Major (or severe) hypoglycaemia: symptomatic events requiring external assistance due to severe impairment in consciousness or behaviour, with or without blood glucose level <3 mmol/L (<54 mg/dL), but with prompt recovery after glucose or glucagon administration. These events may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery, attributable to the restoration of plasma glucose to normal, was considered sufficient evidence that the event was induced by a low plasma glucose concentration. Safety analysis set." (NCT01006603)
Timeframe: From week 0 to week 52.

Proportion of Patients Reaching HbA1c <7% After 52 Weeks of Treatment Without Confirmed or Severe Hypoglycaemia.

"Defined as obtained on or before the 8th day after the last dosing day, as determined by central laboratory. Safety analysis set.~Confirmed hypoglycaemia defined as: any event defined as either a symptomatic event with blood glucose level <3 mmol/L (<54 mg/dL) and no need for external assistance, or an asymptomatic blood glucose measurement <3 mmol/L (<54 mg/dL).~Major (or severe) hypoglycaemia defined as: symptomatic events requiring external assistance due to severe impairment in consciousness or behaviour, with or without blood glucose level <3 mmol/L (<54 mg/dL), but with prompt recovery after glucose or glucagon administration. These events may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery, attributable to the restoration of plasma glucose to normal, was considered sufficient evidence that the event was induced by a low plasma glucose concentration." (NCT01006603)
Timeframe: From week 0 to week 52.

Change in 2-hour Postprandial Glucose Concentrations From Baseline to Week 16 (Visit 8)

The change in 2-hour postprandial plasma glucose from baseline (Day 1) to Visit 8 (Week 16) was analyzed using a general linear model including treatment, and baseline HbA1c stratum (< 9% or ≥ 9%) as fixed factors, and the baseline 2-hour postprandial plasma glucose concentrations as a covariate. (NCT01652729)
Timeframe: Baseline to Week 16

Change in Body Weight (kg) From Baseline to Week 28

The change in body weight (kg) from baseline (Day 1) to Week 28/Study Termination. (NCT01652729)
Timeframe: Baseline to Week 28

Change in Fasting Plasma Glucose Concentrations From Baseline to Week 28

The change in fasting plasma glucose concentrations from baseline (Day 1) to Week 28/Study Termination. (NCT01652729)
Timeframe: Baseline to Week 28

Change in HbA1c (Glycosylated Hemoglobin) From Baseline to Week 28

Absolute change in HbA1c from baseline (Day 1, Visit 3) to Week 28/Study Termination (Visit 11). Hypothesis testing on the primary endpoint followed a serial gated procedure with all tests carried out at a 2-sided significance level of 0.05 to protect the family-wise error rate. These tests were conducted sequentially, and are presented in the statistical analysis section below in the order in which they were performed; each test was the gatekeeper of later tests. (NCT01652729)
Timeframe: Baseline to Week 28

Percentage of Subjects Achieving HbA1c <7% at Week 28

Percentage of subjects achieving HbA1c target values of < 7.0% at Week 28/Study Termination. (NCT01652729)
Timeframe: Baseline to Week 28

Development of Diabetes.

Primary outcome for years 2002-2008 defined according to American Diabetes Association criteria (fasting plasma glucose level >= 126 mg/dL [7.0 mmol/L] or 2-hour plasma glucose >= 200 mg/dL [11.1 mmol/L], after a 75 gram oral glucose tolerance test (OGTT), and confirmed with a repeat test). (NCT00038727)
Timeframe: Outcomes were assessed from 1996-2008 (approximately 12 years including 6 years of DPP).

Mortality

All cause-mortality through clinic reports and National Death Index search (NCT00038727)
Timeframe: Outcomes were assessed throughout follow-up from 1996 to 2022. National Death Index search conducted in 2019 using early release data as of Dec 2018.

Prevalence of Aggregate Microvascular Complication

Aggregate microvascular disease is defined as the average prevalence of 3 components: (1) retinopathy measured by photography (ETDRS of 20 or greater); (2) neuropathy detected by Semmes Weinstein 10 gram monofilament, and (3) nephropathy based on estimated glomerular filtration rate (eGFR by chronic kidney disease (CKD-Epi) equation ) (<45 ml/min, confirmed) and albumin-to-creatinine ratio in spot urine (> 30mg/gm, confirmed). (NCT00038727)
Timeframe: Outcomes were assessed from 2012-2013 (approximately 2 years).

Subclinical Atherosclerosis

Measured using coronary artery calcification (CAC). (NCT00038727)
Timeframe: Outcomes were assessed from 2012-2013 (approximately 2 years).

Hypoglycemia Rate Per 30 Days Per Patient

Average number of episodes of hypoglycemia per 30 days per patient (NCT00135330)
Timeframe: 20 weeks

Incidence of Hypoglycemia Events

Number of subjects experiencing hypoglycemia at any point during the study (NCT00135330)
Timeframe: 20 weeks

Change in ASIiAUC During a Hyperglycemic Clamp Test.

Change in insulin incremental area under the concentration-time curve (ASIiAUC) from baseline to week 20. ASIiAUC is a measure of beta-cell function. (NCT00135330)
Timeframe: 20 weeks

Change in AUC for C-peptide During a Meal Challenge Test (MCT).

Ratio (value at endpoint divided by value at baseline) of AUC(15-180 min) for C-peptide (nmol-min/L) during a MCT from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in AUC for Glucose During a Meal Challenge Test (MCT).

Change in AUC(15-180 min) for glucose during a MCT baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Body Fat Mass During a Meal Challenge Test (MCT)

Change in body fat mass form baseline to week 20, as assessed during an MCT (NCT00135330)
Timeframe: 20 weeks

Change in Body Weight

Change in body weight from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Fasting HDL Cholesterol

Change in fasting high-density lipoprotein (HDL) cholesterol from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Fasting Insulin

Change in fasting insulin from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Fasting LDL Cholesterol

Change in fasting low-density lipoprotein (LDL) cholesterol from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Fasting Proinsulin

Ratio (endpoint value divided by baseline value) for fasting proinsulin, comparing endpoint (week 20) to baseline (NCT00135330)
Timeframe: Week 20

Change in Fasting Serum Glucose Concentration.

Change in fasting serum glucose concentration from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Fasting Total Cholesterol.

Change in fasting total cholestrol from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Fasting Triglycerides

Ratio (endpint value divided by baseline value) of fasting triglycerides from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in HbA1c

Change in Hip Circumference

Change in hip circumference form baseline to week 20 (NCT00135330)
Timeframe: 20 weeks

Change in Incremental for Postprandial C-peptide During Meal Challenge Test (MCT).

Change in incremental for postprandial C-peptide (mmol/L) during MCT from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Incremental for Postprandial Glucose During a Meal Challenge Test (MCT).

Change in incremental for postprandial glucose (mmol/L) during a MCT from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Incremental for Postprandial Insulin During Meal Challenge Test (MCT).

Change in incremental for postprandial insulin (mmol/L) during meal challenge test (MCT) from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Insulin AUC in the First Stage From Baseline to Endpoint.

"Change in insulin AUC in the first stage(uIU-min/ml) from baseline to week 20. First stage represents the first 10 minutes after reaching a steady state during a hyperglycemic clamp test." (NCT00135330)
Timeframe: Week 20

Change in Insulin iAUC From Baseline to Endpoint.

"Change in insulin iAUC in the first stage(uIU-min/ml) from baseline to week 20. First stage represents the first 10 minutes after reaching a steady state during a hyperglycemic clamp test." (NCT00135330)
Timeframe: Week 20

Change in Insulin Sensitivity Index as Measured by M-value.

Change of M-Value (mg/kg-min) during hyperinsulinemic euglycemic clamp test from baseline to week 20. (NCT00135330)
Timeframe: Week 20

Change in Lean Body Mass During a Meal Challenge Test (MCT)

Change in lean body mass from baseline to week 20, as assessed during an MCT (NCT00135330)
Timeframe: 20 weeks

Change in Percent Body Fat During a Meal Challenge Test (MCT)

Change in percent body fat from baseline to week 20, as assessed during an MCT (NCT00135330)
Timeframe: 20 weeks

Change in Waist Circumference

Change in waist circumference from baseline to week 20 (NCT00135330)
Timeframe: 20 weeks

Change in Waist-to-hip Ratio

Change in waist-to-hip ratio (waist circumference divided by hip circumference) from baseline to week 20 (NCT00135330)
Timeframe: 20 weeks

Pedal Edema Score

"Pedal edema scores experienced by each patient throughout the study (1+ indicates a patient experienced a pedal edema score of 1 , 2, or 3; 2+ indicates a patient experienced a pedal edema score of 2 or 3, etc.)~Scale:~Slight pitting, no visible distortion, disappears rapidly~A somewhat deeper pit than in 1+, but again no readily detectable distortion, and it disappears in 10 - 15 seconds~The pit is noticeably deep and may last more than a minute; the dependent extremity looks fuller and swollen~The pit is very deep, lasts as long as 2 - 5 minutes, and the dependent extremity is grossly distorted" (NCT00135330)
Timeframe: 20 weeks

Ratio (Value at Endpoint Divided by Value at Baseline) of AUC for Insulin During a Meal Challenge Test (MCT).

Ratio (value at endpoint divided by value at baseline) of AUC (15-180 min) for insulin (uIU-min/ml) during MCT. (NCT00135330)
Timeframe: Week 20

Change From Baseline in Adiponectin.

The change between Adiponectin collected at week 24 or final visit and Adiponectin collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Diastolic Blood Pressure.

The change between Diastolic Blood Pressure measured at week 24 or final visit and Diastolic Blood Pressure measured at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in E-Selectin.

The change between the value of E-Selectin collected at week 24 or final visit and E-Selectin collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Erythrocyte Deformability (0.30%).

The change between the 0.30 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Erythrocyte Deformability (0.60%)

The change between the 0.60 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Erythrocyte Deformability (1.20).

The change between the 1.20 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Erythrocyte Deformability (12.00).

The change between the 12.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Erythrocyte Deformability (3.00).

The change between the 3.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Erythrocyte Deformability (30.00).

The change between the 30.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Erythrocyte Deformability (6.00).

The change between the 6.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Erythrocyte Deformability (60.00).

The change between the 60.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Fasting Glucose.

The change between Fasting Glucose collected at week 24 or final visit and Fasting Glucose collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Fasting Intact Proinsulin.

The change between Fasting Intact Proinsulin collected at week 24 or final visit and Fasting Intact Proinsulin collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Glycosylated Hemoglobin.

The change between the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 24 or final visit and Glycosylated Hemoglobin collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in High Sensitivity C-reactive Protein (≤ 10 mg/L).

The change between the value of High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at week 24 or final visit and High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in High Sensitivity C-reactive Protein (Original).

The change between the value of High Sensitivity C-reactive Protein collected at week 24 or final visit and High Sensitivity C-reactive Protein collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in High-Density Lipoprotein Cholesterol.

The change between HDL-Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in High-Density Lipoprotein/Low-Density Lipoprotein Ratio.

The change between High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at week 24 or final visit and High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Low-Density Lipoprotein Cholesterol.

The change between Low-Density Lipoprotein Cholesterol collected at week 24 or final visit and Low-Density Lipoprotein Cholesterol collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Low-Density Lipoprotein Subfractions.

The change between the value of Low-Density Lipoprotein Subfractions collected at week 24 or final visit and Low-Density Lipoprotein Subfractions collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Matrix Metallo Proteinase-9.

The change between the value of Baseline in Matrix Metallo Proteinase-9 collected at week 24 or final visit and Baseline in Matrix Metallo Proteinase-9 collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Nitrotyrosine.

The change between the value of Nitrotyrosine collected at week 24 or final visit and Nitrotyrosine collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Platelet Function.

The change between the value of Platelet Function by PFA 100 collected at week 24 or final visit and Platelet Function by PFA 100 collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Soluble CD40 Ligand.

The change between the value of Soluble CD40 Ligand collected at week 24 or final visit and Soluble CD40 Ligand collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Soluble Intracellular Adhesion Molecule.

The change between the value of Baseline in Soluble Intracellular Adhesion molecule at week 24 or final visit and Baseline in Soluble Intracellular Adhesion molecule collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Soluble Vascular Cell Adhesion Molecule.

The change between the value of Soluble Vascular Cell Adhesion Molecule collected at week 24 or final visit and Soluble Vascular Cell Adhesion Molecule collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Systolic Blood Pressure.

The change between Systolic Blood Pressure measured at week 24 or final visit and Systolic Blood Pressure measured at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Thromboxane B2.

The change between the value of Thromboxane B2 collected at week 24 or final visit and Thromboxane B2 collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Triglycerides.

The change between the value of Triglycerides collected at week 24 or final visit and Triglycerides collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Change From Baseline in Von-Willebrand Factor.

The change between the value of Von-Willebrand Factor collected at week 24 or final visit and Von-Willebrand Factor collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

Intake of Study Medication Greater Than 80% and Less Than 120%.

The change between the Intake of study medication greater than 80% at week 24 or final visit and Baseline and the Intake of study medication greater than 80% at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

The Mean Increase From Baseline in High-Density Lipoprotein Cholesterol.

The increase in High-Density Lipoprotein (HDL) Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline. (NCT00770653)
Timeframe: Baseline and Week 24.

1-Year Overall Survival Rate

The overall survival rate defined as percentage of participants in each treatment group who are still alive at 12 months. (NCT00500240)
Timeframe: 1 year

Overall Survival

Overall survival (OS) defined as the interval between the date of randomization and the date of death. Calculation of period was from baseline (date of randomization) to the death or last follow-up. (NCT00500240)
Timeframe: Baseline (date of randomization) to date of death or last follow-up (weekly during treatment then every 2 months post study treatment) up to 6 years

Progression Free Survival (PFS)

PFS was defined as the time interval between the date of complete remission and the date of relapse detection or death. Complete Remission (CR) defined as granulocyte count >1.0 × 10^9/L, platelet count >100 × 10^9/L, no abnormal peripheral blasts, and <5% blasts in normocellular or hypercellular bone marrow. (NCT00500240)
Timeframe: Date of complete remission to disease progression, assessed for approximately 6 years

Change From Baseline in Area Under the Plasma Glucose Concentration Curve From Time 0.5 Hours to 4.5 Hours (GLU-AUC0:30-4:30h) at Day 28

The area under the plasma glucose concentration time curve (GLU-AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast plasma glucose concentration (time: 0.5 hours). GLU-AUC0:30-4:30h on Day -1 was the baseline. Change in GLU-AUC0:30-4:30h = GLU-AUC0:30-4:30h on Day 28 minus GLU-AUC0:30-4:30h on Day -1. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 0.75, 1, 1.5, 2, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 0.75, 1, 1.5, 2, 2.5, 3.5, 4.5 hours post study drug administration on Day 28

Change From Baseline in C-Peptide AUC(0:30-4:30h) at Day 28

The area under the C-peptide concentration time curve (AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast C-peptide concentration (time: 0.5 hours). C-peptide AUC0:30-4:30h on Day -1 was the baseline. Change in C-peptide AUC0:30-4:30h = C-peptide AUC0:30-4:30h on Day 28 minus C-peptide AUC0:30-4:30h on Day -1. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours post study drug administration on Day 28

Change From Baseline in Glucagon AUC(0:30-4:30h) at Day 28

The area under the glucagon concentration time curve (AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast glucagon concentration (time: 0.5 hours). Glucagon AUC0:30-4:30h on Day -1 was the baseline. Change in glucagon AUC0:30-4:30h = glucagon AUC0:30-4:30h on Day 28 minus glucagon AUC0:30-4:30h on Day -1. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours post study drug administration on Day 28

Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Day 29

Change = HbA1c value at Day 29 (24 hours post-dose on Day 28) minus HbA1c value at baseline (pre-dose [Hour 0] on Day 1). (NCT01175473)
Timeframe: Pre-dose (Hour 0) on Day 1 and 29 (that is, 24 hours post-dose on Day 28)

Change From Baseline in Insulin AUC(0:30-4:30h) at Day 28

The area under the insulin concentration time curve (AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast insulin concentration (time: 0.5 hours). Insulin AUC0:30-4:30h on Day -1 was the baseline. Change in insulin AUC0:30-4:30h = insulin AUC0:30-4:30h on Day 28 minus insulin AUC0:30-4:30h on Day -1. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours post study drug administration on Day 28

Change From Baseline in Postprandial Plasma Glucose (PPG) Excursion at Day 28

PPG excursion was determined on Day -1 (Baseline) and 28 as the maximum change in PPG from time of breakfast start (time: 0.5 hours) until 4 hours later subtracted from pre-meal plasma concentration. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 0.75, 1, 1.5, 2, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 0.75, 1, 1.5, 2, 2.5, 3.5, 4.5 hours post study drug administration on Day 28

Change From Baseline in Pro-insulin AUC(0:30-4:30h) at Day 28

The area under the pro-insulin concentration time curve (AUC0:30-4:30h) was calculated using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours] on Day 28) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast pro-insulin concentration (time: 0.5 hours). Pro-insulin AUC0:30-4:30h on Day -1 was the baseline. Change in pro-insulin AUC0:30-4:30h = pro-insulin AUC0:30-4:30h on Day 28 minus pro-insulin AUC0:30-4:30h on Day -1. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 1, 1.5, 2.5, 3.5, 4.5 hours post study drug administration on Day 28

Change From Time-matched Baseline in Obestatin Concentration at Day 28

Change was calculated by subtracting time-matched baseline value from Day 28 value. Baseline value was the Day -1 time-matched obestatin assessment. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 2.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 2.5, 4.5 hours post study drug administration on Day 28

Change From Time-matched Baseline in Peptide YY3-36 (PYY3-36) Concentration at Day 28

Change was calculated by subtracting time-matched baseline value from Day 28 value. Baseline value was the Day -1 time-matched PYY-36 assessment. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 2.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 2.5, 4.5 hours post study drug administration on Day 28

Percentages of Patients by Ranges of Oxyntomodulin Levels

Percentage of patients with oxyntomodulin level less than or equal to (<=) limit of detection (LOD), above limit of quantification (LOQ) and between LOD and LOQ were reported. The LOD and LOQ values for oxyntomodulin were 70 and 200 picogram per milliliter (pg/mL) respectively. (NCT01175473)
Timeframe: 0.5 (8:00 clock time; prior to standardized breakfast), 2.5, 4.5 hours on Day -1 (baseline), 0.5 (prior to standardized breakfast), 2.5, 4.5 hours post study drug administration on Day 28

Comparison of Changes in Fasting Serum Glucose (FSG)With Pioglitazone and Metformin

Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin. (NCT01589445)
Timeframe: 3 months for each drug

Comparison of Changes in Fasting Serum Insulin (FSI)With Pioglitazone and Metformin

Comparison of Changes in Glycosylated Hemoglobin (HbA1c)With Pioglitazone and Metformin

Comparison of Changes in HOMA Percent B and HOMA Percent S With Pioglitazone and Metformin

"Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.~Analysis 1: Homeostatic Model Assessment of Beta cell function(HOMA percent B) Analysis 2: Homeostatic Model Assessment of Insulin Sensitivity (Homa percent S)" (NCT01589445)
Timeframe: 3 months for each drug

Comparison of Changes in Insulin Levels (HOMA IR,QUICKI) With Pioglitazone and Metformin

"Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.~Analysis 1: Homeostasis Model Assessment Insulin Resistance(HOMA IR) Analysis 2: Quantitative Insulin sensitivity Check Index(QUICKI)" (NCT01589445)
Timeframe: 3 months for each drug

Comparison of Changes in Lipid Profiles With Pioglitazone and Metformin

"Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.~Analysis 1:Total Cholesterol(TC) Analysis 2:Triglyceride(TG) Analysis 3:High Density Lipoprotein(HDL) Analysis 4:Low Density Lipoprotein(LDL)" (NCT01589445)
Timeframe: 3 months for each drug

Intervention	Kg/m^2 (Mean)
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	-0.8
DAPA (Dapagliflozin Plus Placebo)	-0.66
PCB (Placebo Plus Placebo)	0.16

Intervention	Kg (Mean)
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	-2.28
DAPA (Dapagliflozin Plus Placebo)	-1.76
PCB (Placebo Plus Placebo)	0.26

Intervention	mg/dl (Mean)
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	-28.52
DAPA (Dapagliflozin Plus Placebo)	26.89
PCB (Placebo Plus Placebo)	6.88

Intervention	mEq/L (Mean)
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	-0.06
DAPA (Dapagliflozin Plus Placebo)	-0.01
PCB (Placebo Plus Placebo)	0.00

Intervention	percentage of oxidation (Mean)
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	-22.07
DAPA (Dapagliflozin Plus Placebo)	-46.54
PCB (Placebo Plus Placebo)	4.65

Intervention	percentage of oxidation (Mean)
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	-11.87
DAPA (Dapagliflozin Plus Placebo)	22.02
PCB (Placebo Plus Placebo)	-6.69

Intervention	percentage change in blood glucose level (Mean)
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	-1.67
DAPA (Dapagliflozin Plus Placebo)	-1.46
PCB (Placebo Plus Placebo)	0.44

Intervention	mg/dl (Mean)
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	-49.62
DAPA (Dapagliflozin Plus Placebo)	-44.24
PCB (Placebo Plus Placebo)	20.26

Intervention	mg/kg*min (Mean)
	Baseline Measurement	16 weeks
DAPA (Dapagliflozin Plus Placebo)	2.56	2.8
DAPA/SAXA (Dapagliflozin Plus Saxagliptin)	2.45	2.4
PCB (Placebo Plus Placebo)	1.95	2.15

Intervention	kilograms (kg) (Mean)
3.0 mg LY2189265	-3.32
2.0 mg LY2189265	-2.15
1.5 mg LY2189265	-2.12
1.0 mg LY2189265	-2.23
0.75 mg LY2189265	-1.17
0.5 mg LY2189265	-1.53
0.25 mg LY2189265	-0.85
Sitagliptin	-0.43
Placebo/Sitagliptin (Baseline Through 26 Weeks)	-0.56

Intervention	beats per minute (bpm) (Mean)
3.0 mg LY2189265	6.63
2.0 mg LY2189265	3.43
1.5 mg LY2189265	2.39
1.0 mg LY2189265	3.34
0.75 mg LY2189265	-1.63
0.5 mg LY2189265	1.91
0.25 mg LY2189265	1.05
Sitagliptin	-0.16
Placebo/Sitagliptin (Baseline Through 26 Weeks)	1.81

Intervention	HOMA2-% (Least Squares Mean)
	HOMA2-%B, 26 Weeks (n=206, 226, 206, 84)	HOMA2-%B, 52 Weeks (n=188, 198, 180)	HOMA2-%B, 104 Weeks (n=148, 154, 134)	HOMA2-%S, 26 Weeks (n=206, 226, 206, 84)	HOMA2-%S, 52 Weeks (n=188, 198, 180)	HOMA2-%S, 104 Weeks (n=148, 154, 134)
0.75 mg LY2189265	26.98	22.30	19.11	0.78	2.28	-0.12
1.5 mg LY2189265	32.28	33.57	30.89	5.75	4.69	3.82
Placebo/Sitagliptin (Baseline Through 26 Weeks)	1.60	NA	NA	9.82	NA	NA
Sitagliptin	10.81	6.66	1.47	2.29	4.25	5.61

Intervention	kilograms (kg) (Least Squares Mean)
	26 Weeks	52 Weeks	104 Weeks
0.75 mg LY2189265	-2.63	-2.60	-2.39
1.5 mg LY2189265	-3.18	-3.03	-2.88
Placebo/Sitagliptin (Baseline Through 26 Weeks)	-1.47	NA	NA
Sitagliptin	-1.46	-1.53	-1.75

Intervention	millimeters of mercury (mmHg) (Least Squares Mean)
	Sitting SBP, 26 Weeks (n=271, 278, 283, 138)	Sitting SBP, 104 Weeks (n=197, 192, 191)	Sitting DBP, 26 Weeks (n=271, 278, 283, 138)	Sitting DBP, 104 Weeks (n=197, 192, 191)	Standing SBP, 26 Weeks (n=271, 277, 281, 138)	Standing SBP, 104 Weeks (n=197, 192, 191)	Standing DBP, 26 Weeks (n=271, 277, 281, 138)	Standing DBP, 104 Weeks (n=197, 192, 191)
0.75 mg LY2189265	-1.40	1.28	-0.20	1.40	-1.72	0.17	0.03	0.36
1.5 mg LY2189265	-1.73	-0.07	-0.43	0.38	-1.53	-1.30	-0.11	-0.23
Placebo/Sitagliptin (Baseline Through 26 Weeks)	1.12	NA	0.68	NA	0.26	NA	-0.52	NA
Sitagliptin	-1.94	0.02	-1.06	-0.36	-2.54	-1.20	-1.36	-0.67

Intervention	millimeters of mercury (mmHg) (Mean)
	Sitting SBP	Sitting DBP
0.25 mg LY2189265	1.67	1.28
0.5 mg LY2189265	0.40	-0.75
0.75 mg LY2189265	-6.21	-3.18
1.0 mg LY2189265	-2.00	-0.08
1.5 mg LY2189265	-4.77	-1.20
2.0 mg LY2189265	-4.63	-1.17
3.0 mg LY2189265	-8.85	-1.21
Placebo/Sitagliptin (Baseline Through 26 Weeks)	-0.61	-0.22
Sitagliptin	-2.16	-1.11

Intervention	milliseconds (msec) (Least Squares Mean)
	PR Interval, 26 Weeks (n=256, 261, 268, 132)	PR Interval, 104 Weeks (n=168, 170, 167)	QTcF Interval, 26 Weeks (n=258, 262, 268, 132)	QTcF Interval, 104 Weeks (n=169, 170, 168)
0.75 mg LY2189265	1.60	3.06	-2.44	-2.49
1.5 mg LY2189265	2.94	4.59	-3.86	-2.71
Placebo/Sitagliptin (Baseline Through 26 Weeks)	2.24	NA	1.76	NA
Sitagliptin	0.42	3.19	-1.31	-0.02

Intervention	beats per minute (bpm) (Least Squares Mean)
	Sitting, 26 Weeks (n=271, 278, 283, 138)	Sitting, 104 Weeks (n=197, 192, 191)	Standing, 26 Weeks (n=271, 277, 281, 138)	Standing, 104 Weeks (n=197, 192, 191)
0.75 mg LY2189265	1.90	2.77	2.00	2.50
1.5 mg LY2189265	2.57	2.28	3.24	2.26
Placebo/Sitagliptin (Baseline Through 26 Weeks)	-0.22	NA	-0.17	NA
Sitagliptin	-0.11	-0.78	-0.24	-1.06

Intervention	kilograms (kg) (Least Squares Mean)
	26 Weeks Versus 13 Weeks (n=271, 278, 282, 138)	52 Weeks Versus 26 Weeks (n=246, 255, 253)	104 Weeks Versus 26 Weeks (n=197, 192, 191)
0.75 mg LY2189265	-0.57	0.06	0.32
1.5 mg LY2189265	-0.53	0.17	0.42
Placebo/Sitagliptin (Baseline Through 26 Weeks)	-0.37	NA	NA
Sitagliptin	-0.42	-0.04	-0.39

Intervention	percentage of HbA1c (Least Squares Mean)
	26 Weeks Versus 13 Weeks (n=269, 269, 276, 136)	52 Weeks Versus 26 Weeks (n=245, 254, 250)	104 Weeks Versus 52 Weeks (n=194, 191, 190)
0.75 mg LY2189265	0.02	0.16	0.16
1.5 mg LY2189265	-0.03	0.14	0.13
Placebo/Sitagliptin (Baseline Through 26 Weeks)	-0.14	NA	NA
Sitagliptin	0.00	0.24	0.09

Intervention	millimoles per liter (mmol/L) (Least Squares Mean)
	26 Weeks (n=265, 271, 276, 135)	52 Weeks (n=239, 247, 244)	104 Weeks (n=190, 187, 181)
0.75 mg LY2189265	-1.97	-1.63	-1.39
1.5 mg LY2189265	-2.38	-2.38	-1.99
Placebo/Sitagliptin (Baseline Through 26 Weeks)	-0.49	NA	NA
Sitagliptin	-0.97	-0.90	-0.47

Intervention	picomoles per liter (pmol/L) (Least Squares Mean)
	26 Weeks (n=238, 249, 230, 115)	52 Weeks (n=207, 218, 200)	104 Weeks (n=187, 200, 183)
0.75 mg LY2189265	10.15	12.95	21.56
1.5 mg LY2189265	11.59	10.57	11.36
Placebo/Sitagliptin (Baseline Through 26 Weeks)	-6.92	NA	NA
Sitagliptin	8.48	4.18	0.29

Intervention	participants (Number)
	Severe HE, 26 Weeks	Severe HE, 104 Weeks	Documented Symptomatic HE, 26 Weeks	Documented Symptomatic HE, 104 Weeks	Asymptomatic HE, 26 Weeks	Asymptomatic HE, 104 Weeks	Nocturnal HE, 26 Weeks	Nocturnal HE, 104 Weeks	Probable HE, 26 Weeks	Probable HE, 104 Weeks
0.75 mg LY2189265	0	0	8	19	5	9	5	13	0	2
1.5 mg LY2189265	0	0	17	33	5	9	7	14	5	6
Placebo/Sitagliptin (Baseline Through 26 Weeks)	0	NA	2	NA	0	NA	0	NA	0	NA
Sitagliptin	0	0	10	18	0	3	2	10	2	6

Intervention	participants (Number)
	Participants With Any CV Event	Participants With a Fatal CV Event	Participants With a Non-fatal CV Event
0.25 mg LY2189265	0	0	0
0.5 mg LY2189265	0	0	0
0.75 mg LY2189265	4	0	4
1.0 mg LY2189265	0	0	0
1.5 mg LY2189265	6	1	6
2.0 mg LY2189265	0	0	0
3.0 mg LY2189265	0	0	0
Placebo/Sitagliptin (26 Weeks Through 104 Weeks)	3	1	2
Placebo/Sitagliptin (Baseline Through 26 Weeks)	0	0	0
Sitagliptin	5	1	4

Intervention	participants (Number)
	Alkaline Phosphate, High (n=276, 258, 281)	ALT/SGPT, High (n=232, 237, 244)	Amylase Pancreatic, High (n=283, 277, 295)	Amylase Total, High (n=266, 265, 277)	AST/SGOT, High (n=273, 269, 284)	Basophils, High (n=276, 268, 288)	Basophils, Low (n=277, 268, 288)	Bilirubin Direct, High (n=295, 291, 307)	Bilirubin Total, High (n=295, 290, 305)	Calcitonin, High (n=233, 239, 235)	Chloride, High (n=299, 293, 310)	Chloride, Low (n=299, 293, 308)	CPK, High (n=273, 262, 276)	Creatinine, High (n=294, 285, 303)	Creatinine Clearance, High (n=164, 186, 180)	Creatinine Clearance, Low (n=292, 278, 303)	Eosinophils, High (n=265, 265, 284)	Eosinophils, Low (n=277, 268, 288)	Erythrocyte Count, High (n=283, 276, 292)	Erythrocyte Count, Low (n=278, 272, 285)	GGT, High (n=234, 240, 245)	Hematocrit, High (n=280, 274, 290)	Hematocrit, Low (n=262, 251, 269)	Hemoglobin, High (n=282, 275, 294)	Hemoglobin, Low (n=265, 253, 269)	Leukocyte Count, High (n=277, 270, 292)	Leukocyte Count, Low (n=277, 267, 284)	Lipase, High (n=255, 248, 269)	Lymphocytes, High (n=257, 262, 279)	Lymphocytes, Low (n=273, 266, 281)	MCHC, High (n=281, 274, 291)	MCHC, Low (n=280, 272, 290)	MCV, High (n=267, 256, 273)	MCV, Low (n=270, 261, 286)	Monocytes, High (n=274, 267, 284)	Monocytes, Low (n=271, 264, 283)	Neutrophils, High (n=272, 263, 286)	Neutrophils, Low (n=271, 260, 280)	Platelet Count, High (n=273, 268, 287)	Platelet Count, Low (n=270, 260, 275)	Potassium, High (n=297, 291, 307)	Potassium, Low (n=298, 293, 308)	Sodium, High (n=291, 291, 307)	Sodium, Low (n=298, 292, 305)	Urea Nitrogen, High (n=287, 282, 305)	UMCR, High (n=223, 212, 239)
0.75 mg LY2189265	11	37	78	55	27	0	0	1	8	3	2	2	41	16	32	25	22	0	2	14	24	6	24	3	28	9	7	132	20	9	0	4	25	3	1	14	12	6	3	7	9	8	10	1	29	27
1.5 mg LY2189265	13	29	81	44	21	1	0	2	3	5	0	3	52	11	26	24	12	0	3	18	16	3	30	4	30	13	9	142	19	5	0	5	39	9	3	10	15	10	2	8	14	8	10	5	17	38
Sitagliptin	20	39	61	43	36	1	0	3	6	4	1	3	54	9	34	20	14	0	1	19	45	3	29	2	25	8	14	126	21	12	0	5	25	4	11	17	13	10	3	8	8	5	6	5	29	30

Intervention	participants (Number)
	Alkaline Phosphatase (n=276, 258, 281, 162)	ALT/SGPT (n=232, 237, 244, 128)	Amylase Pancreatic, High (n=283, 277, 295, 160)	Amylase Total (n=266, 265, 277, 143)	AST/SGOT (n=273, 269, 284, 148)	Basophils, High (n=268, 259, 278, 163)	Basophils, Low (n=269, 259, 278, 163)	Bilirubin Direct, High (n=295, 291, 307, 171)	Bilirubin Total, High (n=295, 290, 305, 168)	Calcitonin, High (n=226, 233, 230, 113)	Chloride, High (n=299, 293, 310, 174)	Chloride, Low (n=299, 293, 308, 174)	CPK, High (n=273, 262, 276, 156	Creatinine, High (n=294, 285, 303, 172)	Creatinine Clearance, High (n=164, 186, 180, 107)	Creatinine Clearance, Low (n=292, 278,303,168)	Eosinophils, High (n=258, 256, 275, 157)	Eosinophils, Low (n=269, 259, 278, 163)	Erythrocyte Count, High (n=279, 272, 287, 164)	Erythrocyte Count, Low (n=274, 268, 280, 161)	GGT, High (n=234, 240, 245, 144)	Hematocrit, High (n=273, 265, 279, 161)	Hematocrit, Low (n=256, 242, 259, 157)	Hemoglobin, High (n=278, 271, 289, 164)	Hemoglobin, Low (n=262, 249, 265, 162)	Leukocyte Count, High (n=272, 265, 286, 165)	Leukocyte Count, Low (n=272, 262, 280, 165)	Lipase, High (n=255, 248, 269, 147)	Lymphocytes, High (n=249, 253, 269, 161)	Lymphocytes, Low (n=265, 258, 273, 159)	MCHC, High (n=274, 265, 280, 163)	MCHC, Low (n=273, 263, 279, 163)	MCV, High (n=261, 248, 263, 156)	MCV, Low (n=264, 252, 275, 162)	Monocytes, High (n=266, 258, 274, 163)	Monocytes, Low (n=265, 255, 274, 158)	Neutrophils, High (n=264, 255, 276, 161)	Neutrophils, Low (n=263, 251, 271, 162)	Platelet Count, High (n=265, 260, 281, 160)	Platelet Count, Low (n=262, 252, 269, 154)	Potassium, High (n=297, 291, 307, 172)	Potassium, Low (n=298, 293, 308, 169)	Sodium, High (n=291, 291, 307, 170)	Sodium, Low (n=298, 292, 305, 174)	Urea Nitrogen, High (n=287, 282, 305, 169)	UMCR, High (n=217, 204, 232, 130)
0.75 mg LY2189265	3	24	55	33	12	0	0	1	4	2	1	2	20	10	28	17	11	0	1	7	11	1	10	1	16	6	3	92	9	3	0	2	12	2	0	5	5	1	0	3	2	6	4	1	17	9
1.5 mg LY2189265	9	18	54	33	14	1	0	1	2	1	0	1	29	7	17	11	4	0	1	12	9	1	13	1	13	3	2	109	5	3	0	0	19	3	1	6	4	2	0	2	7	4	3	2	11	18
Placebo/Sitagliptin (Baseline Through 26 Weeks)	3	8	18	13	7	0	0	2	1	0	0	1	7	5	25	6	2	0	0	3	10	2	5	2	3	0	1	37	3	2	0	0	5	0	1	10	1	1	0	3	4	1	4	1	5	5
Sitagliptin	12	25	42	27	18	1	0	1	4	2	0	1	30	5	26	12	6	0	0	7	23	1	6	1	5	1	4	97	6	4	0	0	14	2	3	8	3	2	1	6	5	3	4	4	13	13

Intervention	participants (Number)
	Alkaline Phosphatase, High (n=276, 258, 281)	ALT/SGPT, High (n=232, 237, 244)	Amylase Pancreatic, High (n=283, 277, 295)	Amylase Total, High (n=266, 265, 277)	AST/SGOT, High (n=273, 269, 284)	Basophils, High (n=276, 268, 287)	Basophils, Low (n=277, 268, 287)	Bilirubin Direct, High (n=295, 291, 307)	Bilirubin Total, High (n=295, 290, 305)	Calcitonin, High (n=233, 239, 235)	Chloride, High (n=299, 293, 310)	Chloride, Low (n=299, 293, 308)	CPK, High (n=273, 262, 276)	Creatinine, High (n=294, 285, 303)	Creatinine Clearance, High (n=164, 186, 180)	Creatinine Clearance, Low (n=292, 278, 303)	Eosinophils, High (n=265, 265, 283)	Eosinophils, Low (n=277, 268, 287)	Erythrocyte Count, High (n=283, 276, 292)	Erythrocyte Count, Low (n=278, 272, 285)	GGT, High (n=234, 240, 245)	Hematocrit, High (n=280, 274, 290)	Hematocrit, Low (n=262, 251, 269)	Hemoglobin, High (n=282, 275, 294)	Hemoglobin, Low (n=265, 253, 269)	Leukocyte Count, High (n=277, 270, 292)	Leukocyte Count, Low (n=277, 267, 284)	Lipase, High (n=255, 248, 269)	Lymphocytes, High (n=257, 262, 278)	Lymphocytes, Low (n=273, 266, 280)	MCHC, High (n=281, 274, 291)	MCHC, Low (n=280, 272, 290)	MCV, High (n=267, 256, 273)	MCV, Low (n=270, 261, 286)	Monocytes, High (n=274, 267, 283)	Monocytes, Low (n=271, 264, 282)	Neutrophils, High (n=272, 263, 285)	Neutrophils, Low (n=271, 260, 279)	Platelet Count, High (n=272, 267, 287)	Platelet Count, Low (n=269, 259, 275)	Potassium, High (n=297, 291, 307)	Potassium, Low (n=298, 293, 308)	Sodium, High (n=291, 291, 307)	Sodium, Low (n=298, 292, 305)	Urea Nitrogen, High (n=287, 282, 305)	UMCR, High (n=223, 212, 238)
0.75 mg LY2189265	6	27	70	42	19	0	0	1	6	2	1	2	28	10	30	20	14	0	1	9	14	2	13	1	19	6	3	111	15	4	0	3	18	2	0	9	7	2	2	5	5	7	8	1	19	21
1.5 mg LY2189265	10	25	67	38	15	1	0	1	2	4	0	1	38	9	23	18	11	0	3	15	10	3	21	3	21	7	5	124	12	4	0	2	25	3	1	8	8	6	0	4	10	6	5	3	14	33
Sitagliptin	16	28	55	36	25	1	0	2	5	2	0	2	43	6	29	15	10	0	1	11	34	2	11	1	11	3	9	110	11	11	0	3	19	4	5	15	7	6	2	8	5	5	4	4	21	18

Intervention	participants (Number)
	Cholesterol, High, 26 Weeks (n=144, 158, 139, 58)	Cholesterol, High, 104 Weeks (n=151, 164, 146)	HDL-C, High, 26 Weeks (n=197, 201, 189, 78)	HDL-C, Low, 26 Weeks (n=127, 137, 129, 52)	HDL-C, High, 104 Weeks (n=206, 212, 199)	HDL-C, Low, 104 Weeks (n=134, 143, 138)	LDL-C, High, 26 Weeks (n=155, 163, 150, 61)	LDL-C, High, 104 Weeks (n=163, 170, 157)	TG, High, 26 Weeks (n=163, 174, 156, 64)	TG, High, 104 Weeks (n=170, 183, 166)
0.75 mg LY2189265	21	29	0	13	1	20	11	23	13	22
1.5 mg LY2189265	16	34	1	9	2	13	15	31	6	13
Placebo/Sitagliptin (Baseline Through 26 Weeks)	8	NA	0	1	NA	NA	7	NA	2	NA
Sitagliptin	20	34	0	8	2	13	19	29	10	15

Intervention	units on a scale (Mean)
	EQ-5D, UK, Baseline (n=285, 281, 300)	EQ-5D, UK, 52 Weeks (n=237, 250, 244)	EQ-5D, UK, 104 Weeks (n=189, 190, 185)	VAS, Baseline (n=285, 284, 301)	VAS, 52 Weeks (n=238, 251, 245)	VAS, 104 Weeks (n=189, 190, 185)
0.75 mg LY2189265	0.82	0.84	0.86	75.35	78.22	78.52
1.5 mg LY2189265	0.80	0.83	0.84	75.57	78.93	79.66
Sitagliptin	0.84	0.85	0.86	76.85	78.79	81.34

Intervention	units on a scale (Mean)
	Total Score, Baseline (n=285, 284, 300)	Total Score, 52 Weeks (n=237, 252, 247)	Total Score, 104 Weeks (n=190, 190, 185)
0.75 mg LY2189265	82.55	86.31	87.47
1.5 mg LY2189265	83.41	86.92	88.08
Sitagliptin	83.97	86.25	86.93

Intervention	percentage of participants (Number)
	<7.0% at 26 Weeks	<7.0% at 52 Weeks	<7.0% at 104 Weeks	≤6.5% at 26 Weeks	≤6.5% at 52 Weeks	≤6.5% at 104 Weeks
0.75 mg LY2189265	55.2	48.8	44.8	31.0	29.0	24.2
1.5 mg LY2189265	60.9	57.6	54.3	46.7	41.7	39.1
Placebo/Sitagliptin (Baseline Through 26 Weeks)	21.0	NA	NA	12.5	NA	NA
Sitagliptin	37.8	33.0	31.1	21.8	19.2	14.1