metformin and Cardiac Failure 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
"The glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes."	9.41	Metformin Lowers Body Weight But Fails to Increase Insulin Sensitivity in Chronic Heart Failure Patients without Diabetes: a Randomized, Double-Blind, Placebo-Controlled Study. ( Brøsen, K; Bøtker, HE; Dollerup, OL; Frøkiær, J; Hansson, NH; Jespersen, NR; Jessen, N; Larsen, AH; Møller, N; Nørrelund, H; Wiggers, H, 2021)
" placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs."	9.41	The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chr ( Abdulla, J; Barasa, A; Bibby, BM; Bruun, NE; Brønnum-Schou, J; Bøtker, HE; Bøttcher, M; Dodt, K; Eiskjær, H; Gislason, G; Gustafsson, F; Hansen, VB; Hassager, C; Hollingdal, M; Høfsten, DE; Jonczy, B; Knudsen, AS; Kristensen, SL; Køber, L; Larsen, AH; Lomholdt, J; Madsen, JS; Mahboubi, K; Mellemkjær, S; Mikkelsen, KV; Møller, J; Nielsen, G; Nielsen, OW; Nørrelund, H; Poenaru, MP; Poulsen, MK; Raymond, I; Refsgaard, J; Schou, M; Serup-Hansen, K; Sillesen, K; Steffensen, FH; Torp-Petersen, C; Vraa, S; Wiggers, H, 2021)
"Whether metformin reduces all-cause cardiovascular mortality and the incidence of cardiovascular events in patients with pre-existing cardiovascular diseases (CVD) remains inconclusive."	9.22	Association of Metformin with the Mortality and Incidence of Cardiovascular Events in Patients with Pre-existing Cardiovascular Diseases. ( Chang, ACY; Gu, C; Jiang, W; Li, T; Liu, M; Ma, H; Providencia, R; Yu, L, 2022)
"A total of 250 patients with type 2 diabetes who are drug-naïve or taking any anti-diabetic agents and suffering from chronic heart failure with a New York Heart Association classification I to III will be randomized centrally into either canagliflozin or glimepiride groups (1: 1) using the dynamic allocation method stratified by age (<65, ≥65 year), HbA1c level (<6."	9.22	Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial. ( Ako, J; Anzai, T; Eguchi, K; Inoue, T; Kitakaze, M; Murohara, T; Node, K; Oyama, J; Saito, Y; Sakata, Y; Sata, M; Sato, Y; Shimizu, W; Suzuki, M; Taguchi, I; Tanaka, A; Tomiyama, H; Ueda, S; Uematsu, M; Watada, H; Yamashina, A, 2016)
"Metformin has had a 'black box' contraindication in diabetic patients with heart failure (HF), but many believe it to be the treatment of choice in this setting."	9.14	Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality. ( Eurich, DT; Johnson, JA; Lewanczuk, R; Majumdar, SR; McAlister, FA; Shibata, MC; Tsuyuki, RT, 2009)
"Aim of the investigation was to study safety of therapy with metformin and its effect on clinical, hemodynamic, functional and neurohumoral status in patients with chronic heart failure and type 2 diabetes mellitus DM)."	9.13	[Efficacy and safety of the use of metformin in patients with chronic heart failure and type 2 diabetes mellitus. results of the study "rational effective mulicomponent therapy in the battle against diabetes mellitus in patients with chronic heart failure ( Arzamastseva, NE; Baklanova, NA; Belenkov, IuN; Bolotina, MG; Lapina, IuV; Litonova, GN; Mareev, VIu; Masenko, VP; Narusov, OIu; Shestakova, MV, 2008)
"Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes (T2D); however, information on its impact on heart failure-related outcomes remains inconclusive."	9.12	Metformin and heart failure-related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials. ( Dludla, PV; Gabuza, KB; Johnson, R; Louw, J; Mazibuko-Mbeje, SE; Mokgalaboni, K; Muller, CJF; Mxinwa, V; Nkambule, BB; Nyambuya, TM; Orlando, P; Silvestri, S; Tiano, L, 2021)
"Observational series suggest a mortality benefit from metformin in the heart failure (HF) population."	9.05	Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. ( Halabi, A; Huynh, Q; Marwick, TH; Sen, J, 2020)
"To synthesize data addressing outcomes of metformin use in populations with type 2 diabetes and moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment."	8.95	Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. ( Cameron, CB; Crowley, MJ; Diamantidis, CJ; Kosinski, AS; McDuffie, JR; Mock, CK; Nagi, A; Stanifer, JW; Tang, S; Wang, X; Williams, JW, 2017)
"There is an ongoing controversy regarding the safety and effectiveness of metformin in the setting of heart failure (HF)."	8.89	Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. ( Eurich, DT; Johnson, JA; Majumdar, SR; McAlister, FA; Tjosvold, L; Tsuyuki, RT; Vanderloo, SE; Weir, DL, 2013)
"Lactic acidosis in diabetic patients undergoing metformin therapy is a widely recognized, rare but usually serious adverse event, particularly in presence of comorbidities such as cardiorespiratory disease, sepsis and renal failure."	8.88	Iodine-based radiographic contrast medium may precipitate metformin-associated lactic acidosis in diabetic patients. A case report, literature review and practical approach. ( Tonolini, M, 2012)
"Metformin is widely used for treating patients with type 2 diabetes mellitus."	8.86	[New clinical data with metformin therapy in patients with diabetes mellitus]. ( Jermendy, G, 2010)
" Search terms included metformin, heart failure, lactic acidosis, clinical trials, and insulin resistance."	8.84	The safety of metformin in heart failure. ( Roberts, F; Ryan, GJ, 2007)
"This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve."	8.31	The safe use of metformin in heart failure patients both with and without T2DM: A cross-sectional and longitudinal study. ( Carland, JE; Chowdhury, G; Day, RO; Graham, G; Greenfield, JR; Hayward, CS; Kumar, S; Kumarasinghe, G; Macdonald, P; Olsen, N; Stocker, SL, 2023)
"The authors sought to characterize associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes (overall and by ejection fraction [EF] phenotype)."	8.12	Clinical Outcomes With Metformin and Sulfonylurea Therapies Among Patients With Heart Failure and Diabetes. ( Butler, J; DeVore, AD; Felker, GM; Fonarow, GC; Green, JB; Greene, SJ; Heidenreich, PA; Hernandez, AF; Khan, MS; Matsouaka, RA; Peterson, PN; Sharma, A; Solomon, N; Yancy, CW, 2022)
"To assess whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improves cognitive impairment in frail older adults with diabetes and heart failure with preserved ejection fraction (HFpEF)."	8.12	Empagliflozin Improves Cognitive Impairment in Frail Older Adults With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction. ( Frullone, S; Gambardella, J; Lombardi, A; Macina, G; Mone, P; Morgante, M; Pansini, A; Santulli, G, 2022)
" This self-controlled case series study aims to evaluate whether metformin use and SGLT2i-associated erythrocytosis influence its cardiovascular benefits."	8.12	Cardiovascular benefits of SGLT2 inhibitors in type 2 diabetes, interaction with metformin and role of erythrocytosis: a self-controlled case series study. ( Au, ICH; Lau, KTK; Lee, CH; Lee, CYY; Lui, DTW; Tan, KCB; Tang, EHM; Wong, CKH; Woo, YC, 2022)
"In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications."	8.02	Risk of Death and Heart Failure among Patients with Type 2 Diabetes Treated by Metformin and Nonmetformin Monotherapy: A Real-World Study. ( Chen, X; Chen, Y; He, S; Li, G; Qian, X; Shen, X; Xu, X; Zhang, B, 2021)
"Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared metformin prescription (n = 130) and non-metformin therapy (n = 260) in patients with T2DM and hypertension and without clinical signs or symptoms of heart failure."	7.96	Association between long-term prescription of metformin and the progression of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and hypertension. ( Gu, J; Wang, CQ; Yin, ZF; Zhang, JF, 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)
"Background A beneficial effect of metformin on heart failure requires confirmation."	7.91	Metformin Use Is Associated With a Lower Risk of Hospitalization for Heart Failure in Patients With Type 2 Diabetes Mellitus: a Retrospective Cohort Analysis. ( Tseng, CH, 2019)
"To compare the risks of hospitalization for heart failure (HHF) associated with sulfonylurea (SU), dipeptidyl peptidase-4 inhibitor (DPP-4i), and thiazolidinedione (TZD) as add-on medications to metformin (MET) therapy using the data of Korean adults with type-2 diabetes from the Korean National Health Insurance database."	7.91	Second-line glucose-lowering drugs added to metformin and the risk of hospitalization for heart failure: A nationwide cohort study. ( Ha, KH; Kim, DJ; Kim, HC; Lee, H; Lee, JH; Lee, SJ, 2019)
"To evaluate the association between metformin use and heart failure (HF) exacerbation in people with type 2 diabetes (T2D) and pre-existing HF using alternative exposure models."	7.88	Acute vs cumulative benefits of metformin use in patients with type 2 diabetes and heart failure. ( Abrahamowicz, M; Beauchamp, ME; Eurich, DT; Weir, DL, 2018)
" All-cause mortality was considered as the primary endpoint and the effect of metformin therapy across the most representative subgroups in heart failure as a secondary endpoint."	7.85	Metformin and risk of long-term mortality following an admission for acute heart failure. ( Bertomeu, V; Fabregat-Andrés, Ó; Fácila, L; García-Blas, S; Miñana, G; Morell, S; Navarro, JP; Núñez, J; Sanchis, J; Valero, E, 2017)
"To investigate whether metformin can improve the cardiac function through improving the mitochondrial function in model of heart failure after myocardial infarction."	7.85	Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism. ( Sun, D; Yang, F, 2017)
"To examine the safety and potential benefits of metformin in diabetic patients with cardiovascular (CV) disease and heart failure (HF)."	7.79	Evaluating the potential benefits of metformin in patients with cardiovascular disease and heart failure. ( Amin, SM; Chilipko, AA; Macharia, D; Norwood, DK; Still, KL, 2013)
"To assess the effect of the commencement of metformin therapy (CMet) on the prognosis of patients with newly diagnosed heart failure (HF) and new-onset diabetes mellitus (DM) treated with a contemporary medical regimen."	7.79	Metformin therapy and prognosis of patients with heart failure and new-onset diabetes mellitus. A propensity-matched study in the community. ( Andrey, JL; Corzo, R; Escobar, MA; Garcia-Domiguez, GJ; Garcia-Egido, A; Gomez, F; Perez, V; Romero, SP, 2013)
"Metformin inhibited cardiac fibrosis induced by pressure overload in vivo and inhibited collagen synthesis in CFs probably via inhibition of the TGF-beta(1)-Smad3 signalling pathway."	7.76	Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. ( Feng, W; Fu, Y; Lu, Z; Ma, X; Shen, Q; Xiao, H; Xu, M; Zhang, Y; Zhu, Y, 2010)
"The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern."	7.76	Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. ( Abildstrøm, SZ; Andersson, C; Gislason, GH; Hansen, PR; Jørgensen, CH; Køber, L; Lange, T; Norgaard, ML; Olesen, JB; Schramm, TK; Torp-Pedersen, C; Vaag, A; Weeke, P, 2010)
"Clinical studies have reported that the widely used antihyperglycemic drug metformin significantly reduces cardiac risk factors and improves clinical outcomes in patients with heart failure."	7.75	Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. ( Anaya-Cisneros, M; Calvert, JW; Gundewar, S; Jha, S; Ji, SY; Lefer, DJ; Nunez, D; Ramachandran, A; Tian, R; Toedt-Pingel, I, 2009)
"Metformin attenuated oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK."	7.75	Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. ( Asakura, M; Asanuma, H; Fujita, M; Ito, S; Kim, J; Kitakaze, M; Komamura, K; Minamino, T; Mochizuki, N; Ogai, A; Sanada, S; Sasaki, H; Sugimachi, M; Takahama, H; Takashima, S; Wakeno, M, 2009)
"Metformin is considered contraindicated in patients with heart failure because of concerns over lactic acidosis, despite increasing evidence of potential benefit."	7.73	Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. ( Eurich, DT; Johnson, JA; Majumdar, SR; McAlister, FA; Tsuyuki, RT, 2005)
"According to package inserts, metformin is contraindicated in diabetic patients receiving drug treatment for heart failure therapy, and thiazolidinediones are not recommended in diabetic patients with symptoms of advanced heart failure."	7.72	Metformin and thiazolidinedione use in Medicare patients with heart failure. ( Foody, JM; Havranek, EP; Inzucchi, SE; Krumholz, HM; Masoudi, FA; Setaro, JF; Wang, Y, 2003)
"Metformin has been in clinical use for the management of type 2 diabetes for more than 60 years and is supported by a vast database of clinical experience: this includes evidence for cardioprotection from randomised trials and real-world studies."	6.82	Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. ( Bailey, CJ; Brand, K; Schernthaner, G, 2022)
"Metformin can also inhibit the generation and accumulation of advanced glycation end products (AGEs) and thereby prevents the development of the adverse structural and functional changes in myocardium."	6.55	The pathophysiological basis of the protective effects of metformin in heart failure. ( Dziubak, A; Wójcicka, G, 2017)
"Cardiac fibrosis is a major structural change observed in the heart of patients with type 2 diabetes mellitus (T2DM), ultimately resulting in heart failure (HF)."	5.72	Gentiopicroside alleviates cardiac inflammation and fibrosis in T2DM rats through targeting Smad3 phosphorylation. ( Hu, XP; Huang, P; Huang, ZJ; Liu, T; Pan, ZF; Shi, JN; Sun, ZY; Xu, YN; Yuan, MN; Zhang, YW; Zou, XZ, 2022)
"Increased age and the presence of congestive heart failure were associated with significantly higher risk of AF in both groups (HR: 1."	5.72	Association between first-line monotherapy with metformin and the risk of atrial fibrillation (AMRAF) in patients with type 2 diabetes. ( Chung, MK; Iqbal, A; Ji, X; Kashyap, SR; Kattan, MW; Milinovich, A; Pantalone, KM; Tekin, Z; Zimmerman, RS, 2022)
"Metformin has been shown to have favorable effects on the course of heart failure in experimental models."	5.48	Is metformin beneficial for heart failure in patients with type 2 diabetes? ( Packer, M, 2018)
"Metformin treatment in patients with different degrees of HF and T2DM is associated with a reduction in mortality and does not affect the hospitalisation rate."	5.48	The influence of metformin and the presence of type 2 diabetes mellitus on mortality and hospitalisation in patients with heart failure. ( Crespo-Leiro, M; Drożdż, J; Drzewoski, J; Jankowska, E; Kosmalski, M; Maggioni, A; Opolski, G; Poloński, L; Ponikowski, P; Retwiński, 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)
"The findings from our analyses substantiate the relevance of treatment with SGLT-2 inhibitors or GLP-1RAs as an add-on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT-2 inhibitor treatment in patients with T2D and heart failure or established kidney disease."	5.41	Effects of DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors and sulphonylureas on mortality, cardiovascular and renal outcomes in type 2 diabetes: A network meta-analyses-driven approach. ( Brønden, A; Christensen, MB; Glintborg, D; Hansen, KB; Hansen, TK; Højlund, K; Kofoed-Enevoldsen, A; Kristensen, JK; Madsen, GK; Snorgaard, O; Søndergaard, E; Toft, K, 2023)
"While substantial preclinical and clinical evidence suggests metformin as a potential cardiovascular protectant, large-scale randomized controlled trials are warranted to establish its clinical efficacy in treating patients with atherosclerotic cardiovascular disease and heart failure."	5.41	Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research. ( Li, JZ; Li, YR, 2023)
"The glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes."	5.41	Metformin Lowers Body Weight But Fails to Increase Insulin Sensitivity in Chronic Heart Failure Patients without Diabetes: a Randomized, Double-Blind, Placebo-Controlled Study. ( Brøsen, K; Bøtker, HE; Dollerup, OL; Frøkiær, J; Hansson, NH; Jespersen, NR; Jessen, N; Larsen, AH; Møller, N; Nørrelund, H; Wiggers, H, 2021)
" placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs."	5.41	The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chr ( Abdulla, J; Barasa, A; Bibby, BM; Bruun, NE; Brønnum-Schou, J; Bøtker, HE; Bøttcher, M; Dodt, K; Eiskjær, H; Gislason, G; Gustafsson, F; Hansen, VB; Hassager, C; Hollingdal, M; Høfsten, DE; Jonczy, B; Knudsen, AS; Kristensen, SL; Køber, L; Larsen, AH; Lomholdt, J; Madsen, JS; Mahboubi, K; Mellemkjær, S; Mikkelsen, KV; Møller, J; Nielsen, G; Nielsen, OW; Nørrelund, H; Poenaru, MP; Poulsen, MK; Raymond, I; Refsgaard, J; Schou, M; Serup-Hansen, K; Sillesen, K; Steffensen, FH; Torp-Petersen, C; Vraa, S; Wiggers, H, 2021)
"Metformin represents the cornerstone of treatment for type 2 diabetes mellitus."	5.38	Metformin and heart failure: never say never again. ( Maltezos, E; Mikhailidis, DP; Papanas, N, 2012)
"Insulin resistance is a recently identified mechanism involved in the pathophysiology of chronic heart failure (CHF)."	5.38	Metformin prevents the development of chronic heart failure in the SHHF rat model. ( Aimaretti, G; Cittadini, A; Isgaard, J; Longobardi, S; Monti, MG; Napoli, R; Netti, PA; Rea, D; Saccà, L; Samà, M; Walser, M, 2012)
"Metformin therapy was associated with lower rates of mortality in ambulatory patients with diabetes and HF."	5.37	Metformin use and mortality in ambulatory patients with diabetes and heart failure. ( Aguilar, D; Bozkurt, B; Chan, W; Deswal, A; Ramasubbu, K, 2011)
"Advanced HF (heart failure) is associated with altered substrate metabolism."	5.37	Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. ( Benada, O; Benes, J; Cervenka, L; Drahota, Z; Houstek, J; Kazdova, L; Kolar, M; Kopecky, J; Kovarova, N; Medrikova, D; Melenovsky, V; Petrak, J; Sedmera, D; Skaroupkova, P; Strnad, H; Vrbacky, M, 2011)
"Metformin was associated with a reduced risk of CHF (HR 0."	5.35	The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. ( Arrigain, S; Atreja, A; Jain, A; Kattan, MW; Pantalone, KM; Wells, BJ; Yu, C; Zimmerman, RS, 2009)
"To determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in the Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure trial (DAPA-HF) varied by background glucose-lowering therapy (GLT)."	5.34	Effect of Dapagliflozin in DAPA-HF According to Background Glucose-Lowering Therapy. ( Bengtsson, O; DeMets, DL; Docherty, KF; Inzucchi, SE; Jhund, PS; Kosiborod, MN; Køber, L; Langkilde, AM; Martinez, FA; McMurray, JJV; Sabatine, MS; Sjöstrand, M; Solomon, SD, 2020)
"All-cause mortality, cardiovascular death, cardiovascular events (death, hospitalization for heart failure, myocardial infarction, stroke or myocardial ischemia), end stage renal disease (ESRD) and the kidney disease composite (ESRD or death) were compared in metformin users and non-users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin-alfa) Therapy (TREAT) (NCT00093015)."	5.30	Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease. ( Burdmann, EA; Charytan, DM; Claggett, B; Cooper, ME; Eckardt, KU; Ivanovich, P; Levey, AS; Lewis, EF; Liu, J; McGill, JB; McMurray, JJV; Parfrey, P; Parving, HH; Pfeffer, MA; Remuzzi, G; Singh, AK; Solomon, SD; Weinrauch, LA, 2019)
"Whether metformin reduces all-cause cardiovascular mortality and the incidence of cardiovascular events in patients with pre-existing cardiovascular diseases (CVD) remains inconclusive."	5.22	Association of Metformin with the Mortality and Incidence of Cardiovascular Events in Patients with Pre-existing Cardiovascular Diseases. ( Chang, ACY; Gu, C; Jiang, W; Li, T; Liu, M; Ma, H; Providencia, R; Yu, L, 2022)
"A total of 250 patients with type 2 diabetes who are drug-naïve or taking any anti-diabetic agents and suffering from chronic heart failure with a New York Heart Association classification I to III will be randomized centrally into either canagliflozin or glimepiride groups (1: 1) using the dynamic allocation method stratified by age (<65, ≥65 year), HbA1c level (<6."	5.22	Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial. ( Ako, J; Anzai, T; Eguchi, K; Inoue, T; Kitakaze, M; Murohara, T; Node, K; Oyama, J; Saito, Y; Sakata, Y; Sata, M; Sato, Y; Shimizu, W; Suzuki, M; Taguchi, I; Tanaka, A; Tomiyama, H; Ueda, S; Uematsu, M; Watada, H; Yamashina, A, 2016)
"Metformin has had a 'black box' contraindication in diabetic patients with heart failure (HF), but many believe it to be the treatment of choice in this setting."	5.14	Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality. ( Eurich, DT; Johnson, JA; Lewanczuk, R; Majumdar, SR; McAlister, FA; Shibata, MC; Tsuyuki, RT, 2009)
"Addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes is confirmed to increase the risk of heart failure and of some fractures, mainly in women."	5.14	Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. ( Beck-Nielsen, H; Curtis, PS; Gomis, R; Hanefeld, M; Home, PD; Jones, NP; Komajda, M; McMurray, JJ; Pocock, SJ, 2009)
"Aim of the investigation was to study safety of therapy with metformin and its effect on clinical, hemodynamic, functional and neurohumoral status in patients with chronic heart failure and type 2 diabetes mellitus DM)."	5.13	[Efficacy and safety of the use of metformin in patients with chronic heart failure and type 2 diabetes mellitus. results of the study "rational effective mulicomponent therapy in the battle against diabetes mellitus in patients with chronic heart failure ( Arzamastseva, NE; Baklanova, NA; Belenkov, IuN; Bolotina, MG; Lapina, IuV; Litonova, GN; Mareev, VIu; Masenko, VP; Narusov, OIu; Shestakova, MV, 2008)
"Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes (T2D); however, information on its impact on heart failure-related outcomes remains inconclusive."	5.12	Metformin and heart failure-related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials. ( Dludla, PV; Gabuza, KB; Johnson, R; Louw, J; Mazibuko-Mbeje, SE; Mokgalaboni, K; Muller, CJF; Mxinwa, V; Nkambule, BB; Nyambuya, TM; Orlando, P; Silvestri, S; Tiano, L, 2021)
"A recent meta-analysis raised concern regarding an increased risk of myocardial infarction and death from cardiovascular causes associated with rosiglitazone treatment of type 2 diabetes."	5.12	Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. ( Beck-Nielsen, H; Gomis, R; Hanefeld, M; Home, PD; Jones, NP; Komajda, M; McMurray, JJ; Pocock, SJ, 2007)
"Observational series suggest a mortality benefit from metformin in the heart failure (HF) population."	5.05	Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. ( Halabi, A; Huynh, Q; Marwick, TH; Sen, J, 2020)
"Accumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients with heart failure (HF), and even able to reduce the incidence of HF and to reduce HF mortality."	4.98	Metabolic Effects of Metformin in the Failing Heart. ( Bełtowski, J; Dziubak, A; Wójcicka, G; Wojtak, A, 2018)
"To synthesize data addressing outcomes of metformin use in populations with type 2 diabetes and moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment."	4.95	Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. ( Cameron, CB; Crowley, MJ; Diamantidis, CJ; Kosinski, AS; McDuffie, JR; Mock, CK; Nagi, A; Stanifer, JW; Tang, S; Wang, X; Williams, JW, 2017)
"Use of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use."	4.90	The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies. ( Calingaert, B; Hazell, L; Margulis, AV; Perez-Gutthann, S; Pladevall, M; Riera-Guardia, N; Romio, S; Varas-Lorenzo, C, 2014)
"There is an ongoing controversy regarding the safety and effectiveness of metformin in the setting of heart failure (HF)."	4.89	Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. ( Eurich, DT; Johnson, JA; Majumdar, SR; McAlister, FA; Tjosvold, L; Tsuyuki, RT; Vanderloo, SE; Weir, DL, 2013)
" The use of pioglitazone has been associated with an increased risk of bladder cancer, edema, heart failure, weight gain, and distal bone fractures in postmenopausal women."	4.89	[Limitations of insulin-dependent drugs in the treatment of type 2 diabetes mellitus]. ( de Pablos-Velasco, PL; Valerón, PF, 2013)
"Lactic acidosis in diabetic patients undergoing metformin therapy is a widely recognized, rare but usually serious adverse event, particularly in presence of comorbidities such as cardiorespiratory disease, sepsis and renal failure."	4.88	Iodine-based radiographic contrast medium may precipitate metformin-associated lactic acidosis in diabetic patients. A case report, literature review and practical approach. ( Tonolini, M, 2012)
"Metformin is widely used for treating patients with type 2 diabetes mellitus."	4.86	[New clinical data with metformin therapy in patients with diabetes mellitus]. ( Jermendy, G, 2010)
" Search terms included metformin, heart failure, lactic acidosis, clinical trials, and insulin resistance."	4.84	The safety of metformin in heart failure. ( Roberts, F; Ryan, GJ, 2007)
"For fear of lactic acidosis the currently listed contraindications to the use of metformin exclude a large number of people with type 2 diabetes from efficacious anti-hyperglycemic and cardioprotective treatment."	4.83	[Traditional contraindications to the use of metformin -- more harmful than beneficial?]. ( Egberts, EH; Holstein, A, 2006)
"This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve."	4.31	The safe use of metformin in heart failure patients both with and without T2DM: A cross-sectional and longitudinal study. ( Carland, JE; Chowdhury, G; Day, RO; Graham, G; Greenfield, JR; Hayward, CS; Kumar, S; Kumarasinghe, G; Macdonald, P; Olsen, N; Stocker, SL, 2023)
"The authors sought to characterize associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes (overall and by ejection fraction [EF] phenotype)."	4.12	Clinical Outcomes With Metformin and Sulfonylurea Therapies Among Patients With Heart Failure and Diabetes. ( Butler, J; DeVore, AD; Felker, GM; Fonarow, GC; Green, JB; Greene, SJ; Heidenreich, PA; Hernandez, AF; Khan, MS; Matsouaka, RA; Peterson, PN; Sharma, A; Solomon, N; Yancy, CW, 2022)
"To assess whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improves cognitive impairment in frail older adults with diabetes and heart failure with preserved ejection fraction (HFpEF)."	4.12	Empagliflozin Improves Cognitive Impairment in Frail Older Adults With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction. ( Frullone, S; Gambardella, J; Lombardi, A; Macina, G; Mone, P; Morgante, M; Pansini, A; Santulli, G, 2022)
"Among 8613 first-line SGLT-2i initiators matched to 17 226 metformin initiators, SGLT-2i initiators had a similar risk for MI/stroke/mortality (HR, 0."	4.12	Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study. ( Glynn, RJ; Patorno, E; Schneeweiss, S; Shin, H, 2022)
" This self-controlled case series study aims to evaluate whether metformin use and SGLT2i-associated erythrocytosis influence its cardiovascular benefits."	4.12	Cardiovascular benefits of SGLT2 inhibitors in type 2 diabetes, interaction with metformin and role of erythrocytosis: a self-controlled case series study. ( Au, ICH; Lau, KTK; Lee, CH; Lee, CYY; Lui, DTW; Tan, KCB; Tang, EHM; Wong, CKH; Woo, YC, 2022)
"To compare the risk of myocardial infarction (MI), ischemic stroke, or cardiovascular death in patients with T2D treated with mitoKATP channel high-affinity sulfonylureas and low-affinity sulfonylureas as add-on to metformin."	4.12	Comparison of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channel High- vs Low-Affinity Sulfonylureas and Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated With Metformin. ( Hsu, YJ; Huang, YL; Lai, JH; Lee, CH; Lin, C; Lin, TC; Pan, HY; Wang, MT; Wang, PC; Wu, LW, 2022)
"This study aims to assess the prevalence of atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), chronic kidney disease (CKD), and their combined presence in type 2 diabetes (T2D) patients in primary care for whom the 2019 ADA/EASD consensus update "Management of Hyperglycemia in Type 2 Diabetes" recommends GLP-1 receptor agonists (GLP-1RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-I) as first-line medications after metformin."	4.12	Prevalence of Atherosclerotic Cardiovascular Disease, Heart Failure, and Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus: A Primary Care Research Network-based Study. ( Goderis, G; Mamouris, P; Mathieu, C; Vaes, B; van Craeyveld, E, 2022)
"In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications."	4.02	Risk of Death and Heart Failure among Patients with Type 2 Diabetes Treated by Metformin and Nonmetformin Monotherapy: A Real-World Study. ( Chen, X; Chen, Y; He, S; Li, G; Qian, X; Shen, X; Xu, X; Zhang, B, 2021)
" However, the potential effects of metformin on cardiac hypertrophy are still unclear."	4.02	Metformin suppresses phenylephrine-induced hypertrophic responses by inhibiting p300-HAT activity in cardiomyocytes. ( Funamoto, M; Hasegawa, K; Katanasaka, Y; Katayama, A; Miyazaki, Y; Morimoto, T; Nurmila, S; Shimizu, K; Shimizu, S; Sunagawa, Y, 2021)
"Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared metformin prescription (n = 130) and non-metformin therapy (n = 260) in patients with T2DM and hypertension and without clinical signs or symptoms of heart failure."	3.96	Association between long-term prescription of metformin and the progression of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and hypertension. ( Gu, J; Wang, CQ; Yin, ZF; Zhang, JF, 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)
"In patients with T2DM, SGLT2i as first-line treatment may be associated with decreased events of heart failure hospitalization, acute coronary syndrome, and all-cause mortality, compared with metformin as first-line treatment."	3.96	Sodium-glucose cotransporter 2 inhibitor versus metformin as first-line therapy in patients with type 2 diabetes mellitus: a multi-institution database study. ( Chang, CH; Chen, DY; Chen, SW; Chen, TH; Chu, PH; Li, YR; Lin, YS; Mao, CT; Sun, CC; Wu, M; Wu, VC, 2020)
"Background A beneficial effect of metformin on heart failure requires confirmation."	3.91	Metformin Use Is Associated With a Lower Risk of Hospitalization for Heart Failure in Patients With Type 2 Diabetes Mellitus: a Retrospective Cohort Analysis. ( Tseng, CH, 2019)
"To compare the risks of hospitalization for heart failure (HHF) associated with sulfonylurea (SU), dipeptidyl peptidase-4 inhibitor (DPP-4i), and thiazolidinedione (TZD) as add-on medications to metformin (MET) therapy using the data of Korean adults with type-2 diabetes from the Korean National Health Insurance database."	3.91	Second-line glucose-lowering drugs added to metformin and the risk of hospitalization for heart failure: A nationwide cohort study. ( Ha, KH; Kim, DJ; Kim, HC; Lee, H; Lee, JH; Lee, SJ, 2019)
"Metformin is a popular antidiabetic agent that is also used to treat heart failure patients with type 2 diabetes mellitus."	3.91	Metformin Enhances Autophagy and Provides Cardioprotection in δ-Sarcoglycan Deficiency-Induced Dilated Cardiomyopathy. ( Kanamori, H; Kawaguchi, T; Kawasaki, M; Mikami, A; Minatoguchi, S; Naruse, G; Takemura, G; Watanabe, T; Yamada, Y; Yoshida, A, 2019)
"To evaluate the association between metformin use and heart failure (HF) exacerbation in people with type 2 diabetes (T2D) and pre-existing HF using alternative exposure models."	3.88	Acute vs cumulative benefits of metformin use in patients with type 2 diabetes and heart failure. ( Abrahamowicz, M; Beauchamp, ME; Eurich, DT; Weir, DL, 2018)
" A low prevalence of AD in patients with T2D was associated with residency in urban areas, the comorbidity of hemiplegia or paraplegia, the usage of metformin and sulfonylureas, and rapid-acting insulin injection therapy."	3.85	Prevalence of anxiety disorder in patients with type 2 diabetes: a nationwide population-based study in Taiwan 2000-2010. ( Hsieh, HM; Huang, CJ; Jiang, HJ; Lin, CH; Tu, HP; Wang, PW, 2017)
" All-cause mortality was considered as the primary endpoint and the effect of metformin therapy across the most representative subgroups in heart failure as a secondary endpoint."	3.85	Metformin and risk of long-term mortality following an admission for acute heart failure. ( Bertomeu, V; Fabregat-Andrés, Ó; Fácila, L; García-Blas, S; Miñana, G; Morell, S; Navarro, JP; Núñez, J; Sanchis, J; Valero, E, 2017)
"DPP4is as a second-line add-on to metformin had a significantly lower stroke risk [hazard ratio (HR) 0."	3.85	Comparative cardiovascular risks of dipeptidyl peptidase 4 inhibitors with other second- and third-line antidiabetic drugs in patients with type 2 diabetes. ( Chang, KC; Li, CY; Ou, HT; Wu, JS, 2017)
"To investigate whether metformin can improve the cardiac function through improving the mitochondrial function in model of heart failure after myocardial infarction."	3.85	Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism. ( Sun, D; Yang, F, 2017)
"The aim of the present study was to assess the risk of overall mortality, coronary artery disease (CAD), and congestive heart failure (CHF) in patients with type 2 diabetes mellitus (T2DM) treated with metformin (MF) and an additional antidiabetic agent."	3.83	Risk of overall mortality and cardiovascular events in patients with type 2 diabetes on dual drug therapy including metformin: A large database study from the Cleveland Clinic. ( Kannan, S; Karafa, M; Matsuda, S; Pantalone, KM; Wells, BJ; Zimmerman, RS, 2016)
"56]) compared with sulfonylureas as add-on therapy to metformin but had no effect on risks for myocardial infarction and hospitalization for heart failure."	3.81	Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus. ( Chao, PW; Chen, TJ; Chen, YT; Chu, H; Kuo, SC; Lee, YJ; Li, SY; Lin, CC; Ou, SM; Shih, CJ; Tarng, DC; Wang, SJ; Yang, CY, 2015)
" The risk of all-cause mortality was also significantly lower in the PIO cohort than the INS cohort among subgroups based on baseline variables such as sex, age (<55 years, ≥55 years), antidiabetic medication use (sulfonylureas or metformin), lipid-altering medication use, and congestive heart failure status."	3.80	A comparison of all-cause mortality with pioglitazone and insulin in type 2 diabetes: an expanded analysis from a retrospective cohort study. ( Bron, M; Joseph, G; Liang, H; Perez, A; Vallarino, C; Yang, J; Yu, S, 2014)
"To examine the safety and potential benefits of metformin in diabetic patients with cardiovascular (CV) disease and heart failure (HF)."	3.79	Evaluating the potential benefits of metformin in patients with cardiovascular disease and heart failure. ( Amin, SM; Chilipko, AA; Macharia, D; Norwood, DK; Still, KL, 2013)
"To assess the effect of the commencement of metformin therapy (CMet) on the prognosis of patients with newly diagnosed heart failure (HF) and new-onset diabetes mellitus (DM) treated with a contemporary medical regimen."	3.79	Metformin therapy and prognosis of patients with heart failure and new-onset diabetes mellitus. A propensity-matched study in the community. ( Andrey, JL; Corzo, R; Escobar, MA; Garcia-Domiguez, GJ; Garcia-Egido, A; Gomez, F; Perez, V; Romero, SP, 2013)
"Higher risks for death (overall and due to cardiovascular disease) and heart failure were found for rosiglitazone compared to pioglitazone."	3.77	Risk of death and cardiovascular outcomes with thiazolidinediones: a study with the general practice research database and secondary care data. ( Gallagher, AM; Leufkens, HG; Seabroke, S; Smeeth, L; van Staa, TP, 2011)
"Metformin inhibited cardiac fibrosis induced by pressure overload in vivo and inhibited collagen synthesis in CFs probably via inhibition of the TGF-beta(1)-Smad3 signalling pathway."	3.76	Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. ( Feng, W; Fu, Y; Lu, Z; Ma, X; Shen, Q; Xiao, H; Xu, M; Zhang, Y; Zhu, Y, 2010)
"Diabetes and heart failure commonly coexist, and prior studies have suggested better outcomes with metformin than other antidiabetic agents."	3.76	Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K. General Practice Research Database. ( Bhagra, S; Eurich, DT; Jhund, PS; Lewsey, JD; MacDonald, MR; Majumdar, SR; McAlister, FA; McMurray, JJ; Petrie, JR; Petrie, MC, 2010)
"The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern."	3.76	Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. ( Abildstrøm, SZ; Andersson, C; Gislason, GH; Hansen, PR; Jørgensen, CH; Køber, L; Lange, T; Norgaard, ML; Olesen, JB; Schramm, TK; Torp-Pedersen, C; Vaag, A; Weeke, P, 2010)
"Clinical studies have reported that the widely used antihyperglycemic drug metformin significantly reduces cardiac risk factors and improves clinical outcomes in patients with heart failure."	3.75	Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. ( Anaya-Cisneros, M; Calvert, JW; Gundewar, S; Jha, S; Ji, SY; Lefer, DJ; Nunez, D; Ramachandran, A; Tian, R; Toedt-Pingel, I, 2009)
"Metformin attenuated oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK."	3.75	Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. ( Asakura, M; Asanuma, H; Fujita, M; Ito, S; Kim, J; Kitakaze, M; Komamura, K; Minamino, T; Mochizuki, N; Ogai, A; Sanada, S; Sasaki, H; Sugimachi, M; Takahama, H; Takashima, S; Wakeno, M, 2009)
"To determine if the risk of developing heart failure (HF) is associated with the use of sulfonylurea or metformin in patients with diabetes."	3.74	The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy. ( Eurich, DT; Johnson, JA; Majumdar, SR; McAlister, FA, 2008)
"Metformin is considered contraindicated in patients with heart failure because of concerns over lactic acidosis, despite increasing evidence of potential benefit."	3.73	Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. ( Eurich, DT; Johnson, JA; Majumdar, SR; McAlister, FA; Tsuyuki, RT, 2005)
"According to package inserts, metformin is contraindicated in diabetic patients receiving drug treatment for heart failure therapy, and thiazolidinediones are not recommended in diabetic patients with symptoms of advanced heart failure."	3.72	Metformin and thiazolidinedione use in Medicare patients with heart failure. ( Foody, JM; Havranek, EP; Inzucchi, SE; Krumholz, HM; Masoudi, FA; Setaro, JF; Wang, Y, 2003)
"In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups."	3.11	Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes. ( Bebu, I; Burch, HB; Buse, JB; Cherrington, AL; Fortmann, SP; Green, JB; Kahn, SE; Kirkman, MS; Krause-Steinrauf, H; Lachin, JM; Larkin, ME; Nathan, DM; Phillips, LS; Pop-Busui, R; Steffes, M; Tiktin, M; Tripputi, M; Wexler, DJ; Younes, N, 2022)
"While type 2 diabetes mellitus (T2DM) increases the risk of cardiac complications, diabetes treatment choices may increase or decrease the rates of cardiac events."	3.01	Treatment of type 2 diabetes patients with heart conditions. ( Aktas, G; Atak Tel, BM; Balci, B; Tel, R, 2023)
"Metformin has been in clinical use for the management of type 2 diabetes for more than 60 years and is supported by a vast database of clinical experience: this includes evidence for cardioprotection from randomised trials and real-world studies."	2.82	Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. ( Bailey, CJ; Brand, K; Schernthaner, G, 2022)
"There is a bi-directional link between type 2 diabetes mellitus (T2DM) and heart failure (HF) and their co-existence markedly increases an individual's morbidity and mortality."	2.82	Contemporary choice of glucose lowering agents in heart failure patients with type 2 diabetes. ( Katsiki, N; Kazakos, K; Triposkiadis, F, 2022)
"Metformin is the drug of choice in the treatment of type 2 diabetes mellitus."	2.72	Novel Targets of Metformin in Cardioprotection: Beyond the Effects Mediated by AMPK. ( Bolívar, S; Mendoza, X; Mendoza-Torres, E; Noriega, L; Ortega, S; Osorio, E; Rosales, W, 2021)
"However, statin failed to reduce chronic kidney diseases (CKD) and heart failure (HF)."	2.66	Second revolution in cardiovascular prevention. ( Chao, TF; Cheng, HM; Chiang, CE; Sung, SH; Wang, KL, 2020)
"Type 2 diabetes mellitus has long been recognized as a major risk factor for adverse atherosclerotic cardiovascular disease events; however, recent data indicate that heart failure is now emerging as the most common and morbid cardiovascular complication of type 2 diabetes mellitus."	2.61	A Review of Cardiovascular Outcomes Trials of Glucose-Lowering Therapies and Their Effects on Heart Failure Outcomes. ( Kosiborod, M; Nassif, ME, 2019)
"Metformin can also inhibit the generation and accumulation of advanced glycation end products (AGEs) and thereby prevents the development of the adverse structural and functional changes in myocardium."	2.55	The pathophysiological basis of the protective effects of metformin in heart failure. ( Dziubak, A; Wójcicka, G, 2017)
" The cardiovascular effects of these drugs are multiple, their knowledge is important in the everyday practice, as the use of safe drugs regarding of heart failure is preferred."	2.55	[The safety of anti-diabetic drugs in heart failure]. ( Frigy, A; Germán-Salló, M; Máthé, L; Szabó, M, 2017)
"Type 2 diabetes is not only an independent risk factor for cardiovascular (CV) disease but is also associated with a greater incidence of heart failure (HF)."	2.52	Oral hypoglycemic agents and the heart failure conundrum: Lessons from and for outcome trials. ( Federici, M; Kappel, BA; Marx, N, 2015)
"In patients with type 2 diabetes mellitus, treatment with metformin is associated with a lower cardiovascular morbidity and mortality, compared with alternative glucose-lowering drugs."	2.47	The cardioprotective effects of metformin. ( de Boer, RA; El Messaoudi, S; Riksen, NP; Rongen, GA, 2011)
"Metformin is a biguanide, insulin sensitiser that reduces blood sugar levels."	2.46	Metformin: safety in cardiac patients. ( Khurana, R; Malik, IS, 2010)
"Metformin is a biguanide, insulin sensitiser that reduces blood sugar levels."	2.46	Metformin: safety in cardiac patients. ( Khurana, R; Malik, IS, 2010)
"The incidence of congestive cardiac failure was similar with pioglitazone (12/1857) and non-pioglitazone (10/1856) treatments."	2.42	Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and gliclazide. ( Belcher, G; Edwards, G; Goh, KL; Lambert, C; Valbuena, M, 2004)
"The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades."	1.91	Clinical pharmacology of antidiabetic drugs: What can be expected of their use? ( Scheen, AJ, 2023)
"We enrolled type 2 diabetes patients who received DPP4i or SU in addition to metformin."	1.72	Cardioprotective effects of dipeptidyl peptidase-4 inhibitors versus sulfonylureas in addition to metformin: A nationwide cohort study of patients with type 2 diabetes. ( Chien, KL; Wang, J; Wu, HY, 2022)
"Cardiac fibrosis is a major structural change observed in the heart of patients with type 2 diabetes mellitus (T2DM), ultimately resulting in heart failure (HF)."	1.72	Gentiopicroside alleviates cardiac inflammation and fibrosis in T2DM rats through targeting Smad3 phosphorylation. ( Hu, XP; Huang, P; Huang, ZJ; Liu, T; Pan, ZF; Shi, JN; Sun, ZY; Xu, YN; Yuan, MN; Zhang, YW; Zou, XZ, 2022)
"Left ventricular hypertrophy is a common finding in patients with ischemic heart disease and is associated with mortality in patients with cardiovascular disease (CVD)."	1.72	Effect of metformin on left ventricular mass and functional parameters in non-diabetic patients: a meta-analysis of randomized clinical trials. ( Farid, S; Kamel, AM; Sabry, N, 2022)
"Increased age and the presence of congestive heart failure were associated with significantly higher risk of AF in both groups (HR: 1."	1.72	Association between first-line monotherapy with metformin and the risk of atrial fibrillation (AMRAF) in patients with type 2 diabetes. ( Chung, MK; Iqbal, A; Ji, X; Kashyap, SR; Kattan, MW; Milinovich, A; Pantalone, KM; Tekin, Z; Zimmerman, RS, 2022)
"In the treatment of heart failure with reduced ejection fraction (with or without diabetes), dapagliflozin and empagliflozin have been recommended by cardiologists since 2021 to prevent hospitalizations for heart failure and to reduce mortality with the strongest class and level of evidence."	1.72	The position of SGLT2 inhibitors in current medical practice - update 2022. ( Prázný, M, 2022)
"no comorbidities) but more likely in congestive heart failure (OR 1."	1.56	Pharmacological treatment initiation for type 2 diabetes in Australia: are the guidelines being followed? ( Bell, JS; Ilomäki, J; Keen, CS; Magliano, DJ; Shaw, JE; Wood, SJ, 2020)
"Metformin use was associated with reduced lipid accumulation independently of immunosuppressive therapy."	1.56	Lipid Accumulation in Hearts Transplanted From Nondiabetic Donors to Diabetic Recipients. ( Amarelli, C; Balestrieri, ML; Cacciatore, F; D'Amico, M; D'Onofrio, N; De Feo, M; Esposito, S; Golino, P; Maiello, C; Mansueto, G; Marfella, R; Mattucci, I; Napoli, C; Paolisso, G; Salerno, G, 2020)
"The global incidence and prevalence of type 2 diabetes have been escalating in recent decades."	1.56	2020 Consensus of Taiwan Society of Cardiology on the pharmacological management of patients with type 2 diabetes and cardiovascular diseases. ( Chang, KC; Chao, TF; Chao, TH; Chen, WJ; Cheng, HM; Cheng, SM; Chiang, CE; Chu, PH; Huang, JL; Hung, HF; Hwang, JJ; Lai, WT; Li, YH; Lin, SJ; Lin, TH; Liu, ME; Liu, PY; Shyu, KG; Sung, SH; Tsai, CD; Ueng, KC; Wang, KL; Wu, YJ; Wu, YW; Yeh, HI; Yeh, SJ; Yin, WH, 2020)
"Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT."	1.51	Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation. ( Amunts, S; Fisman, EZ; Klempfner, R; Lavee, J; Maor, E; Ovdat, T; Peled, Y; Ram, E; Sternik, L; Tenenbaum, A, 2019)
"Metformin-treated mice have unaltered PEVK phosphorylation but increased phosphorylation of PKA sites in the N2B element, a change which has previously been shown to lower titin's stiffness."	1.51	Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance. ( Gotthardt, M; Granzier, HL; Liss, M; Methawasin, M; Slater, RE; Strom, JG; Sweitzer, N, 2019)
"Metformin has been shown to have favorable effects on the course of heart failure in experimental models."	1.48	Is metformin beneficial for heart failure in patients with type 2 diabetes? ( Packer, M, 2018)
"Metformin treatment in patients with different degrees of HF and T2DM is associated with a reduction in mortality and does not affect the hospitalisation rate."	1.48	The influence of metformin and the presence of type 2 diabetes mellitus on mortality and hospitalisation in patients with heart failure. ( Crespo-Leiro, M; Drożdż, J; Drzewoski, J; Jankowska, E; Kosmalski, M; Maggioni, A; Opolski, G; Poloński, L; Ponikowski, P; Retwiński, A, 2018)
"The included 3810 patients with type 2 diabetes had their treatment intensified at baseline."	1.43	Incidence, characteristics and impact of hypoglycaemia in patients receiving intensified treatment for inadequately controlled type 2 diabetes mellitus. ( Bramlage, P; Gitt, AK; Schneider, S; Tschöpe, D, 2016)
"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)
"Patients with type 2 diabetes who had been on metformin monotherapy and started another agent in addition to metformin were eligible for inclusion."	1.43	Cardiovascular safety of glucose-lowering agents as add-on medication to metformin treatment in type 2 diabetes: report from the Swedish National Diabetes Register. ( Ekström, N; Eliasson, B; Franzén, S; Gudbjörnsdottir, S; Miftaraj, M; Svensson, AM; Zethelius, B, 2016)
" These results, which do not account for levels of adherence or dosage information and which are subject to confounding by indication, might have implications for prescribing of diabetes drugs."	1.43	Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care. ( Coupland, C; Hippisley-Cox, J, 2016)
"Data on risk factors for Clostridium difficile infection (CDI) in diabetic patients are scarce."	1.42	Predicting Clostridium difficile infection in diabetic patients and the effect of metformin therapy: a retrospective, case-control study. ( Barsheshet, A; Bishara, J; Eliakim-Raz, N; Fishman, G; Goldberg, E; Stein, GY; Yahav, D; Zvi, HB, 2015)
"Individuals with type 2 diabetes (T2DM) are at increased risk of cardiovascular disease, including heart failure (HF)."	1.39	Metformin treatment may be associated with decreased levels of NT-proBNP in patients with type 2 diabetes. ( Czlonkowski, A; Filipiak, KJ; Kaplon-Cieslicka, A; Opolski, G; Postula, M; Rosiak, M; Trzepla, E, 2013)
"Metformin represents the cornerstone of treatment for type 2 diabetes mellitus."	1.38	Metformin and heart failure: never say never again. ( Maltezos, E; Mikhailidis, DP; Papanas, N, 2012)
"Insulin resistance is a recently identified mechanism involved in the pathophysiology of chronic heart failure (CHF)."	1.38	Metformin prevents the development of chronic heart failure in the SHHF rat model. ( Aimaretti, G; Cittadini, A; Isgaard, J; Longobardi, S; Monti, MG; Napoli, R; Netti, PA; Rea, D; Saccà, L; Samà, M; Walser, M, 2012)
"Metformin therapy was associated with lower rates of mortality in ambulatory patients with diabetes and HF."	1.37	Metformin use and mortality in ambulatory patients with diabetes and heart failure. ( Aguilar, D; Bozkurt, B; Chan, W; Deswal, A; Ramasubbu, K, 2011)
"Advanced HF (heart failure) is associated with altered substrate metabolism."	1.37	Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. ( Benada, O; Benes, J; Cervenka, L; Drahota, Z; Houstek, J; Kazdova, L; Kolar, M; Kopecky, J; Kovarova, N; Medrikova, D; Melenovsky, V; Petrak, J; Sedmera, D; Skaroupkova, P; Strnad, H; Vrbacky, M, 2011)
"Metformin is recommended in type 2 diabetes mellitus because it reduced mortality among overweight participants in the United Kingdom Prospective Diabetes Study when used mainly as a means of primary prevention."	1.36	Metformin use and mortality among patients with diabetes and atherothrombosis. ( Bhatt, DL; Goto, S; Marre, M; Pasquet, B; Porath, A; Ravaud, P; Roussel, R; Smith, SC; Steg, PG; Travert, F; Wilson, PW, 2010)
"Metformin was associated with a reduced risk of CHF (HR 0."	1.35	The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. ( Arrigain, S; Atreja, A; Jain, A; Kattan, MW; Pantalone, KM; Wells, BJ; Yu, C; Zimmerman, RS, 2009)
"Pioglitazone was associated with reduced all cause mortality compared with metformin."	1.35	Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. ( Curcin, V; Elliott, P; Hughes, RI; Khunti, K; Little, MP; Majeed, A; Millett, CJ; Molokhia, M; Ng, A; Tzoulaki, I; Wilkins, MR, 2009)

Research

Studies (200)

Authors

Clinical Trials (18)

Trial Overview

Trial Outcomes

Myocyte Lipid Accumulation as Oil Red-O Positive Biopsie

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	40 (20.00)	29.6817
2010's	95 (47.50)	24.3611
2020's	65 (32.50)	2.80

Authors	Studies
Wang, J	6
Wu, HY	1
Chien, KL	1
Khan, MS	2
Solomon, N	1
DeVore, AD	2
Sharma, A	1
Felker, GM	2
Hernandez, AF	2
Heidenreich, PA	1
Matsouaka, RA	1
Green, JB	3
Butler, J	2
Yancy, CW	1
Peterson, PN	1
Fonarow, GC	2
Greene, SJ	2
Vicha, M	1
Skala, T	1
Jelinek, L	1
Pavlu, L	1
Jarkovsky, J	1
Dusek, L	1
Benesova, K	1
Taborsky, M	1
Salvatore, T	1
Galiero, R	1
Caturano, A	1
Vetrano, E	1
Rinaldi, L	1
Coviello, F	1
Di Martino, A	1
Albanese, G	1
Marfella, R	2
Sardu, C	1
Sasso, FC	1
Li, T	1
Providencia, R	1
Jiang, W	1
Liu, M	1
Yu, L	1
Gu, C	1
Chang, ACY	1
Ma, H	2
Schernthaner, G	1
Brand, K	1
Bailey, CJ	1
Mone, P	2
Lombardi, A	2
Gambardella, J	1
Pansini, A	2
Macina, G	2
Morgante, M	1
Frullone, S	2
Santulli, G	2
Godec, TR	1
Bromage, DI	1
Pujades-Rodriguez, M	1
Cannatà, A	1
Gonzalez-Izquierdo, A	1
Denaxas, S	1
Hemingway, H	1
Shah, AM	1
Yellon, DM	1
McDonagh, TA	1
Dia, M	1
Leon, C	1
Chanon, S	1
Bendridi, N	1
Gomez, L	1
Rieusset, J	1
Thibault, H	1
Paillard, M	1
Tanaka, A	2
Node, K	2
Shin, H	1
Schneeweiss, S	1
Glynn, RJ	1
Patorno, E	1
Wong, CKH	1
Lau, KTK	1
Tang, EHM	1
Lee, CH	3
Lee, CYY	1
Woo, YC	2
Au, ICH	1
Tan, KCB	1
Lui, DTW	1
Liu, S	1
Liu, Q	2
Peng, Q	1
Zhang, Y	6
Benes, J	2
Kotrc, M	1
Kroupova, K	1
Wohlfahrt, P	1
Kovar, J	1
Franekova, J	1
Hegarova, M	1
Hoskova, L	1
Hoskova, E	1
Pelikanova, T	1
Jarolim, P	1
Kautzner, J	1
Melenovsky, V	2
Zou, XZ	1
Zhang, YW	1
Pan, ZF	1
Hu, XP	1
Xu, YN	1
Huang, ZJ	1
Sun, ZY	1
Yuan, MN	1
Shi, JN	1
Huang, P	1
Liu, T	1
Kamel, AM	1
Sabry, N	1
Farid, S	1
Nathan, DM	2
Lachin, JM	1
Bebu, I	1
Burch, HB	1
Buse, JB	1
Cherrington, AL	1
Fortmann, SP	1
Kahn, SE	1
Kirkman, MS	1
Krause-Steinrauf, H	1
Larkin, ME	1
Phillips, LS	1
Pop-Busui, R	2
Steffes, M	1
Tiktin, M	1
Tripputi, M	1
Wexler, DJ	1
Younes, N	1
Mannucci, E	1
Gallo, M	1
Giaccari, A	1
Candido, R	1
Pintaudi, B	1
Targher, G	1
Monami, M	1
Iqbal, A	1
Tekin, Z	1
Kattan, MW	2
Ji, X	1
Milinovich, A	1
Pantalone, KM	3
Zimmerman, RS	3
Chung, MK	1
Kashyap, SR	1
Prázný, M	1
Katsiki, N	1
Kazakos, K	1
Triposkiadis, F	1
Wang, MT	2
Pan, HY	2
Huang, YL	2
Wu, LW	2
Wang, PC	2
Hsu, YJ	2
Lin, TC	2
Lin, C	2
Lai, JH	2
Kansakar, U	1
Varzideh, F	1
Jankauskas, SS	1
Marzocco, S	1
De Gennaro, S	1
Famiglietti, M	1
Scheen, AJ	1
Chowdhury, G	1
Carland, JE	1
Kumar, S	1
Olsen, N	1
Graham, G	1
Kumarasinghe, G	1
Hayward, CS	1
Greenfield, JR	1
Macdonald, P	1
Day, RO	1
Stocker, SL	1
Aktas, G	1
Atak Tel, BM	1
Tel, R	1
Balci, B	1
Brønden, A	1
Christensen, MB	1
Glintborg, D	1
Snorgaard, O	1
Kofoed-Enevoldsen, A	1
Madsen, GK	1
Toft, K	1
Kristensen, JK	1
Højlund, K	1
Hansen, TK	1
Søndergaard, E	1
Hansen, KB	1
Li, JZ	1
Li, YR	2
McNair, BD	1
Polson, SM	1
Shorthill, SK	1
Yusifov, A	1
Walker, LA	1
Weiser-Evans, MCM	1
Kovacs, EJ	1
Bruns, DR	1
Oikonomou, E	1
Xenou, M	1
Zakynthinos, GE	1
Tsaplaris, P	1
Lampsas, S	1
Bletsa, E	1
Gialamas, I	1
Kalogeras, K	1
Goliopoulou, A	1
Gounaridi, MI	1
Pesiridis, T	1
Tsatsaragkou, A	1
Vavouranakis, M	1
Siasos, G	1
Tousoulis, D	1
Povar-Echeverría, M	1
Méndez-Bailón, M	1
Martín-Sánchez, FJ	1
Montero-Pérez-Barquero, M	1
Trullàs, JC	1
Miró, Ò	1
Ram, E	1
Lavee, J	1
Tenenbaum, A	1
Klempfner, R	1
Fisman, EZ	1
Maor, E	1
Ovdat, T	1
Amunts, S	1
Sternik, L	1
Peled, Y	1
Wood, SJ	1
Magliano, DJ	1
Bell, JS	1
Shaw, JE	1
Keen, CS	1
Ilomäki, J	1
Tseng, CH	1
Gu, J	1
Yin, ZF	1
Zhang, JF	1
Wang, CQ	1
Nassif, ME	1
Kosiborod, M	1
Mordi, IR	2
Mohan, M	1
Lang, CC	6
Bergmark, BA	2
Bhatt, DL	3
McGuire, DK	4
Scirica, BM	2
Packer, M	4
Chiang, CE	2
Wang, KL	2
Cheng, HM	2
Sung, SH	2
Chao, TF	2
Dong, YH	1
Wang, SV	1
Gagne, JJ	1
Wu, LC	1
Chang, CH	2
Dludla, PV	1
Nyambuya, TM	1
Johnson, R	1
Silvestri, S	1
Orlando, P	1
Mazibuko-Mbeje, SE	1
Gabuza, KB	1
Mxinwa, V	1
Mokgalaboni, K	1
Tiano, L	1
Muller, CJF	1
Louw, J	1
Nkambule, BB	1
Amarelli, C	1
Cacciatore, F	1
Balestrieri, ML	1
Mansueto, G	1
D'Onofrio, N	1
Esposito, S	1
Mattucci, I	1
Salerno, G	1
De Feo, M	1
D'Amico, M	1
Golino, P	1
Maiello, C	1
Paolisso, G	1
Napoli, C	1
Wang, L	2
Halliday, G	1
Huot, JR	1
Satoh, T	1
Baust, JJ	2
Fisher, A	1
Cook, T	1
Hu, J	4
Avolio, T	1
Goncharov, DA	3
Bai, Y	1
Vanderpool, RR	3
Considine, RV	1
Bonetto, A	1
Tan, J	1
Bachman, TN	1
Sebastiani, A	1
McTiernan, CF	1
Mora, AL	3
Machado, RF	1
Goncharova, EA	3
Gladwin, MT	4
Lai, YC	4
Bolívar, S	1
Noriega, L	1
Ortega, S	1
Osorio, E	1
Rosales, W	1
Mendoza, X	1
Mendoza-Torres, E	1
Hirsch, IB	1
Gaudiani, LM	1
Bajaj, NS	1
Vaduganathan, M	1
Ueng, KC	1
Chao, TH	1
Lin, TH	1
Wu, YJ	1
Yeh, HI	1
Li, YH	1
Liu, PY	1
Chang, KC	2
Shyu, KG	1
Huang, JL	1
Tsai, CD	1
Hung, HF	1
Liu, ME	1
Cheng, SM	1
Chu, PH	2
Yin, WH	1
Wu, YW	1
Chen, WJ	1
Lai, WT	1
Lin, SJ	1
Yeh, SJ	1
Hwang, JJ	1
Thein, D	1
Christiansen, MN	1
Mogensen, UM	1
Bundgaard, JS	1
Rørth, R	1
Madelaire, C	1
Fosbøl, EL	1
Schou, M	2
Torp-Pedersen, C	2
Gislason, G	2
Køber, L	4
Kristensen, SL	2
Halabi, A	1
Sen, J	1
Huynh, Q	1
Marwick, TH	1
Larsen, AH	2
Wiggers, H	2
Dollerup, OL	1
Jespersen, NR	1
Hansson, NH	1
Frøkiær, J	1
Brøsen, K	1
Nørrelund, H	2
Bøtker, HE	2
Møller, N	1
Jessen, N	1
Wang, D	2
Mao, Y	1
Wang, T	2
Xiong, T	1
Yang, X	4
Nguépy Keubo, FR	1
Mboua, PC	1
Djifack Tadongfack, T	1
Fokouong Tchoffo, E	1
Tasson Tatang, C	1
Ide Zeuna, J	1
Noupoue, EM	1
Tsoplifack, CB	1
Folefack, GO	1
Kettani, M	1
Bandelier, P	1
Huo, J	1
Li, H	4
Yu, D	1
Arulsamy, N	1
AlAbbad, S	1
Sardot, T	1
Lekashvili, O	1
Decato, D	1
Lelj, F	1
Alexander Ross, JB	1
Rosenberg, E	1
Nazir, H	1
Muthuswamy, N	1
Louis, C	1
Jose, S	1
Prakash, J	1
Buan, MEM	1
Flox, C	1
Chavan, S	1
Shi, X	1
Kauranen, P	1
Kallio, T	1
Maia, G	1
Tammeveski, K	1
Lymperopoulos, N	1
Carcadea, E	1
Veziroglu, E	1
Iranzo, A	1
M Kannan, A	1
Arunamata, A	1
Tacy, TA	1
Kache, S	1
Mainwaring, RD	1
Ma, M	1
Maeda, K	1
Punn, R	1
Noguchi, S	1
Hahn, S	3
Iwasa, Y	3
Ling, J	2
Voccio, JP	2
Kim, Y	3
Song, J	3
Bascuñán, J	2
Chu, Y	1
Tomita, M	1
Cazorla, M	1
Herrera, E	1
Palomeque, E	1
Saud, N	1
Hoplock, LB	1
Lobchuk, MM	1
Lemoine, J	1
Li, X	10
Henson, MA	1
Unsihuay, D	1
Qiu, J	1
Swaroop, S	1
Nagornov, KO	1
Kozhinov, AN	1
Tsybin, YO	1
Kuang, S	1
Laskin, J	1
Zin, NNINM	1
Mohamad, MN	1
Roslan, K	1
Abdul Wafi, S	1
Abdul Moin, NI	1
Alias, A	1
Zakaria, Y	1
Abu-Bakar, N	1
Naveed, A	1
Jilani, K	1
Siddique, AB	1
Akbar, M	1
Riaz, M	1
Mushtaq, Z	1
Sikandar, M	1
Ilyas, S	1
Bibi, I	1
Asghar, A	1
Rasool, G	1
Irfan, M	1
Li, XY	1
Zhao, S	1
Fan, XH	1
Chen, KP	1
Hua, W	1
Liu, ZM	1
Xue, XD	1
Zhou, B	1
Zhang, S	2
Xing, YL	1
Chen, MA	1
Sun, Y	2
Neradilek, MB	1
Wu, XT	1
Zhang, D	2
Huang, W	1
Cui, Y	1
Yang, QQ	1
Li, HW	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
Cognitive and Physical Impairment in Frail Older Adults[NCT04962841]		485 participants (Anticipated)	Observational	2020-04-01	Recruiting
Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study[NCT01794143]	Phase 3	5,047 participants (Actual)	Interventional	2013-05-31	Completed
Lipid Accumulation in Heart Transplant From Non-diabetic Donors to Diabetic Recipients[NCT03546062]		177 participants (Actual)	Observational	2010-01-01	Completed
The Effect of Addition of Metformin In Obese Non- Diabetic Patients With Heart Failure With Preserved Ejection Fraction[NCT05847244]	Phase 2	80 participants (Anticipated)	Interventional	2023-10-01	Recruiting
Effects of Metformin Treatment on Myocardial Efficiency in Patients With Heart Failure: A Randomized, Double-blind, Placebo-controlled Study[NCT02810132]	Phase 2	36 participants (Actual)	Interventional	2017-01-20	Completed
A Randomized, Double-blind, Placebo Controlled Study (DANHEART): Hydralazine-ISDN in Patients With Chronic Heart Failure - Hydralazine Heart Failure Trial (H-HeFT) and Metformin in Patients With Chronic Heart Failure and Diabetes or Insulin Resistance - M[NCT03514108]	Phase 4	1,500 participants (Anticipated)	Interventional	2018-03-01	Recruiting
Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure With Reduced Ejection Fraction[NCT03036124]	Phase 3	4,744 participants (Actual)	Interventional	2017-02-08	Completed
A Multicentre, Randomised, Double-Blind, Placebo-Controlled Phase IV Trial to Evaluate the Effect of Saxagliptin on the Incidence of Cardiovascular Death, Myocardial Infarction or Ischaemic Stroke in Patients With Type 2 Diabetes[NCT01107886]	Phase 4	18,206 participants (Actual)	Interventional	2010-05-31	Completed
BIO-2-HEART Study (Identifying New BIOmarkers in Patients With Type 2 Diabetes Mellitus and HEArt Failure Receiving Cardiac Resynchronization Therapy Device Implantation)[NCT03323216]		200 participants (Anticipated)	Observational	2018-04-01	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
Patients With Heart Failure ANd Type 2 Diabetes Treated With Placebo Or Metformin (PHANTOM) Pilot Study[NCT00325910]	Phase 3	100 participants	Interventional	2006-05-31	Terminated (stopped due to Insufficient study participants)
A Long Term, Open Label, Randomised Study in Patients With Type 2 Diabetes, Comparing the Combination of Rosiglitazone and Either Metformin or Sulfonylurea With Metformin Plus Sulfonylurea on Cardiovascular Endpoints and Glycaemia[NCT00379769]	Phase 3	4,447 participants (Actual)	Interventional	2001-04-30	Completed
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
Use of Metformin in Prevention and Treatment of Cardiac Fibrosis in PAI-1 Deficient Population[NCT05317806]	Phase 4	15 participants (Anticipated)	Interventional	2022-10-10	Active, not recruiting
Effect of Metformin Glycinate on Postprandial Lipemia, Glycemic Control and Oxidation Markers in Type 2 Diabetes Patients[NCT02064881]	Phase 2/Phase 3	72 participants (Anticipated)	Interventional	2015-10-31	Recruiting
The Influence of Rosiglitazone on the Diuretic Effect of Furosemide and Amiloride. A Double-blind Placebo Controlled Cross Over Study.[NCT00285805]		13 participants (Actual)	Interventional	2006-02-28	Completed
Characterization of the Cardiotoxic Effects of Chemotherapies With Anthracyclines and Trastuzumab for Breast Cancer by Contrast-enhanced Cardiovascular Magnetic Resonance Imaging (CMR).[NCT00679874]		66 participants (Anticipated)	Observational	2008-05-31	Terminated (stopped due to No subjects indentifiable)
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Authors will evaluate myocyte lipid accumulation as Oil Red-O positive biopsie after heart transplant at follow up. (NCT03546062)
Timeframe: 12 months.

Change From Baseline in the KCCQ Total Symptom Score

Intervention	Endomyocardial Biopsies (Count of Units)
Diabetic Metformin Group	54
Diabetic Group Without Metformin Therapy	21
Non-diabetic Group	0

KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ total symptom score incorporates the symptom domains into a single score. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. (NCT03036124)
Timeframe: Baseline and 8 months or death before 8 months

Events Included in the Composite Endpoint of Recurrent Hospitalizations Due to Heart Failure and CV Death.

Subjects Included in the Composite Endpoint of ≥50% Sustained Decline in eGFR, ESRD or Renal Death.

Subjects Included in the Composite Endpoint of CV Death or Hospitalization Due to Heart Failure.

Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure.

Subjects Included in the Endpoint of All-cause Mortality.

Participants With Any Event From the Composite of Cardiovascular Death (CV Death), Non-fatal Myocardial Infarction (MI), or Non-fatal Ischaemic Stroke

Intervention	Scores on a scale (Mean)
Dapa 10 mg	6.1
Placebo	3.3

Intervention	events (Number)
Dapa 10 mg	567
Placebo	742

Intervention	Participants (Count of Participants)
Dapa 10 mg	28
Placebo	39

Intervention	Participants (Count of Participants)
Dapa 10 mg	382
Placebo	495

Intervention	Participants (Count of Participants)
Dapa 10 mg	386
Placebo	502

Intervention	Participants (Count of Participants)
Dapa 10 mg	276
Placebo	329

Participants with CV death, non-fatal MI or non-fatal ischaemic stroke. If no event, censoring occurs at the patient withdrawal of consent, last contact, or death (when applicable)-whichever was later. (NCT01107886)
Timeframe: Randomization (day 0) up to 2.9 years

Participants With Any Event From the Composite of CV Death, Non-fatal MI, Non-fatal Ischaemic Stroke, Hospitalisation for Heart Failure, Hospitalisation for Unstable Angina Pectoris, or Hospitalisation for Coronary Revascularisation

Intervention	participants (Number)
Saxagliptin	613
Placebo	609

Participants with CV death, non-fatal MI, non-fatal ischaemic stroke, hospitalisation for heart failure, hospitalisation for unstable angina pectoris, or hospitalisation for coronary revascularisation. If no event, censoring occurs at the patient withdrawal of consent, last contact, or death (when applicable)-whichever was later. (NCT01107886)
Timeframe: Randomization (day 0) up to 2.9 years

Participants With Event of Death

Intervention	participants (Number)
Saxagliptin	1059
Placebo	1034

Participants with event of death. If no event, censoring occurs at the patient withdrawal of consent, or last contact -whichever was later. (NCT01107886)
Timeframe: Randomization (day 0) up to 2.9 years

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

Intervention	participants (Number)
Saxagliptin	420
Placebo	378

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

Intervention	picomoles O2/min (Mean)
WHO Group I Pulmonary Arterial Hypertension (PAH)	-17.58
WHO Group II Pulmonary Hypertension (PH)	8.62
WHO Group III Pulmonary Hypertension (PH)	-11.64

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

Intervention	micromolar (Mean)
WHO Group I Pulmonary Arterial Hypertension (PAH)	9.9
WHO Group II Pulmonary Hypertension (PH)	7.0
WHO Group III Pulmonary Hypertension (PH)	7.4

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

Intervention	micromolar (Mean)
WHO Group I Pulmonary Arterial Hypertension (PAH)	9.2
WHO Group III Pulmonary Hypertension (PH)	2.4

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)

Intervention	dyne*sec/cm5 (Median)
WHO Group I Pulmonary Arterial Hypertension (PAH)	-0.004
WHO Group II Pulmonary Hypertension (PH)	-0.34
WHO Group III Pulmonary Hypertension (PH)	-0.20

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)

Intervention	Woods units (Mean)
WHO Group I Pulmonary Arterial Hypertension (PAH)	0.77
WHO Group II Pulmonary Hypertension (PH)	0.40
WHO Group III Pulmonary Hypertension (PH)	-0.39

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)

Intervention	mmHg (Mean)
WHO Group I Pulmonary Arterial Hypertension (PAH)	-5.1
WHO Group II Pulmonary Hypertension (PH)	-3.4
WHO Group III Pulmonary Hypertension (PH)	-9.5

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

Intervention	mmHg⋅min/L (Mean)
WHO Group I Pulmonary Arterial Hypertension (PAH)	-0.43
WHO Group II Pulmonary Hypertension (PH)	1.19
WHO Group III Pulmonary Hypertension (PH)	-2.04

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

Independent Re-adjudication (IR) Outcome: Number of Participants With a First Occurrence of a Major Adverse Cardiovascular Event (MACE) Defined as CV (or Unknown) Death, Non-fatal MI, and Non-fatal Stroke Based on Original RECORD Endpoint Definitions

Intervention	minutes (Mean)
WHO Group I Pulmonary Arterial Hypertension (PAH)	42.0
WHO Group II Pulmonary Hypertension (PH)	33.0
WHO Group III Pulmonary Hypertension (PH)	42.5

IR was based on original RECORD endpoint definitions. CV death= no unequivocal non-CV cause (sudden death, death from acute vascular events, heart failure, acute MI, other CV causes, and deaths adjudicated as unknown cause). MI event=hospitalization + elevation of specific cardiac biomarkers above the upper limit of normal + cardiac ischemia symptoms/new pathological electrocardiogram findings. Stroke event=hospitalization + rapidly developed clinical signs of focal/global disturbance of cerebral function for more than 24 hours, with no apparent cause other than a vascular origin. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Independent Re-adjudication Outcome: Number of Participants (Par.) With an Event of Stroke (Fatal and Non-fatal), Based on Original RECORD Endpoint Definitions

Intervention	participants (Number)
Combined RSG	181
Combined MET/SU	188

Par. with a stroke (fatal or non-fatal) event as determined by independent re-adjudication using the original RECORD endpoint definitions was recorded. A stroke event=hospitalization plus rapidly developed clinical signs of focal (or global) disturbance of cerebral function lasting more than 24 hours (unless interrupted by thrombolysis, surgery, or death), with no apparent cause other than a vascular origin, including par. presenting clinical signs/symptoms suggestive of subarachnoid haemorrhage/intracerebral haemorrhage/cerebral ischemic necrosis or cause of death adjudicated as stroke. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Independent Re-adjudication Outcome: Number of Participants Who Died Due to Any Cause

Intervention	participants (Number)
Combined RSG	50
Combined MET/SU	63

All deaths identified during the original record study and discovered after the re-adjudication efforts began were included. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Independent Re-adjudication Outcome: Number of Participants With a CV (or Unknown) Death, Based on Contemporary Endpoint Definitions

Intervention	participants (Number)
Combined RSG	139
Combined MET/SU	160

The number of participants with a CV (or unknown) death as determined by independent re-adjudication using the Standard Data Collection for Cardiovascular Trials Initiative (draft October 2011) endpoint definitions was recorded. CV death included death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure, death due to stroke, and death due to other CV causes. Deaths of unknown cause were counted as CV deaths. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Independent Re-adjudication Outcome: Number of Participants With a CV (or Unknown) Death, Based on Original RECORD Endpoint Definitions

Intervention	participants (Number)
Combined RSG	88
Combined MET/SU	96

"The number of participants with a CV death (or unknown) as determined by independent re-adjudication using the original RECORD endpoint definitions was recorded. CV death was defined as any death for which an unequivocal non-CV cause could not be established. CV death included death following heart failure, death following acute myocardial infarction (MI), sudden death, death due to acute vascular events, and other CV causes. Deaths due to unknown causes were classified as unknown deaths, but were counted as CV deaths for the analysis of this endpoint." (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Independent Re-adjudication Outcome: Number of Participants With a First Occurrence of a Major Adverse Cardiovascular Event (MACE) Defined as CV (or Unknown) Death, Non-fatal MI, and Non-fatal Stroke Based on Contemporary Endpoint Definitions

Intervention	participants (Number)
Combined RSG	88
Combined MET/SU	96

Independent re-adjudication was based on the Standard Data Collection for Cardiovascular Trials Initiative (draft October 2011) endpoint definitions. CV death included death resulting from an acute MI; sudden cardiac death and death due to heart failure, stroke, and to other CV causes. Deaths of unknown cause were counted as CV deaths. MI was defined as evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Stroke was defined as an acute episode of neurological dysfunction caused by focal or global brain, spinal cord, or retinal vascular injury. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Independent Re-adjudication Outcome: Number of Participants With an Event of Myocardial Infarction (Fatal and Non-fatal), Based on Contemporary Endpoint Definitions

Intervention	participants (Number)
Combined RSG	186
Combined MET/SU	191

The number of participants with an MI (fatal or non-fatal) event as determined by independent re-adjudication using the Standard Data Collection for Cardiovascular Trials Initiative (draft October 2011) endpoint definitions was recorded. An event of MI was defined as evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Independent Re-adjudication Outcome: Number of Participants With an Event of Myocardial Infarction (Fatal and Non-fatal), Based on Original RECORD Endpoint Definitions

Intervention	participants (Number)
Combined RSG	72
Combined MET/SU	62

The number of participants with an MI (fatal or non-fatal) event as determined by independent re-adjudication using the original RECORD endpoint definitions was recorded. An event of MI was defined as hospitalization plus elevation of cardiac biomarkers troponin (TN) I and/or TNT above the upper limit of normal (ULN) or creatinine kinase (CK) MB (M=muscle type; B=brain type) isoenzyme >= 2x the ULN or CK > 2x the ULN plus typical symptoms of cardiac ischemia or new pathological electrocardiogram findings, or cause of death adjudicated as MI. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Independent Re-adjudication Outcome: Number of Participants With an Event of Stroke (Fatal and Non-fatal), Based on Contemporary Endpoint Definitions

Intervention	participants (Number)
Combined RSG	68
Combined MET/SU	60

The number of participants with a stroke (fatal or non-fatal) event as determined by independent re-adjudication using the Standard Data Collection for Cardiovascular Trials Initiative (draft October 2011) endpoint definitions was recorded. An event of stroke was defined as an acute episode of neurological dysfunction caused by focal or global brain, spinal cord, or retinal vascular injury. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Model Adjusted Change From Baseline in Alanine Aminotransferase at Month 60

Intervention	participants (Number)
Combined RSG	53
Combined MET/SU	64

Model adjusted (adjusted for any imbalances in the baseline values between within stratum treatment groups) change from baseline in alanine aminotransferase was calculated as the value at Month 60 minus the Baseline value. (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Model Adjusted Change From Baseline in Body Weight at Month 60

Intervention	U/L (Units/Liter) (Mean)
RSG in Addition to Background MET	-37.43
SU in Addition to Background MET	-21.73
RSG in Addition to Background SU	-30.17
MET in Addition to Background SU	-24.00

Model adjusted (adjusted for any imbalances in the baseline values between within stratum treatment groups) change from baseline in body weight was calculated as the value at Month 60 minus the Baseline value. (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Model Adjusted Change From Baseline in Fasting Plasma Glucose at Month 60

Intervention	kilograms (Mean)
RSG in Addition to Background MET	3.93
SU in Addition to Background MET	-0.54
RSG in Addition to Background SU	4.72
MET in Addition to Background SU	-2.16

Model adjusted (adjusted for any imbalances in the baseline values between within stratum treatment groups) change from baseline in fasting plasma glucose was calculated as the value at Month 60 minus the Baseline value. (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment period

Model Adjusted Change From Baseline in HbA1c at Month 60

Intervention	mmol/L (millimoles/Liter) (Mean)
RSG in Addition to Background MET	-1.38
SU in Addition to Background MET	-0.29
RSG in Addition to Background SU	-2.00
MET in Addition to Background SU	-0.94

Model adjusted (adjusted for any imbalances in the baseline values between within stratum treatment groups) change from baseline in HbA1c was calculated as the value at Month 60 minus the Baseline value. (NCT00379769)
Timeframe: Baseline and Month 60 of randomised dual therapy treatment period

Model Adjusted Change From Baseline in Waist Circumference at Month 60

Intervention	Percent (Mean)
RSG in Addition to Background MET	-0.14
SU in Addition to Background MET	0.17
RSG in Addition to Background SU	-0.24
MET in Addition to Background SU	-0.10

Model adjusted (adjusted for any imbalances in the baseline values between within stratum treatment groups) change from baseline in waist circumference was calculated as the value at Month 60 minus the Baseline value. (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Apolipoprotein B (Apo-B) at Month 60

Intervention	cm (centimeters) (Mean)
RSG in Addition to Background MET	2.70
SU in Addition to Background MET	0.65
RSG in Addition to Background SU	3.00
MET in Addition to Background SU	-0.60

The model adjusted (adjusted for any imbalances in the baseline [BL] values between within stratum treatment groups) ratio to BL in Apo-B was calculated as the ratio of the Month 60 value to the BL value and was expressed as percent change from BL. For each treatment group, the model-adjusted mean change from BL at Month 60 was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the Month 60 value to BL on the original scale. The GM was expressed as a percentage (100*[GM^-1]). (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment period

Model Adjusted Ratio to Baseline (Expressed as a Percentage) for C-Reactive Protein at Month 60

Intervention	percent change (Geometric Mean)
RSG in Addition to Background MET	-13.77
SU in Addition to Background MET	-11.63
RSG in Addition to Background SU	-9.68
MET in Addition to Background SU	-12.09

The model adjusted (adjusted for any imbalances in the baseline [BL] values between within stratum treatment groups) ratio to BL in C-Reactive Protein was calculated as the ratio of the Month 60 value to the BL value and was expressed as percent change from BL. For each treatment group, the model-adjusted mean change from BL at Month 60 was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the Month 60 value to BL on the original scale. The GM was expressed as a percentage (100*[GM^-1]). (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Fibrinogen at Month 60

Intervention	percent change (Geometric Mean)
RSG in Addition to Background MET	-57.40
SU in Addition to Background MET	-28.92
RSG in Addition to Background SU	-56.50
MET in Addition to Background SU	-36.29

The model adjusted (adjusted for any imbalances in the baseline [BL] values between within stratum treatment groups) ratio to BL in fibrinogen was calculated as the ratio of the Month 60 value to the BL value and was expressed as percent change from BL. For each treatment group, the model-adjusted mean change from BL at Month 60 was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the Month 60 value to BL on the original scale. The GM was expressed as a percentage (100*[GM^-1]). (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Plasminogen Activator Inhibitor-1 (PAI-1) Antigen at Month 60

Intervention	percent change (Geometric Mean)
RSG in Addition to Background MET	2.12
SU in Addition to Background MET	5.74
RSG in Addition to Background SU	-0.23
MET in Addition to Background SU	3.14

The model adjusted (adjusted for any imbalances in the baseline [BL] values between within stratum treatment groups) ratio to BL in plasminogen activator inhibitor-1 (PAI-1) antigen was calculated as the ratio of the Month 60 value to the BL value and was expressed as percent change from BL. For each treatment group, the model-adjusted mean change from BL at Month 60 was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the Month 60 value to BL on the original scale. The GM was expressed as a percentage (100*[GM^-1]). (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Urinary Albumin Creatinine Ratio at Month 60

Intervention	percent change (Geometric Mean)
RSG in Addition to Background MET	-9.85
SU in Addition to Background MET	15.01
RSG in Addition to Background SU	-7.79
MET in Addition to Background SU	-0.64

The model adjusted (adjusted for any imbalances in the baseline [BL] values between within stratum treatment groups) ratio to BL in urinary albumin creatinine ratio was calculated as the ratio of the Month 60 value to the BL value and was expressed as percent change from BL. For each treatment group, the model-adjusted mean change from BL at Month 60 was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the Month 60 value to BL on the original scale. The GM was expressed as a percentage (100*[GM^-1]). (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Number of Participants With an Event of Death Due to a Bone Fracture-related Event: Main Study + Observational Follow-up Combined

Intervention	percent change (Geometric Mean)
RSG in Addition to Background MET	8.31
SU in Addition to Background MET	15.17
RSG in Addition to Background SU	-3.43
MET in Addition to Background SU	11.91

Number of Participants With Cardiovascular Death/Cardiovascular Hospitalisation Events

Intervention	participants (Number)
Combined RSG: Main Study and Observational Follow-up	0
Combined MET/SU: Main Study and Observational Follow-up	0

The number of participants with cardiovascular death events (death due to cardiovascular causes or deaths with insufficient information to rule out a cardiovascular cause) and cardiovascular hospitalisation events (hospitalisation for a cardiovascular event, excluding planned admissions not associated with a worsening of the disease/condition of the participant) was recorded. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Number of Participants With First Cardiovascular Hospitalisations/Cardiovascular Deaths by Stratum

Intervention	participants (Number)
Combined RSG	321
Combined MET/SU	323

Participants with first cardiovascular death (death due to cardiovascular causes or deaths with insufficient information to rule out a cardiovascular cause) and cardiovascular hospitalisation (hospitalisation for a cardiovascular event, excluding planned admissions not associated with a worsening of the disease/condition of the participant) were recorded by study stratum. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Number of Participants With Glycaemic Failure Events

Intervention	partcipants (Number)
RSG in Addition to Background MET	158
SU in Addition to Background MET	154
RSG in Addition to Background SU	163
MET in Addition to Background SU	169

Failure of glycaemic control was defined as two consecutive HbA1c values of ≥8.5 percent, or HbA1c ≥8.5percent at a single visit, after which the subject was either moved to the post-randomised treatment phase or triple therapy was started. (NCT00379769)
Timeframe: Baseline through to end of randomised dual therapy

The Number of Participants Starting Insulin at Any Time During the Study

Intervention	participants (Number)
RSG in Addition to Background MET	281
SU in Addition to Background MET	451
RSG in Addition to Background SU	365
MET in Addition to Background SU	424

The number of participants starting insulin at any time during the study was recorded. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Model Adjusted Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Month 60

Intervention	participants (Number)
RSG in Addition to Background MET	126
SU in Addition to Background MET	276
RSG in Addition to Background SU	168
MET in Addition to Background SU	259

Model adjusted (adjusted for any imbalances in the baseline values between within treatment groups) change from baseline in SBP and DBP was calculated as the value at Month 60 minus the Baseline value. (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Model Adjusted Mean Change From Baseline in Insulin and Pro-insulin at Month 60

Intervention	mmHg (millimeters of mercury) (Mean)
	SBP	DBP
MET in Addition to Background SU	-0.6	-2.3
RSG in Addition to Background MET	-1.9	-3.6
RSG in Addition to Background SU	-2.3	-3.6
SU in Addition to Background MET	-2.2	-3.4

Model adjusted (adjusted for any imbalances in the baseline values between within stratum treatment groups) change from baseline in insulin and pro-insulin was calculated as the value at Month 60 minus the Baseline value. (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment period

Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Total Cholesterol (TC), Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, Triglycerides, and Free Fatty Acids (FFAs) at Month 60

Intervention	picamoles/liter (pmol/L) (Mean)
	Insulin, Adjusted Change from Baseline	Pro-insulin, Adjusted Change from Baseline
MET in Addition to Background SU	-12.1	-3.0
RSG in Addition to Background MET	-18.6	-2.4
RSG in Addition to Background SU	-16.9	-3.2
SU in Addition to Background MET	3.7	4.2

The model adjusted (adjusted for any imbalances in the baseline [BL] values between within stratum treatment groups) ratio to BL in TC, LDL cholesterol, HDL cholesterol, triglycerides, and FFAs was calculated as the ratio of the Month 60 value to the BL value and was expressed as percent change from BL. For each treatment group, the model-adjusted mean change from BL at Month 60 was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the Month 60 value to BL on the original scale. The GM was expressed as a percentage (100*[GM^-1]). (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Model Adjusted Ratio to Baseline (Expressed as a Percentage) for Total Cholesterol (TC):High-density Lipoprotein (HDL) Cholesterol and Low-density Lipoprotein (LDL) Cholesterol:HDL Cholesterol Ratios at Month 60

Intervention	percent change (Geometric Mean)
	Total cholesterol	HDL-cholesterol	LDL-cholesterol	Triglycerides	Free fatty acids
MET in Addition to Background SU	-9.68	6.14	-17.80	-2.50	4.47
RSG in Addition to Background MET	-5.49	9.95	-12.70	-7.97	-16.46
RSG in Addition to Background SU	-2.91	7.73	-8.99	-2.68	-11.58
SU in Addition to Background MET	-9.09	2.57	-17.68	-1.95	2.79

The model adjusted (adjusted for any imbalances in the baseline [BL] values between within stratum treatment groups) ratio to BL in TC:HDL cholesterol and LDL cholesterol:HDL cholesterol was calculated as the ratio of the Month 60 value to the BL value and was expressed as percent change from BL. For each treatment group, the model-adjusted mean change from BL at Month 60 was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the Month 60 value to BL on the original scale. The GM was expressed as a percentage (100*[GM^-1]). (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment period

Model Adjusted Ratio to Baseline (Expressed as a Percentage) Homeostasis Model Assessment (HOMA) Beta Cell Function and Insulin Sensitivity at Month 60

Intervention	percent change (Geometric Mean)
	Total Cholesterol: HDL Cholesterol Ratio	LDL Cholesterol: HDL-Cholesterol Ratio
MET in Addition to Background SU	-15.01	-22.53
RSG in Addition to Background MET	-14.20	-20.89
RSG in Addition to Background SU	-9.93	-15.85
SU in Addition to Background MET	-11.33	-20.04

The model adjusted (adjusted for any imbalances in the baseline [BL] values between within stratum treatment groups) ratio to BL in HOMA beta-cell function and insulin sensitivity was calculated as the ratio of the Month 60 value to the BL value and was expressed as percent change from BL. For each treatment group, the model-adjusted mean change from BL at Month 60 was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the Month 60 value to BL on the original scale. The GM was expressed as a percentage (100*[GM^-1]). (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment phase

Number of Bone Fracture Events With the Indicated Outcome: Main Study + Observational Follow-up Combined

"The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. A bone fracture event is defined as one or more fractured bones occurring on the same date and that had the same Higher Level Group Term (HLGT) for fracture location, per participant. The indicated fracture outcome was pre-specified in the CRF and included Unknown as a category. Fracture events with missing outcome data were reported as Data unavailable." (NCT00379769)
Timeframe: From the beginning of the main study through the end of the observational follow-up (up to 11.4 years)

Number of Bone Fracture Events With the Indicated Outcome: Observational Follow-up

"The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. A bone fracture event is defined as one or more fractured bones occurring on the same date and that had the same Higher Level Group Term (HLGT) for fracture location, per participant. The indicated fracture outcome was pre-specified in the CRF and included Unknown as a category. Fracture events with missing outcome data were reported as Data unavailable." (NCT00379769)
Timeframe: From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years)

Number of HbA1c and Fasting Plasma Glucose (FPG) Responders at Month 60

Number of responders, i.e., participants meeting glycaemic targets (HbA1c less than or equal to 7 percent, FPG less than or equal to 7 mmol/L) (NCT00379769)
Timeframe: Baseline to Month 60 of the randomised dual therapy treatment period

Number of Participants Who Died Due to the Indicated Cancer-related Event: Main Study + Observational Follow-up Combined

The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. An SAE is defined as any event that is fatal; life threatening; disabling/incapacitating; results in hospitalization (excluding elective surgery or routine clinical procedures); prolongs a hospital stay; is associated with a congenital abnormality; cancer; is associated with an overdose. In addition, any event that the investigator regards as serious or that would suggest any significant hazard, contraindication, side effect, or precaution that may be associated with the study procedures should be reported as an SAE. (NCT00379769)
Timeframe: From the beginning of the main study through the end of the observational follow-up (up to 11.4 years)

Number of Participants Who Died Due to the Indicated Cancer-related Event: Observational Follow-up

The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. An SAE is defined as any event that is fatal; life threatening; disabling/incapacitating; results in hospitalization (excluding elective surgery or routine clinical procedures); prolongs a hospital stay; is associated with a congenital abnormality; cancer; is associated with an overdose. In addition, any event that the investigator regards as serious or that would suggest any significant hazard, contraindication, side effect, or precaution that may be associated with the study procedures should be reported as an SAE. (NCT00379769)
Timeframe: From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years)

Number of Participants With a Bone Fracture Event - Overall and by Gender: Main Study and Observational Follow-up Combined

Number of Participants With a Bone Fracture Event - Overall and by Gender: Observational Follow-up

Number of Participants With a Bone Fracture Event Reported as the Indicated Serious Adverse Event (by Higher Level Group Term) or Death: Main Study + Observational Follow-up Combined

The OFU was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the OFU. A bone fracture event is defined as one or more fractured bones occurring on the same date and that had the same Higher Level Group Term (HLGT) for fracture location, per participant. An SAE is defined as any event that is fatal; life threatening; disabling/incapacitating; results in hospitalization (excluding elective surgery or routine clinical procedures); prolongs a hospital stay; is associated with a congenital abnormality; cancer; is associated with an overdose. In addition, any event that the investigator regards as serious or that would suggest any significant hazard, contraindication, side effect, or precaution that may be associated with the study procedures should be reported as an SAE. (NCT00379769)
Timeframe: From the beginning of the main study through the end of the observational follow-up (up to 11.4 years)

Number of Participants With a Bone Fracture Event Reported as the Indicated Serious Adverse Event (by Higher Level Group Term) or Death: Observational Follow-up

The OFU was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the OFU. A bone fracture event is defined as one or more fractured bones occurring on the same date and that had the same Higher Level Group Term (HLGT) for fracture location, per participant. An SAE is defined as any event that is fatal; life threatening; disabling/incapacitating; results in hospitalization (excluding elective surgery or routine clinical procedures); prolongs a hospital stay; is associated with a congenital abnormality; cancer; is associated with an overdose. In addition, any event that the investigator regards as serious or that would suggest any significant hazard, contraindication, side effect, or precaution that may be associated with the study procedures should be reported as an SAE. (NCT00379769)
Timeframe: From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years)

Number of Participants With Addition of Third Oral Agent/Switch to Insulin

The number of participants with addition of a third oral agent or switch to insulin from randomised dual combination treatment were recorded. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Number of Participants With Bone Fracture Events of the Indicated Cause: Main Study + Observational Follow-up Combined

Number of Participants With Bone Fracture Events of the Indicated Cause: Observational Follow-up

"The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. A bone fracture event is defined as one or more fractured bones occurring on the same date and that had the same Higher Level Group Term (HLGT) for fracture location, per participant. The indicated fracture outcome was pre-specified in the CRF and included Unknown as a category. Fracture events with missing outcome data were reported as Data unavailable." (NCT00379769)
Timeframe: From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years)

Number of Participants With Cardiovascular Events and All-cause Deaths

Composites of participants with first cardiovascular (CV) hospitalisations and CV death or all-cause death and individual first events of acute myocardial infarction (MI) , stroke, congestive heart failure (CHF), CV death, and all-cause death. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Number of Participants With CV/Microvascular Events

The number of participants with first cardiovascular or microvascular events (renal, foot, eye) were recorded. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Number of Participants With Potentially High Morbidity Fracture Events and Non-high Morbidity Fracture Events, in Participants With Prior Hand/Upper Arm/Foot Fractures (H/UA/FF): Main Study + Observational Follow-up Combined

The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. A bone fracture event is defined as one or more fractured bones occurring on the same date and that had the same Higher Level Group Term (HLGT) for fracture location, per participant. The following bone fractures were grouped and were identified as potentially high morbidity bone fractures: hip, pelvis, upper leg, vertebral (lumbar spine, thoracic spine, cervical spine, spine - site unknown). (NCT00379769)
Timeframe: From the beginning of the main study through the end of the observational follow-up (up to 11.4 years)

Number of Participants With Potentially High Morbidity Fractures: Main Study + Observational Follow-up Combined

The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. A bone fracture event is defined as one or more fractured bones occurring on the same date and that had the same Higher Level Group Term (HLGT) for fracture location, per participant. The following bone fractures were grouped and were identified as potentially high morbidity bone fractures: hip, pelvis, upper leg, vertebral (lumbar spine, thoracic spine, cervical spine, spine - site unknown). (NCT00379769)
Timeframe: From the beginning of the main study through the end of the observational follow-up (up to 11.4 years)

Number of Participants With the Indicated Bone Fracture by Fracture Site: Main Study + Observational Follow-up Combined

Number of Participants With the Indicated Bone Fracture by Fracture Site: Observational Follow-up

Number of Participants With the Indicated Serious Adverse Event: Observational Follow-up

The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. An SAE is defined as any event that is fatal; life threatening; disabling/incapacitating; results in hospitalization (excluding elective surgery or routine clinical procedures); prolongs a hospital stay; is associated with a congenital abnormality; cancer; is associated with an overdose. In addition, any event that the investigator regards as serious or that would suggest any significant hazard, contraindication, side effect, or precaution that may be associated with the study procedures should be reported as an SAE. (NCT00379769)
Timeframe: From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years)

Number of Participants With the Indicated Type of Malignant Neoplasms/Cancer Events Reported as an SAE or Death by Location (Including Location of Special Interest): Main Study + Observational Follow-up Combined

The observational follow-up (OFU) was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the OFU. The neoplasms/cancer events of bladder, breast, colon, liver, pancreatic, prostate cancer, and melanoma were pre-specified as cancers of interest for the OFU. An SAE is defined as any event that is fatal; life threatening; disabling/incapacitating; results in hospitalization (excluding elective surgery or routine clinical procedures); prolongs a hospital stay; is associated with a congenital abnormality; cancer; is associated with an overdose. In addition, any event that the investigator regards as serious or that would suggest any significant hazard, contraindication, side effect, or precaution that may be associated with the study procedures should be reported as an SAE. (NCT00379769)
Timeframe: From the beginning of the main study through the end of the observational follow-up (up to 11.4 years)

Number of Participants With the Indicated Type of Malignant Neoplasms/Cancer Events Reported as an SAE or Death by Location (Including Location of Special Interest): Observational Follow-up

The observational follow-up (OFU) was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the OFU. The neoplasms/cancer events of bladder, breast, colon, liver, pancreatic, prostate cancer, and melanoma were pre-specified as cancers of interest for the OFU. An SAE is defined as any event that is fatal; life threatening; disabling/incapacitating; results in hospitalization (excluding elective surgery or routine clinical procedures); prolongs a hospital stay; is associated with a congenital abnormality; cancer; is associated with an overdose. In addition, any event that the investigator regards as serious or that would suggest any significant hazard, contraindication, side effect, or precaution that may be associated with the study procedures should be reported as an SAE. (NCT00379769)
Timeframe: From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years)

Number of Participants With the Indicated Type of Neoplasm/Cancer Event Reported as a Serious Adverse Event (SAE) or Death: Main Study + Observational Follow-up Combined

Number of Participants With the Indicated Type of Neoplasm/Cancer Event Reported as a Serious Adverse Event (SAE) or Death: Observational Follow-up

The observational follow-up was designed to collect data concerning cancer and bone fractures in RECORD participants during a 4-year period after the end of the main RECORD study. At the end of the main study, all study medication was stopped. Participants were not provided with study medication in the observational follow-up; instead, anti-diabetic treatment was prescribed at the investigator's discretion. An SAE is defined as any event that is fatal; life threatening; disabling/incapacitating; results in hospitalization (excluding elective surgery or routine clinical procedures); prolongs a hospital stay; is associated with a congenital abnormality; cancer; is associated with an overdose. In addition, any event that the investigator regards as serious or that would suggest any significant hazard, contraindication, side effect, or precaution that may be associated with the study procedures should be reported as an SAE. (NCT00379769)
Timeframe: From the end of the RECORD study through the end of the observational follow-up (up to 4.0 years)

Total Number of Cardiovascular Hospitalisations and Cardiovascular Deaths

The total number of events for individual components of cardiovascular (CV) hospitalisations and cardiovascular deaths were recorded. MI, myocardial infarction. (NCT00379769)
Timeframe: Baseline through End of Study (up to 7.5 years)

Intervention	percent change (Geometric Mean)
	Beta cell function	Insulin sensitivity
MET in Addition to Background SU	12.43	23.90
RSG in Addition to Background MET	20.54	42.57
RSG in Addition to Background SU	32.35	42.07
SU in Addition to Background MET	19.28	-3.45

Intervention	bone fracture events (Number)
	Number of bone fracture events	Unknown	Normal healing with standard management	Complication	Additional therapeutic measures required	Data unavailable
Combined MET/SU: Main Study and Observational Follow-up	174	5	142	13	9	5
Combined RSG: Main Study and Observational Follow-up	299	7	250	14	16	12

Intervention	participants (Number)
	HbA1c Responders	FPG Responders
MET in Addition to Background SU	180	154
RSG in Addition to Background MET	265	300
RSG in Addition to Background SU	235	257
SU in Addition to Background MET	208	180

Intervention	participants (Number)
	Any cancer-related death	Any gastrointestinal event	Pancreatic	Colon/rectal	Gastric	Liver	Gall bladder/biliary	Gastrointestinal event; not specified	Any genitourinary event	Renal	Uterine	Prostate	Bladder	Ovarian	Lung	Any hematologic event	Skin (melanoma)	Skin (non-melanomatous)	Metastases	Breast	Head and neck	Any neurologic event	Endocrine	Not specified
Combined MET/SU: Main Study and Observational Follow-up	72	34	12	11	3	4	3	1	15	3	5	2	3	2	11	0	0	0	4	3	2	2	0	1
Combined RSG: Main Study and Observational Follow-up	59	25	4	6	7	4	4	0	6	2	1	1	1	1	13	4	3	1	2	2	1	2	1	0

Intervention	participants (Number)
	Overall, n=2220, 2227	Male, n=1142, 1152	Female, n=1078, 1075
Combined MET/SU: Main Study and Observational Follow-up	151	60	91
Combined RSG: Main Study and Observational Follow-up	238	82	156

Intervention	participants (Number)
	Overall, n=1280, 1250	Male, n=665, 635	Female, n=615, 615
Combined MET/SU: Observational Follow-up	37	11	26
Combined RSG: Observational Follow-up	64	25	39

Intervention	participants (Number)
	Any event	Upper limb	Distal lower limb	Femur/hip	Spinal	Pelvic	Other
Combined MET/SU: Main Study and Observational Follow-up	57	17	16	11	9	3	4
Combined RSG: Main Study and Observational Follow-up	81	41	24	15	7	0	7

Intervention	participants (Number)
	Participants with an event	First Event - Triple Therapy	First Event - Insulin
MET in Addition to Background SU	171	6	165
RSG in Addition to Background MET	295	257	38
RSG in Addition to Background SU	344	296	49
SU in Addition to Background MET	183	7	176

Intervention	participants (Number)
	Any event	Non-traumatic event	Traumatic event	Pathologic	Unknown	Data unavailable
Combined MET/SU: Main Study and Observational Follow-up	151	55	77	4	19	3
Combined RSG: Main Study and Observational Follow-up	238	113	110	1	20	9

Intervention	participants (Number)
	Any event	Non-traumatic event,	Traumatic event	Pathologic	Unknown	Data unavailable
Combined MET/SU: Observational Follow-up	37	14	17	2	4	1
Combined RSG: Observational Follow-up	64	36	24	1	1	3

Intervention	participants (Number)
	CV death, acute MI, stroke	CV death, acute MI, stroke, unstable angina	CV death, acute MI, stroke, unstable angina, CHF	All-cause death,acuteMI,stroke,unstable angina,CHF	Acute MI (fatal or non-fatal)	Stroke (fatal or non-fatal)	CHF (fatal or non-fatal)	Death from CV causes	Death (all cause) during CV follow-up	Death (all-cause) including survival status
Combined MET/SU	165	184	206	268	56	63	29	71	139	157
Combined RSG	154	171	204	251	64	46	61	60	111	136

Intervention	participants (Number)
	Participants with a CV/Microvascular event	Participants with any microvascular event	Participants with any eye event	Participants with any foot event	Participants with any renal event
Combined MET/SU	385	78	52	28	0
Combined RSG	363	59	42	19	0

Intervention	participants (Number)
	Any H/UA/FF event, overall, n=2220, 2227	Any H/UA/FF event, male, n=1142, 1152	Any H/UA/FF event, female, n=1078, 1075	High morbidity fractures, overall, n=2220, 2227	High morbidity fractures, male, n=1142, 1152	High morbidity fractures, female, n=1078, 1075	Non-high morbidity fractures, overall, n=2220, 222	Non-high morbidity fractures, male, n=1142, 1152	Non-high morbidity fractures, female, n=1078, 1075
Combined MET/SU: Main Study and Observational Follow-up	46	15	31	1	0	1	4	3	1
Combined RSG: Main Study and Observational Follow-up	86	28	58	5	0	5	15	2	13

Intervention	participants (Number)
	Any event, overall, n=2220, 2227	Any event, male, n=1142, 1152	Any event, female, n=1078, 1075	Hip, overall, n=2220, 2227	Hip, male, n=1142, 1152	Hip, female, n=1078, 1075	Pelvis, overall, n=2220, 2227	Pelvis, male, n=1142, 1152	Pelvis, female, n=1078, 1075	Upper leg, overall, n=2220, 2227	Upper leg, male, n=1142, 1152	Upper leg, female, n=1078, 1075	Any vertebral event, overall, n=2220, 2227	Any vertebral event, male, n=1142, 1152	Any vertebral event, female, n=1078, 1075	Lumbar spine, overall, n=2220, 2227	Lumbar spine, male, n=1142, 1152	Lumbar spine, female, n=1078, 1075	Thoracic spine, overall, n=2220, 2227	Thoracic spine, male, n=1142, 1152	Thoracic spine, female, n=1078, 1075	Cervical spine, overall, n=2220, 2227	Cervical spine, male, n=1142, 1152	Cervical spine, female, n=1078, 1075
Combined MET/SU: Main Study and Observational Follow-up	31	13	18	7	1	6	5	4	1	6	0	6	13	8	5	4	3	1	8	4	4	1	1	0
Combined RSG: Main Study and Observational Follow-up	31	10	21	9	0	9	0	0	0	7	4	3	16	6	10	10	5	5	5	1	4	1	0	1

Intervention	participants (Number)
	Any event, overall; n=2220, 2227	Any event, male; n=1142, 1152	Any event, female; n=1078, 1075	Upper limb, any event, overall; n=2220, 2227	Upper limb, any event, male; n=1142, 1152	Upper limb, any event, female; n=1078, 1075	Distal lower limb, any event, overall; n=2220, 222	Distal lower limb, any event, male; n=1142, 1152	Distal lower limb, any event, female; n=1078, 1075	Femur/hip, any event, overall; n=2220, 2227	Femur/hip, any event, male; n=1142, 1152	Femur/hip, any event, female; n=1078, 1075	Spinal, any event, overall; n=2220, 2227	Spinal, any event, male; n=1142, 1152	Spinal, any event, female; n=1078, 1075	Pelvic, any event, overall; n=2220, 2227	Pelvic, any event, male; n=1142, 1152	Pelvic, any event, female; n=1078, 1075	Unclassified, any event, overall; n=2220, 2227	Unclassified, any event, male; n=1142, 1152	Unclassified, any event, female; n=1078, 1075	Other, any event, overall; n=2220, 2227	Other, any event, male; n=1142, 1152	Other, any event, female; n=1078, 1075
Combined MET/SU: Main Study and Observational Follow-up	151	60	91	70	22	48	40	14	26	13	1	12	14	9	5	5	4	1	0	0	0	26	16	10
Combined RSG: Main Study and Observational Follow-up	238	82	156	116	32	84	88	31	57	16	4	12	18	7	11	0	0	0	1	1	0	31	18	13

Intervention	participants (Number)
	Any event, overall; n=1280, 1250	Any event, male; n=665, 635	Any event, female; n=615, 615	Upper limb, any event, overall; n=1280, 1250	Upper limb, any event, male; n=665, 635	Upper limb, any event, female; n=615, 615	Distal lower limb, any event, overall; n=1280,1250	Distal lower limb, any event, male; n=665, 635	Distal lower limb, any event, female; n=615, 615	Femur/hip, any event, overall; n=1280, 1250	Femur/hip, any event, male; n=665, 635	Femur/hip, any event, female; n=615, 615	Spinal, any event, overall; n=1280, 1250	Spinal, any event, male; n=665, 635	Spinal, any event, female; n=615, 615	Pelvic, any event, overall; n=1280, 1250	Pelvic, any event, male; n=665, 635	Pelvic, any event, female; n=615, 615	Unclassified, any event, overall; n=1280, 1250	Unclassified, any event, male; n=665, 635	Unclassified, any event, female; n=615, 615	Other, any event, overall; n=1280, 1250	Other, any event, male; n=665, 635	Other, any event, female; n=615, 615
Combined MET/SU: Observational Follow-up	37	11	26	15	3	12	13	4	9	5	0	5	5	4	1	1	1	0	0	0	0	1	1	0
Combined RSG: Observational Follow-up	64	25	39	33	10	23	18	9	9	6	1	5	4	1	3	0	0	0	1	1	0	6	4	2

Intervention	participants (Number)
	Any event	Ankle fracture	Prostate cancer	Lung neoplasm malignant	Breast cancer	Basal cell carcinoma	Pancreatic carcinoma	Colon cancer	Humerus fracture	Upper limb fracture	Malignant melanoma	Uterine cancer	Gastric cancer	Wrist fracture	Hip fracture	Radius fracture	Forearm fracture	Hepatic neoplasm malignant	Rectal cancer	Renal cancer	Foot fracture	Renal cell carcinoma	Femur fracture	Femoral neck fracture	Lumbar vertebral fracture	Metastases to bone	Metastases to liver	Bladder cancer	Fall	Metastases to central nervous system	Rib fracture	Squamous cell carcinoma	Acute myocardial infarction	Brain neoplasm	Gastric neoplasm	Metastases to lung	Patella fracture	Death	Abdominal pain	Acute myeloid leukaemia	Acute respiratory failure	Anaemia	Benign salivary gland neoplasm	Biliary colic	Biliary neoplasm	Bone neoplasm malignant	Bronchial carcinoma	Cardiac failure acute	Chest pain	Chronic lymphocytic leukaemia	Colon neoplasm	Contusion	Drowning	Dysplasia	Endometrial cancer stage I	Leukaemia	Lower limb fracture	Lung squamous cell carcinoma stage unspecified	Lymphoma	Malignant neoplasm of pleura	Metastases to skin	Metastases to testicle	Metastatic renal cell carcinoma	Oesophageal carcinoma	Osteoarthritis	Pancreatic necrosis	Rectal cancer stage II	Spinal fracture	T-cell lymphoma	Urinary tract infection	Uterine leiomyosarcoma	Biliary cancer metastatic	Cervix carcinoma	Chronic obstructive pulmonary disease	Comminuted fracture	Craniocerebral injury	Gastrointestinal neoplasm	Hepatic lesion	Joint dislocation	Laryngeal cancer	Lip neoplasm malignant stage unspecified	Lung neoplasm	Metastases to lymph nodes	Metastasis	Musculoskeletal chest pain	Myocardial infarction	Non-Hodgkin's lymphoma	Pubis fracture	Pulmonary embolism	Rectal cancer recurrent	Rectal neoplasm	Skin cancer	Skin ulcer	Small cell lung cancer stage unspecified	Sternal fracture	Subdural haemorrhage	Sudden death	Thoracic vertebral fracture	Thyroid cancer	Vulval cancer
Combined MET/SU: Observational Follow-up	76	3	1	4	6	3	3	6	1	1	2	3	0	0	1	1	2	2	2	2	3	0	1	2	2	2	2	0	0	0	0	0	1	1	1	1	1	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1	1	0	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
Combined RSG: Observational Follow-up	99	6	7	4	2	4	4	1	5	5	3	2	4	4	3	3	2	2	2	2	1	3	2	1	1	1	1	2	2	2	2	2	1	1	1	1	1	0	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Intervention	participants (Number)
	Any genitourinary	Prostate	Renal	Uterine	Bladder	Vaginal/vulvar	Ovarian	Any gastrointestinal	Colon/rectal cancer	Colon	Gastric	Pancreatic	Liver	Gall bladder/biliary	Gastrointestinal; not specified	Any hematologic	Lung	Skin (non-melanomatous)	Skin (melanomatous)	Metastases	Breast	Head and neck	Neurologic	Endocrine	Not specified	Other
Combined MET/SU: Main Study and Observational Follow-up	57	22	9	16	5	1	4	62	30	21	5	16	5	5	1	6	15	13	4	18	23	7	3	6	1	3
Combined RSG: Main Study and Observational Follow-up	57	22	12	11	8	1	5	48	22	14	13	5	4	4	0	12	19	19	6	12	12	4	3	3	0	0

Intervention	participants (Number)
	All neoplasms/cancer (N/C) (benign/malignant)	Malignant (Mal.) N/C	Mal. N/C; excluding non-melanomatous skin cancers
Combined MET/SU: Main Study and Observational Follow-up	215	195	186
Combined RSG: Main Study and Observational Follow-up	196	179	164

Intervention	Number of events (Number)
	CV deaths	Death due to acute MI	Death due to heart failure	Sudden death	Death due to acute vascular events	Other CV mortality	Death of presumed CV cause	Cardiovascular hospitalisation	Hospitalisation for acute MI	Hospitalisation for unstable angina	Hospitalisation for congestive heart failure	Hospitalisation for stroke	Hospitalisation for transient ischaemic attack	Hospitalisation for invasive CV procedure	Hospitalisation for amputation of extremities	Other CV hospitalisations
Combined MET/SU	71	10	2	12	10	4	33	490	57	28	36	67	10	116	23	153
Combined RSG	60	7	10	8	1	6	28	483	66	28	69	51	10	99	6	154

Article	Year
Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence. Biomolecules, 2021, 12-04, Volume: 11, Issue:12 Topics: Diabetes Mellitus, Type 2; Heart Failure; Humans; Metformin; Randomized Controlled Trials as Topic	2021
Association of Metformin with the Mortality and Incidence of Cardiovascular Events in Patients with Pre-existing Cardiovascular Diseases. Drugs, 2022, Volume: 82, Issue:3 Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Humans; Incidence; Metformin; Myo	2022
Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. Metabolism: clinical and experimental, 2022, Volume: 130 Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucose; Heart	2022
Effects of glucose-lowering agents on cardiovascular and renal outcomes in subjects with type 2 diabetes: An updated meta-analysis of randomized controlled trials with external adjudication of events. Diabetes, obesity & metabolism, 2023, Volume: 25, Issue:2 Topics: Adult; Albuminuria; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Glucagon-Like Pe	2023
Contemporary choice of glucose lowering agents in heart failure patients with type 2 diabetes. Expert opinion on pharmacotherapy, 2022, Volume: 23, Issue:17 Topics: Contraindications, Drug; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Lik	2022
Treatment of type 2 diabetes patients with heart conditions. Expert review of endocrinology & metabolism, 2023, Volume: 18, Issue:3 Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Humans; Metformin; Sodium-Glucose	2023
Effects of DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors and sulphonylureas on mortality, cardiovascular and renal outcomes in type 2 diabetes: A network meta-analyses-driven approach. Diabetic medicine : a journal of the British Diabetic Association, 2023, Volume: 40, Issue:8 Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Lik	2023
Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research. Cardiology, 2023, Volume: 148, Issue:4 Topics: Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucose; Heart Failure; Humans;	2023
Novel Approaches to the Management of Diabetes Mellitus in Patients with Coronary Artery Disease. Current pharmaceutical design, 2023, Volume: 29, Issue:23 Topics: Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV	2023
A Review of Cardiovascular Outcomes Trials of Glucose-Lowering Therapies and Their Effects on Heart Failure Outcomes. The American journal of cardiology, 2019, 12-15, Volume: 124 Suppl 1 Topics: Acarbose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Rec	2019
Second revolution in cardiovascular prevention. Journal of the Chinese Medical Association : JCMA, 2020, Volume: 83, Issue:4 Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Lik	2020
Metformin and heart failure-related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials. Heart failure reviews, 2021, Volume: 26, Issue:6 Topics: Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Metformin; Randomized Control	2021
Novel Targets of Metformin in Cardioprotection: Beyond the Effects Mediated by AMPK. Current pharmaceutical design, 2021, Volume: 27, Issue:1 Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Heart Failure; Metformin; Myocard	2021
Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs. Cardiovascular diabetology, 2020, 05-13, Volume: 19, Issue:1 Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Biomarkers; Blood Glucose; Diabetes Mellitus; Dia	2020
Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovascular diabetology, 2020, 08-05, Volume: 19, Issue:1 Topics: Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Hypoglyce	2020
Psychological distress among health care professionals of the three COVID-19 most affected Regions in Cameroon: Prevalence and associated factors. Annales medico-psychologiques, 2021, Volume: 179, Issue:2 Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acryli	2021
Psychological distress among health care professionals of the three COVID-19 most affected Regions in Cameroon: Prevalence and associated factors. Annales medico-psychologiques, 2021, Volume: 179, Issue:2 Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acryli	2021
Psychological distress among health care professionals of the three COVID-19 most affected Regions in Cameroon: Prevalence and associated factors. Annales medico-psychologiques, 2021, Volume: 179, Issue:2 Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acryli	2021
Psychological distress among health care professionals of the three COVID-19 most affected Regions in Cameroon: Prevalence and associated factors. Annales medico-psychologiques, 2021, Volume: 179, Issue:2 Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acryli	2021
Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis. PloS one, 2021, Volume: 16, Issue:2 Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV I	2021
Novel antidiabetic drugs and risk of cardiovascular events in patients without baseline metformin use: a meta-analysis. European journal of preventive cardiology, 2021, 03-23, Volume: 28, Issue:1 Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Heart Failure;	2021
Metformin in patients with type 2 diabetes mellitus and heart failure: a review. Endokrynologia Polska, 2021, Volume: 72, Issue:2 Topics: Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Metformin; Pharmaceutical Pre	2021
Still sour about lactic acidosis years later: role of metformin in heart failure. Heart failure reviews, 2018, Volume: 23, Issue:3 Topics: Acidosis, Lactic; Blood Glucose; Diabetes Mellitus, Type 2; Global Health; Heart Failure; Humans; Hy	2018
The pathophysiological basis of the protective effects of metformin in heart failure. Postepy higieny i medycyny doswiadczalnej (Online), 2017, Aug-24, Volume: 71, Issue:1 Topics: Diabetes Mellitus, Type 2; Heart; Heart Failure; Humans; Hypoglycemic Agents; Metformin; Myocardium;	2017
Higher mortality rate in patients with heart failure who are taking commonly prescribed antidiabetic medications and achieve recommended levels of glycaemic control. Diabetes, obesity & metabolism, 2018, Volume: 20, Issue:7 Topics: Chronic Disease; Comorbidity; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Heart Failure; Humans;	2018
Clinical implications of current cardiovascular outcome trials with sodium glucose cotransporter-2 (SGLT2) inhibitors. Atherosclerosis, 2018, Volume: 272 Topics: Albuminuria; Atherosclerosis; Benzhydryl Compounds; Body Weight; Canagliflozin; Cardiovascular Disea	2018
Metabolic Effects of Metformin in the Failing Heart. International journal of molecular sciences, 2018, Sep-21, Volume: 19, Issue:10 Topics: Animals; Diabetes Mellitus, Type 2; Glycation End Products, Advanced; Heart Failure; Humans; Hypogly	2018
Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circulation. Heart failure, 2013, Volume: 6, Issue:3 Topics: Comorbidity; Comparative Effectiveness Research; Contraindications; Diabetic Angiopathies; Heart Fai	2013
[Limitations of insulin-dependent drugs in the treatment of type 2 diabetes mellitus]. Medicina clinica, 2013, Volume: 141 Suppl 2 Topics: Contraindications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Comb	2013
Use of metformin in diseases of aging. Current diabetes reports, 2014, Volume: 14, Issue:6 Topics: Aging; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Administratio	2014
The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies. BMC cardiovascular disorders, 2014, Sep-26, Volume: 14 Topics: Bias; Biomarkers; Blood Glucose; Chi-Square Distribution; Diabetes Mellitus, Type 2; Heart Failure;	2014
Is AMPK the savior of the failing heart? Trends in endocrinology and metabolism: TEM, 2015, Volume: 26, Issue:1 Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Energy Metabolism; Heart; Heart	2015
Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: review of a hypothesis. Cardiology, 2015, Volume: 130, Issue:4 Topics: 3-O-Methylglucose; Animals; Disease Models, Animal; Endoplasmic Reticulum Stress; Fatty Acids; Gluco	2015
Oral hypoglycemic agents and the heart failure conundrum: Lessons from and for outcome trials. Nutrition, metabolism, and cardiovascular diseases : NMCD, 2015, Volume: 25, Issue:8 Topics: Adamantane; Administration, Oral; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic;	2015
Pharmacogenomics in diabetes mellitus: insights into drug action and drug discovery. Nature reviews. Endocrinology, 2016, Volume: 12, Issue:6 Topics: Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Drug Discovery; Drug-Related Side	2016
The emerging role of Toll-like receptor 4 in myocardial inflammation. Cell death & disease, 2016, 05-26, Volume: 7 Topics: Animals; Cardiotonic Agents; Clinical Trials as Topic; Disaccharides; Follistatin; Gene Expression R	2016
Energy Remodeling, Mitochondrial Disorder and Heart Failure. Current pharmaceutical design, 2016, Volume: 22, Issue:31 Topics: Aminoimidazole Carboxamide; Animals; Energy Metabolism; Heart Failure; Humans; Hydroxymethylglutaryl	2016
Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells. Biochimica et biophysica acta. Molecular basis of disease, 2017, Volume: 1863, Issue:8 Topics: Animals; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Insulin-Secreting Ce	2017
Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Annals of internal medicine, 2017, Feb-07, Volume: 166, Issue:3 Topics: Cause of Death; Chronic Disease; Contraindications; Diabetes Mellitus, Type 2; Heart Failure; Humans	2017
[The safety of anti-diabetic drugs in heart failure]. Orvosi hetilap, 2017, Volume: 158, Issue:5 Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Heart Fail	2017
Thiazolidinediones in type 2 diabetes: a cardiology perspective. The Annals of pharmacotherapy, 2008, Volume: 42, Issue:10 Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Met	2008
Insulin resistance: a potential new target for therapy in patients with heart failure. Cardiovascular therapeutics, 2008,Fall, Volume: 26, Issue:3 Topics: Chronic Disease; Heart Failure; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Thiazoli	2008
Metformin: safety in cardiac patients. Heart (British Cardiac Society), 2010, Volume: 96, Issue:2 Topics: Acidosis, Lactic; Contraindications; Contrast Media; Heart Failure; Humans; Hypoglycemic Agents; Iod	2010
Metformin: safety in cardiac patients. Postgraduate medical journal, 2010, Volume: 86, Issue:1016 Topics: Acidosis, Lactic; Diabetes Mellitus; Diabetic Angiopathies; Heart Failure; Humans; Hypoglycemic Agen	2010
Impaired glucose tolerance and insulin resistance in heart failure: underrecognized and undertreated? Journal of cardiac failure, 2010, Volume: 16, Issue:9 Topics: Blood Glucose; Fatty Acids; Glucose Intolerance; Heart Failure; Humans; Hypoglycemic Agents; Increti	2010
[New clinical data with metformin therapy in patients with diabetes mellitus]. Orvosi hetilap, 2010, Dec-05, Volume: 151, Issue:49 Topics: Administration, Oral; Adult; Aged; Biomarkers; Clinical Trials as Topic; Diabetes Complications; Dia	2010
The cardioprotective effects of metformin. Current opinion in lipidology, 2011, Volume: 22, Issue:6 Topics: Animals; Cardiotonic Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Cardiomyo	2011
[Metformin and insulin in chronic heart failure: contraindications not contraindicated and indications not indicated]. Giornale italiano di cardiologia (2006), 2011, Volume: 12, Issue:12 Topics: Acidosis, Lactic; Cardiovascular Agents; Clinical Trials as Topic; Contraindications; Diabetes Melli	2011
Iodine-based radiographic contrast medium may precipitate metformin-associated lactic acidosis in diabetic patients. A case report, literature review and practical approach. La Clinica terapeutica, 2012, Volume: 163, Issue:1 Topics: Acidosis, Lactic; Aged, 80 and over; Atrial Fibrillation; Contraindications; Contrast Media; Creatin	2012
Insulin sensitization therapy and the heart: focus on metformin and thiazolidinediones. Heart failure clinics, 2012, Volume: 8, Issue:4 Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Heart; Heart Failur	2012
Diabetes and chronic heart failure: from diabetic cardiomyopathy to therapeutic approach. Endocrine, metabolic & immune disorders drug targets, 2013, Volume: 13, Issue:1 Topics: Chronic Disease; Diabetes Mellitus; Diabetic Cardiomyopathies; Heart Failure; Humans; Hypoglycemic A	2013
Management of diabetes mellitus and insulin resistance in patients with cardiovascular disease. The American journal of cardiology, 2003, Aug-18, Volume: 92, Issue:4A Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hyperlipidemias; Hyperten	2003
Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation, 2003, Dec-09, Volume: 108, Issue:23 Topics: Blood Volume; Clinical Trials as Topic; Comorbidity; Contraindications; Diabetes Mellitus, Type 2; D	2003
Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and gliclazide. International journal of clinical practice, 2004, Volume: 58, Issue:9 Topics: Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Female; Glicl	2004
Metformin's contraindications should be contraindicated. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 2005, Aug-30, Volume: 173, Issue:5 Topics: Acidosis, Lactic; Age Factors; Aged; Aged, 80 and over; Contraindications; Diabetes Mellitus, Type 2	2005
[Traditional contraindications to the use of metformin -- more harmful than beneficial?]. Deutsche medizinische Wochenschrift (1946), 2006, Jan-20, Volume: 131, Issue:3 Topics: Acidosis, Lactic; Age Factors; Contraindications; Diabetes Mellitus, Type 2; Drug Interactions; Hear	2006
The safety of metformin in heart failure. The Annals of pharmacotherapy, 2007, Volume: 41, Issue:4 Topics: Acidosis, Lactic; Aged; Clinical Trials as Topic; Contraindications; Female; Health Status; Heart Fa	2007
Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ (Clinical research ed.), 2007, Sep-08, Volume: 335, Issue:7618 Topics: Acidosis, Lactic; Contraindications; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic	2007
Type 2 diabetes mellitus and heart failure. Pharmacotherapy, 2008, Volume: 28, Issue:2 Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibit	2008

metformin and Cardiac Failure