pioglitazone and Apoplexy studies

Pioglitazone: A thiazolidinedione and PPAR GAMMA agonist that is used in the treatment of TYPE 2 DIABETES MELLITUS.
pioglitazone : A member of the class of thiazolidenediones that is 1,3-thiazolidine-2,4-dione substituted by a benzyl group at position 5 which in turn is substituted by a 2-(5-ethylpyridin-2-yl)ethoxy group at position 4 of the phenyl ring. It exhibits hypoglycemic activity.

Research Excerpts

Excerpt	Relevance	Reference
"Pioglitazone improves glycaemic control, not only by lowering insulin resistance, but also by improving beta cell function."	9.41	In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome. ( Bell, DSH; Jerkins, T, 2023)
"To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial."	9.30	Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial. ( Dearborn-Tomazos, J; Ford, GA; Furie, KL; Gorman, M; Inzucchi, SE; Kernan, WN; Lovejoy, AM; Spence, JD; Viscoli, CM; Young, LH, 2019)
"The IRIS trial (Insulin Resistance Intervention After Stroke) demonstrated that pioglitazone reduced the risk for both cardiovascular events and diabetes mellitus in insulin-resistant patients."	9.27	Heart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With Pioglitazone. ( Abbott, JD; Conwit, R; Curtis, JP; Furie, KL; Gorman, MJ; Inzucchi, SE; Jacoby, DL; Kernan, WN; Kolansky, DM; Ling, FS; Lovejoy, A; Pfau, SE; Schwartz, GG; Spatz, ES; Viscoli, CM; Young, LH, 2018)
"The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone reduced the risk for a composite outcome of stroke or myocardial infarction among nondiabetic patients with insulin resistance and a recent stroke or transient ischemic attack."	9.27	Pioglitazone Prevents Stroke in Patients With a Recent Transient Ischemic Attack or Ischemic Stroke: A Planned Secondary Analysis of the IRIS Trial (Insulin Resistance Intervention After Stroke). ( Conwit, R; Dearborn, J; Furie, KL; Gorman, M; Inzucchi, SE; Kamel, H; Kasner, SE; Kernan, WN; Lovejoy, AM; Viscoli, CM; Yaghi, S; Young, LH, 2018)
"In the Insulin Resistance Intervention after Stroke (IRIS) trial, patients with a recent ischaemic stroke or transient ischaemic attack (TIA) were randomised to pioglitazone (target 45 mg daily) or placebo."	9.27	Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial. ( Conwit, R; Ford, GA; Furie, KL; Gorman, M; Guarino, PD; Inzucchi, SE; Kernan, WN; Lovejoy, AM; Tanne, D; Viscoli, CM; Young, LH, 2018)
"Among patients with insulin resistance without diabetes mellitus, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event."	9.24	Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus. ( Abbott, JD; Conwit, R; Curtis, JP; Furie, KL; Gorman, MJ; Inzucchi, SE; Jacoby, DL; Kernan, WN; Kolansky, DM; Ling, FS; Lovejoy, AM; Pfau, SE; Schwartz, GG; Viscoli, CM; Young, LH, 2017)
"To determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk."	9.24	Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction. ( Conwit, R; Dearborn, JL; Fayad, P; Furie, KL; Gorman, M; Guarino, PD; Inzucchi, SE; Kent, DM; Kernan, WN; Stuart, A; Viscoli, CM; Young, LH, 2017)
"Efficacy [myocardial infarction (MI) or recurrent stroke] new-onset diabetes) and adverse outcomes (oedema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken (i."	9.22	Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance. ( Abdul-Ghani, M; Dandona, P; DeFronzo, R; Furie, K; Inzucchi, SE; Kernan, WN; Spence, JD; Viscoli, C; Young, LH, 2022)
"The Insulin Resistance Intervention after Stroke (IRIS) trial recently found that pioglitazone reduced risk for stroke and myocardial infarction in patients with insulin resistance but without diabetes who had had a recent ischemic stroke or transient ischemic attack (TIA)."	9.22	Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease. ( Dagogo-Jack, S; Furie, KL; Gorman, M; Inzucchi, SE; Ismail-Beigi, F; Kernan, WN; Korytkowski, MT; Lovejoy, AM; Pratley, RE; Schwartz, GG; Viscoli, CM; Young, LH, 2016)
" The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease."	9.22	Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. ( Adams, HP; Berger, L; Brass, LM; Carolei, A; Clark, W; Conwit, R; Coull, B; Ford, GA; Furie, KL; Gorman, M; Guarino, PD; Inzucchi, SE; Kernan, WN; Kleindorfer, D; Lovejoy, AM; O'Leary, JR; Parsons, MW; Peduzzi, PN; Ringleb, P; Schwartz, GG; Sen, S; Spence, JD; Tanne, D; Viscoli, CM; Wang, D; Winder, TR; Young, LH, 2016)
"While this study was too underpowered to determine the effect of pioglitazone, the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes."	9.20	Effects of Pioglitazone for Secondary Stroke Prevention in Patients with Impaired Glucose Tolerance and Newly Diagnosed Diabetes: The J-SPIRIT Study. ( Furukawa, Y; Hattori, N; Kawamori, R; Miyamoto, N; Nakahara, T; Nakamura, S; Okuma, Y; Shimura, H; Tanaka, R; Tanaka, Y; Tomizawa, Y; Ueno, Y; Urabe, T; Watada, H; Yamashiro, K, 2015)
" Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA."	9.19	Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the Insulin Resistance Intervention after Stroke Trial. ( Brass, LM; Carolei, A; Conwit, R; Ford, GA; Furie, KL; Gorman, M; Guarino, PD; Inzucchi, SE; Kernan, WN; Lovejoy, AM; Parsons, MW; Peduzzi, PN; Ringleb, PA; Schwartz, GG; Spence, JD; Tanne, D; Viscoli, CM; Young, LH, 2014)
" A total of 522 patients with hypertension and/or dyslipidemia who had one or more silent cerebral infarcts, advanced carotid atherosclerosis or microalbuminuria at baseline were randomly treated with (n=254) or without pioglitazone (n=268) and observed for a medium of 672 days."	9.19	Effects of pioglitazone on macrovascular events in patients with type 2 diabetes mellitus at high risk of stroke: the PROFIT-J study. ( Kawamori, R; Kitagawa, K; Kitakaze, M; Matsuhisa, M; Matsumoto, M; Onuma, T; Watada, H; Yamasaki, Y; Yamazaki, T; Yoshii, H, 2014)
"In patients with previous stroke (n=486 in the pioglitazone group and n=498 in the placebo group), there was a trend of benefit with pioglitazone for the primary end point of all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac intervention (including coronary artery bypass graft or percutaneous coronary intervention), stroke, major leg amputation, or bypass surgery or leg revascularization (hazard ratio[HR]=0."	9.12	Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). ( Betteridge, DJ; Bousser, MG; Dormandy, J; Kupfer, S; Pirags, V; Schernthaner, G; Wilcox, R, 2007)
"The aim of this study was to determine the effectiveness of pioglitazone compared with placebo for improving insulin sensitivity among nondiabetic patients with a recent transient ischemic attack (TIA) or nondisabling ischemic stroke and impaired insulin sensitivity."	9.10	Pioglitazone improves insulin sensitivity among nondiabetic patients with a recent transient ischemic attack or ischemic stroke. ( Brass, LM; Bravata, DM; Horwitz, RI; Inzucchi, SE; Kernan, WN; McVeety, JC; Shulman, GI; Viscoli, CM, 2003)
" Use of pioglitazone in stroke patients with insulin resistance, prediabetes, and diabetes mellitus was associated with lower risk of recurrent stroke (hazard ratio 0."	8.95	Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis. ( Lee, M; Liao, HW; Lin, CH; Ovbiagele, B; Saver, JL, 2017)
"Pioglitazone use is associated with a lower risk of dementia in patients with DM, particularly in those with a history of stroke or ischemic heart disease, suggesting the possibility of applying a personalized approach when choosing pioglitazone to suppress dementia in patients with DM."	8.31	Pioglitazone Use and Reduced Risk of Dementia in Patients With Diabetes Mellitus With a History of Ischemic Stroke. ( Choi, DW; Ha, J; Kim, E; Kim, KJ; Kim, KY; Nam, CM, 2023)
"In T2D patients with ischemic stroke, lobeglitazone reduced the risk of cardiovascular complications similar to that of pioglitazone without an increased risk of HF."	8.31	Lobeglitazone, a novel thiazolidinedione, for secondary prevention in patients with ischemic stroke: a nationwide nested case-control study. ( Baik, M; Jeon, J; Kim, J; Yoo, J, 2023)
"Studies assessing the efficacy of pioglitazone solely for primary stroke prevention in Asian patients with type 2 diabetes mellitus (DM) and present multiple cardiovascular (CV) risk factors are rare."	7.96	Pioglitazone for primary stroke prevention in Asian patients with type 2 diabetes and cardiovascular risk factors: a retrospective study. ( Bau, DT; Chiu, LT; Huang, HY; Hung, YC, 2020)
"In this nested case-control study using real-world data, treatment with pioglitazone exhibited significant cardiovascular preventive effect in diabetic patients with acute ischemic stroke."	7.91	Effect of pioglitazone in acute ischemic stroke patients with diabetes mellitus: a nested case-control study. ( Kim, J; Lee, HS; Woo, MH, 2019)
"Randomized controlled trials have reported an association between pioglitazone and reduced incidence of stroke in type 2 diabetic (T2DM) and insulin-resistant populations."	7.88	Impact of treatment with pioglitazone on stroke outcomes: A real-world database analysis. ( Currie, CJ; Inzucchi, SE; Jenkins-Jones, S; Morgan, CL; Puelles, J, 2018)
"Individual end points of acute myocardial infarction (AMI), stroke, heart failure, and all-cause mortality (death), and composite end point of AMI, stroke, heart failure, or death, assessed using incidence rates by thiazolidinedione, attributable risk, number needed to harm, Kaplan-Meier plots of time to event, and Cox proportional hazard ratios for time to event, adjusted for potential confounding factors, with pioglitazone as reference."	7.76	Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. ( Ali, F; Graham, DJ; Kelman, JA; MaCurdy, TE; Ouellet-Hellstrom, R; Sholley, C; Worrall, C, 2010)
"Pioglitazone (1 mg x kg(-1) x d(-1)) was orally administered to stroke-prone spontaneously hypertensive rats (SHRSP) to examine the effect on incidental stroke, cerebrovascular injury, brain inflammation, oxidative stress, and vascular endothelial dysfunction induced by hypertension."	7.74	Pioglitazone exerts protective effects against stroke in stroke-prone spontaneously hypertensive rats, independently of blood pressure. ( Dong, YF; Kataoka, K; Kim-Mitsuyama, S; Matsuba, S; Nakamura, T; Ogawa, H; Tokutomi, Y; Yamamoto, E; Yamashita, T, 2007)
"We investigated the long-term effects of the thiazolidinedione PPARgamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats (SHRSP), a model of malignant of hypertension."	7.72	Long-term effects of the PPAR gamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats. ( Amiri, F; Benkirane, K; Diep, QN; Paradis, P; Schiffrin, EL, 2004)
"Pioglitazone was also associated with reduced recurrent IS in patients who also used telmisartan (p for interaction = 0."	5.56	Pioglitazone and PPAR-γ modulating treatment in hypertensive and type 2 diabetic patients after ischemic stroke: a national cohort study. ( Lee, TH; Li, YR; Lin, YS; Liu, CH; Sung, PS; Wei, YC, 2020)
"Pioglitazone improves glycaemic control, not only by lowering insulin resistance, but also by improving beta cell function."	5.41	In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome. ( Bell, DSH; Jerkins, T, 2023)
" IRIS was a randomized, placebo controlled, double-blind trial testing pioglitazone to prevent stroke or myocardial infarction in patients with a recent ischemic stroke or transient ischemic attack."	5.34	Adherence to study drug in a stroke prevention trial"?>. ( Furie, KL; Gorman, M; Kernan, WN; Kiran, A; Viscoli, CM, 2020)
"To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial."	5.30	Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial. ( Dearborn-Tomazos, J; Ford, GA; Furie, KL; Gorman, M; Inzucchi, SE; Kernan, WN; Lovejoy, AM; Spence, JD; Viscoli, CM; Young, LH, 2019)
"The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone reduced the risk for a composite outcome of stroke or myocardial infarction among nondiabetic patients with insulin resistance and a recent stroke or transient ischemic attack."	5.27	Pioglitazone Prevents Stroke in Patients With a Recent Transient Ischemic Attack or Ischemic Stroke: A Planned Secondary Analysis of the IRIS Trial (Insulin Resistance Intervention After Stroke). ( Conwit, R; Dearborn, J; Furie, KL; Gorman, M; Inzucchi, SE; Kamel, H; Kasner, SE; Kernan, WN; Lovejoy, AM; Viscoli, CM; Yaghi, S; Young, LH, 2018)
"The IRIS trial (Insulin Resistance Intervention After Stroke) demonstrated that pioglitazone reduced the risk for both cardiovascular events and diabetes mellitus in insulin-resistant patients."	5.27	Heart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With Pioglitazone. ( Abbott, JD; Conwit, R; Curtis, JP; Furie, KL; Gorman, MJ; Inzucchi, SE; Jacoby, DL; Kernan, WN; Kolansky, DM; Ling, FS; Lovejoy, A; Pfau, SE; Schwartz, GG; Spatz, ES; Viscoli, CM; Young, LH, 2018)
"In the Insulin Resistance Intervention after Stroke (IRIS) trial, patients with a recent ischaemic stroke or transient ischaemic attack (TIA) were randomised to pioglitazone (target 45 mg daily) or placebo."	5.27	Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial. ( Conwit, R; Ford, GA; Furie, KL; Gorman, M; Guarino, PD; Inzucchi, SE; Kernan, WN; Lovejoy, AM; Tanne, D; Viscoli, CM; Young, LH, 2018)
"To determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk."	5.24	Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction. ( Conwit, R; Dearborn, JL; Fayad, P; Furie, KL; Gorman, M; Guarino, PD; Inzucchi, SE; Kent, DM; Kernan, WN; Stuart, A; Viscoli, CM; Young, LH, 2017)
"Among patients with insulin resistance without diabetes mellitus, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event."	5.24	Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus. ( Abbott, JD; Conwit, R; Curtis, JP; Furie, KL; Gorman, MJ; Inzucchi, SE; Jacoby, DL; Kernan, WN; Kolansky, DM; Ling, FS; Lovejoy, AM; Pfau, SE; Schwartz, GG; Viscoli, CM; Young, LH, 2017)
"Patients were 3876 nondiabetic participants in the Insulin Resistance Intervention after Stroke trial randomized to pioglitazone or placebo and followed for a median of 4."	5.24	Pioglitazone and Risk for Bone Fracture: Safety Data From a Randomized Clinical Trial. ( Conwit, R; Furie, KL; Gorman, M; Insogna, KL; Inzucchi, SE; Kelly, MA; Kernan, WN; Lovejoy, AM; Viscoli, CM; Young, LH, 2017)
"Efficacy [myocardial infarction (MI) or recurrent stroke] new-onset diabetes) and adverse outcomes (oedema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken (i."	5.22	Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance. ( Abdul-Ghani, M; Dandona, P; DeFronzo, R; Furie, K; Inzucchi, SE; Kernan, WN; Spence, JD; Viscoli, C; Young, LH, 2022)
"The Insulin Resistance Intervention after Stroke (IRIS) trial recently found that pioglitazone reduced risk for stroke and myocardial infarction in patients with insulin resistance but without diabetes who had had a recent ischemic stroke or transient ischemic attack (TIA)."	5.22	Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease. ( Dagogo-Jack, S; Furie, KL; Gorman, M; Inzucchi, SE; Ismail-Beigi, F; Kernan, WN; Korytkowski, MT; Lovejoy, AM; Pratley, RE; Schwartz, GG; Viscoli, CM; Young, LH, 2016)
" The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease."	5.22	Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. ( Adams, HP; Berger, L; Brass, LM; Carolei, A; Clark, W; Conwit, R; Coull, B; Ford, GA; Furie, KL; Gorman, M; Guarino, PD; Inzucchi, SE; Kernan, WN; Kleindorfer, D; Lovejoy, AM; O'Leary, JR; Parsons, MW; Peduzzi, PN; Ringleb, P; Schwartz, GG; Sen, S; Spence, JD; Tanne, D; Viscoli, CM; Wang, D; Winder, TR; Young, LH, 2016)
"While this study was too underpowered to determine the effect of pioglitazone, the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes."	5.20	Effects of Pioglitazone for Secondary Stroke Prevention in Patients with Impaired Glucose Tolerance and Newly Diagnosed Diabetes: The J-SPIRIT Study. ( Furukawa, Y; Hattori, N; Kawamori, R; Miyamoto, N; Nakahara, T; Nakamura, S; Okuma, Y; Shimura, H; Tanaka, R; Tanaka, Y; Tomizawa, Y; Ueno, Y; Urabe, T; Watada, H; Yamashiro, K, 2015)
" Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA."	5.19	Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the Insulin Resistance Intervention after Stroke Trial. ( Brass, LM; Carolei, A; Conwit, R; Ford, GA; Furie, KL; Gorman, M; Guarino, PD; Inzucchi, SE; Kernan, WN; Lovejoy, AM; Parsons, MW; Peduzzi, PN; Ringleb, PA; Schwartz, GG; Spence, JD; Tanne, D; Viscoli, CM; Young, LH, 2014)
" A total of 522 patients with hypertension and/or dyslipidemia who had one or more silent cerebral infarcts, advanced carotid atherosclerosis or microalbuminuria at baseline were randomly treated with (n=254) or without pioglitazone (n=268) and observed for a medium of 672 days."	5.19	Effects of pioglitazone on macrovascular events in patients with type 2 diabetes mellitus at high risk of stroke: the PROFIT-J study. ( Kawamori, R; Kitagawa, K; Kitakaze, M; Matsuhisa, M; Matsumoto, M; Onuma, T; Watada, H; Yamasaki, Y; Yamazaki, T; Yoshii, H, 2014)
"To assess the association of weight and weight change with mortality and non-fatal cardiovascular outcomes (hospitalisation, myocardial infarction and stroke) in T2DM patients with cardiovascular co-morbidity and the effect of pioglitazone-induced weight change on mortality."	5.16	Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity: an analysis of the PROactive study population. ( Anker, SD; Cairns, R; Clark, AL; Doehner, W; Dormandy, JA; Erdmann, E; Ferrannini, E, 2012)
" This analysis from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive) evaluated the effects of pioglitazone on the prespecified MACE end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE1) and on 6 post hoc MACE composites (various combinations of all-cause, cardiovascular, or cardiac mortality; plus nonfatal myocardial infarction; plus nonfatal stroke; and/or acute coronary syndrome) in patients with type 2 diabetes."	5.13	Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10). ( Erdmann, E; Kupfer, S; Wilcox, R, 2008)
"While there is no evidence that metabolic control reduces the risk of stroke, some families of antidiabetic drugs with vascular benefits have been shown to reduce these effects when added to conventional treatments, both in the field of primary prevention in patients presenting type 2 diabetes and high vascular risk or established atherosclerosis (GLP-1 agonists) and in secondary stroke prevention in patients with type 2 diabetes or prediabetes (pioglitazone)."	5.12	Stroke prevention in patients with type 2 diabetes or prediabetes. Recommendations from the Cerebrovascular Diseases Study Group, Spanish Society of Neurology. ( Alonso de Leciñana, M; Amaro, S; Arenillas, JF; Ayo-Martín, O; Castellanos, M; Freijo, M; Fuentes, B; García-Pastor, A; Gómez Choco, M; Gomis, M; López-Cancio, E; Martínez Sánchez, P; Morales, A; Palacio-Portilla, EJ; Rodríguez-Yáñez, M; Roquer, J; Segura, T; Serena, J; Vivancos-Mora, J, 2021)
"In patients with previous stroke (n=486 in the pioglitazone group and n=498 in the placebo group), there was a trend of benefit with pioglitazone for the primary end point of all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac intervention (including coronary artery bypass graft or percutaneous coronary intervention), stroke, major leg amputation, or bypass surgery or leg revascularization (hazard ratio[HR]=0."	5.12	Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). ( Betteridge, DJ; Bousser, MG; Dormandy, J; Kupfer, S; Pirags, V; Schernthaner, G; Wilcox, R, 2007)
"Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events."	5.11	Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. ( Betteridge, J; Birkeland, K; Charbonnel, B; Dormandy, JA; Eckland, DJ; Erdmann, E; Golay, A; Heine, RJ; Korányi, L; Laakso, M; Lefèbvre, PJ; Massi-Benedetti, M; Mokán, M; Moules, IK; Murray, GD; Norkus, A; Pirags, V; Podar, T; Scheen, A; Scherbaum, W; Schernthaner, G; Schmitz, O; Skene, AM; Skrha, J; Smith, U; Standl, E; Tan, MH; Taton, J; Wilcox, RG; Wilhelmsen, L, 2005)
"The aim of this study was to determine the effectiveness of pioglitazone compared with placebo for improving insulin sensitivity among nondiabetic patients with a recent transient ischemic attack (TIA) or nondisabling ischemic stroke and impaired insulin sensitivity."	5.10	Pioglitazone improves insulin sensitivity among nondiabetic patients with a recent transient ischemic attack or ischemic stroke. ( Brass, LM; Bravata, DM; Horwitz, RI; Inzucchi, SE; Kernan, WN; McVeety, JC; Shulman, GI; Viscoli, CM, 2003)
" These include new evidence about nutrition, antiplatelet therapy, anticoagulation, lipid-lowering therapy, hypertension control, pioglitazone, and carotid endarterectomy and stenting."	5.05	Recent advances in preventing recurrent stroke. ( Spence, JD, 2020)
" Pioglitazone (an oral hypoglycemic agent of the thiazolidinedione drug class) was shown in the IRIS trial to reduce the risk of recurrent stroke in patients with impaired glucose tolerance who had not developed type 2 diabetes mellitus."	4.98	Updates in Stroke Treatment. ( Mac Grory, B; Yaghi, S, 2018)
" Use of pioglitazone in stroke patients with insulin resistance, prediabetes, and diabetes mellitus was associated with lower risk of recurrent stroke (hazard ratio 0."	4.95	Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis. ( Lee, M; Liao, HW; Lin, CH; Ovbiagele, B; Saver, JL, 2017)
" High rates of crossover to statin use confound the interpretation of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, which found a less than expected reduction in coronary and stroke events with fenofibrate."	4.84	Update on PPAR agonists: the clinical significance of FIELD and PROACTIVE. ( Robinson, JG, 2007)
" Together with the recent observation that the PPAR-gamma ligand pioglitazone reduces the incidence of stroke in patients with type 2 diabetes, this review supports the concept that activators of PPAR-gamma are effective drugs against ischemic injury."	4.84	PPAR-gamma: therapeutic target for ischemic stroke. ( Culman, J; Gohlke, P; Herdegen, T; Zhao, Y, 2007)
"In T2D patients with ischemic stroke, lobeglitazone reduced the risk of cardiovascular complications similar to that of pioglitazone without an increased risk of HF."	4.31	Lobeglitazone, a novel thiazolidinedione, for secondary prevention in patients with ischemic stroke: a nationwide nested case-control study. ( Baik, M; Jeon, J; Kim, J; Yoo, J, 2023)
"Pioglitazone use is associated with a lower risk of dementia in patients with DM, particularly in those with a history of stroke or ischemic heart disease, suggesting the possibility of applying a personalized approach when choosing pioglitazone to suppress dementia in patients with DM."	4.31	Pioglitazone Use and Reduced Risk of Dementia in Patients With Diabetes Mellitus With a History of Ischemic Stroke. ( Choi, DW; Ha, J; Kim, E; Kim, KJ; Kim, KY; Nam, CM, 2023)
"IRIS tested pioglitazone for prevention of stroke and myocardial infarction in patients with a recent transient ischemic attack or ischemic stroke."	4.12	Central vs site outcome adjudication in the IRIS trial. ( Bath, PM; Forman, R; Furie, KL; Guarino, P; Inzucchi, SE; Kernan, WN; Viscoli, CM; Young, L, 2022)
"Studies assessing the efficacy of pioglitazone solely for primary stroke prevention in Asian patients with type 2 diabetes mellitus (DM) and present multiple cardiovascular (CV) risk factors are rare."	3.96	Pioglitazone for primary stroke prevention in Asian patients with type 2 diabetes and cardiovascular risk factors: a retrospective study. ( Bau, DT; Chiu, LT; Huang, HY; Hung, YC, 2020)
"In this nested case-control study using real-world data, treatment with pioglitazone exhibited significant cardiovascular preventive effect in diabetic patients with acute ischemic stroke."	3.91	Effect of pioglitazone in acute ischemic stroke patients with diabetes mellitus: a nested case-control study. ( Kim, J; Lee, HS; Woo, MH, 2019)
" Pioglitazone use was determined in 6-month study intervals, with outcome events of myocardial infarction (MI), ischemic stroke, and heart failure."	3.91	Detecting pioglitazone use and risk of cardiovascular events using electronic health record data in a large cohort of Chinese patients with type 2 diabetes. ( Dong, X; Du, X; Jing, S; Liu, Y; Miao, S; Wang, L; Xu, H; Xu, T; Zhang, X, 2019)
"Randomized controlled trials have reported an association between pioglitazone and reduced incidence of stroke in type 2 diabetic (T2DM) and insulin-resistant populations."	3.88	Impact of treatment with pioglitazone on stroke outcomes: A real-world database analysis. ( Currie, CJ; Inzucchi, SE; Jenkins-Jones, S; Morgan, CL; Puelles, J, 2018)
"Compared with insulin, pioglitazone was associated with a significant reduction in the risk of MI and stroke requiring hospitalization, and a significant reduction in the risk of other selected cancers."	3.79	Comparing pioglitazone to insulin with respect to cancer, cardiovascular and bone fracture endpoints, using propensity score weights. ( Bron, M; Fusco, G; Joseph, G; Liang, H; Manne, S; Perez, A; Vallarino, C; Yu, S, 2013)
"This population-based cohort study shows that rosiglitazone imposes a higher risk of developing stroke or heart failure in this Asian patient population, suggesting the adverse side effects of rosiglitazone across ethnic boundaries."	3.79	Risk of stroke with thiazolidinediones: a ten-year nationwide population-based cohort study. ( Chen, PC; Chen, RC; Hsu, CY; Lu, CJ; Muo, CH; Sun, Y, 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)
"Individual end points of acute myocardial infarction (AMI), stroke, heart failure, and all-cause mortality (death), and composite end point of AMI, stroke, heart failure, or death, assessed using incidence rates by thiazolidinedione, attributable risk, number needed to harm, Kaplan-Meier plots of time to event, and Cox proportional hazard ratios for time to event, adjusted for potential confounding factors, with pioglitazone as reference."	3.76	Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. ( Ali, F; Graham, DJ; Kelman, JA; MaCurdy, TE; Ouellet-Hellstrom, R; Sholley, C; Worrall, C, 2010)
"We assembled an inception cohort of Medicare beneficiaries older than 65 years with state-sponsored prescription drug benefits who had diabetes mellitus and initiated treatment with rosiglitazone or pioglitazone between January 1, 2000, and December 31, 2005."	3.74	Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. ( Levin, R; Setoguchi, S; Solomon, DH; Winkelmayer, WC, 2008)
"Pioglitazone (1 mg x kg(-1) x d(-1)) was orally administered to stroke-prone spontaneously hypertensive rats (SHRSP) to examine the effect on incidental stroke, cerebrovascular injury, brain inflammation, oxidative stress, and vascular endothelial dysfunction induced by hypertension."	3.74	Pioglitazone exerts protective effects against stroke in stroke-prone spontaneously hypertensive rats, independently of blood pressure. ( Dong, YF; Kataoka, K; Kim-Mitsuyama, S; Matsuba, S; Nakamura, T; Ogawa, H; Tokutomi, Y; Yamamoto, E; Yamashita, T, 2007)
" Stroke-prone spontaneously hypertensive rats (SHRSP) were orally given pioglitazone, candesartan, or combined pioglitazone and candesartan for 4 weeks to compare their effects on cardiovascular injury."	3.74	Beneficial effects of pioglitazone on hypertensive cardiovascular injury are enhanced by combination with candesartan. ( Dong, YF; Kataoka, K; Kim-Mitsuyama, S; Matsuba, S; Nakamura, T; Ogawa, H; Tokutomi, Y; Yamamoto, E; Yamashita, T, 2008)
"We investigated the long-term effects of the thiazolidinedione PPARgamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats (SHRSP), a model of malignant of hypertension."	3.72	Long-term effects of the PPAR gamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats. ( Amiri, F; Benkirane, K; Diep, QN; Paradis, P; Schiffrin, EL, 2004)
"Pioglitazone has shown promise in secondary stroke prevention for insulin-resistant patients; however, its use is not yet widespread."	2.72	Diabetes, stroke, and neuroresilience: looking beyond hyperglycemia. ( Krinock, MJ; Singhal, NS, 2021)
"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)
"Pioglitazone was also associated with reduced recurrent IS in patients who also used telmisartan (p for interaction = 0."	1.56	Pioglitazone and PPAR-γ modulating treatment in hypertensive and type 2 diabetic patients after ischemic stroke: a national cohort study. ( Lee, TH; Li, YR; Lin, YS; Liu, CH; Sung, PS; Wei, YC, 2020)
" Translation of these findings into clinical therapy will require careful assessment of dosing paradigms and effective time windows for treatment."	1.36	Extension of the neuroprotective time window for thiazolidinediones in ischemic stroke is dependent on time of reperfusion. ( Blankenship, DA; Gamboa, J; Hilow, E; Karl, M; Landreth, GE; Niemi, JP; Sundararajan, S, 2010)

Research

Studies (82)

Authors

Clinical Trials (7)

Trial Overview

Trial Outcomes

Acute Coronary Syndrome

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	19 (23.17)	29.6817
2010's	51 (62.20)	24.3611
2020's	12 (14.63)	2.80

Authors	Studies
Spence, JD	5
Viscoli, C	1
Kernan, WN	17
Young, LH	12
Furie, K	1
DeFronzo, R	1
Abdul-Ghani, M	1
Dandona, P	1
Inzucchi, SE	16
Forman, R	1
Viscoli, CM	16
Bath, PM	1
Furie, KL	13
Guarino, P	1
Young, L	1
Guo, Y	1
Zuo, W	1
Yin, L	1
Gu, T	1
Wang, S	1
Fang, Z	1
Wang, B	1
Dong, H	1
Hou, W	1
Zuo, Z	1
Deng, J	1
Ha, J	1
Choi, DW	1
Kim, KJ	1
Kim, KY	1
Nam, CM	1
Kim, E	1
Yoo, J	1
Jeon, J	1
Baik, M	1
Kim, J	2
Bell, DSH	1
Jerkins, T	1
Liu, CH	1
Lee, TH	1
Lin, YS	1
Sung, PS	1
Wei, YC	1
Li, YR	1
Hung, YC	1
Chiu, LT	1
Huang, HY	1
Bau, DT	1
Kiran, A	1
Gorman, M	10
Fuentes, B	1
Amaro, S	1
Alonso de Leciñana, M	1
Arenillas, JF	1
Ayo-Martín, O	1
Castellanos, M	1
Freijo, M	1
García-Pastor, A	1
Gomis, M	1
Gómez Choco, M	1
López-Cancio, E	1
Martínez Sánchez, P	1
Morales, A	1
Palacio-Portilla, EJ	1
Rodríguez-Yáñez, M	1
Roquer, J	1
Segura, T	1
Serena, J	1
Vivancos-Mora, J	1
Krinock, MJ	1
Singhal, NS	1
Katsiki, N	1
Mikhailidis, DP	1
Castilla-Guerra, L	3
Fernandez-Moreno, MDC	2
Perez de Leon, JA	1
Lee, M	3
Ovbiagele, B	3
Rydén, L	1
Mellbin, L	1
Iguchi, M	1
Nango, E	1
Saver, JL	2
Leon-Jimenez, D	1
Carmona-Nimo, E	1
Ford, GA	4
Guarino, PD	4
Lovejoy, AM	8
Conwit, R	8
Tanne, D	3
Hankey, GJ	1
Dearborn, JL	1
Kent, DM	1
Fayad, P	1
Stuart, A	1
Musso, G	1
Cassader, M	1
Gambino, R	1
Jin-Shan, H	1
Xue-Bin, L	1
Yaghi, S	2
Kamel, H	1
Dearborn, J	1
Kasner, SE	1
Liu, J	3
Wang, LN	3
Mac Grory, B	1
Leira, EC	1
Polgreen, LA	1
Morgan, CL	1
Puelles, J	1
Jenkins-Jones, S	1
Currie, CJ	1
Schwartz, GG	5
Curtis, JP	2
Gorman, MJ	2
Spatz, ES	1
Lovejoy, A	1
Abbott, JD	2
Jacoby, DL	2
Kolansky, DM	2
Ling, FS	2
Pfau, SE	2
Dawson, J	1
Miao, S	1
Dong, X	1
Zhang, X	2
Jing, S	1
Xu, T	1
Wang, L	1
Du, X	1
Xu, H	1
Liu, Y	1
Pantoni, L	1
Dearborn-Tomazos, J	1
Woo, MH	1
Lee, HS	1
Vallarino, C	1
Perez, A	1
Fusco, G	1
Liang, H	1
Bron, M	1
Manne, S	1
Joseph, G	1
Yu, S	1
Lu, CJ	1
Sun, Y	1
Muo, CH	1
Chen, RC	1
Chen, PC	1
Hsu, CY	1
Green, JB	1
Bethel, MA	1
Paul, SK	1
Ring, A	1
Kaufman, KD	1
Shapiro, DR	1
Califf, RM	1
Holman, RR	1
Yoshii, H	1
Onuma, T	1
Yamazaki, T	1
Watada, H	2
Matsuhisa, M	1
Matsumoto, M	1
Kitagawa, K	1
Kitakaze, M	1
Yamasaki, Y	1
Kawamori, R	2
Varughese, MC	1
Brass, LM	3
Carolei, A	2
Parsons, MW	2
Peduzzi, PN	2
Ringleb, PA	1
Dangi-Garimella, S	1
Seong, JM	1
Choi, NK	1
Shin, JY	1
Chang, Y	1
Kim, YJ	1
Lee, J	1
Kim, JY	1
Park, BJ	1
Yu, SJ	1
Reiner, D	1
Shen, H	1
Wu, KJ	1
Liu, QR	1
Wang, Y	1
Tanaka, R	1
Yamashiro, K	1
Okuma, Y	1
Shimura, H	1
Nakamura, S	1
Ueno, Y	1
Tanaka, Y	1
Miyamoto, N	1
Tomizawa, Y	1
Nakahara, T	1
Furukawa, Y	1
Hattori, N	1
Urabe, T	1
Pladevall, M	2
Riera-Guardia, N	1
Margulis, AV	1
Varas-Lorenzo, C	1
Calingaert, B	1
Perez-Gutthann, S	1
Adams, HP	1
Berger, L	1
Clark, W	1
Coull, B	1
Kleindorfer, D	1
O'Leary, JR	1
Ringleb, P	1
Sen, S	1
Wang, D	1
Winder, TR	1
Mayor, S	1
Ntaios, G	1
Kent, TA	1
Dagogo-Jack, S	1
Ismail-Beigi, F	1
Korytkowski, MT	1
Pratley, RE	1
Insogna, KL	1
Kelly, MA	1
Liao, HW	1
Lin, CH	1
Fernandez-Moreno, MD	1
Colmero-Camacho, MA	1
Winkelmayer, WC	1
Setoguchi, S	1
Levin, R	1
Solomon, DH	1
Habib, ZA	1
Tzogias, L	1
Havstad, SL	1
Wells, K	1
Divine, G	1
Lanfear, DE	1
Tang, J	1
Krajenta, R	1
Williams, LK	1
Retnakaran, R	1
Zinman, B	1
Graham, DJ	1
Ouellet-Hellstrom, R	1
MaCurdy, TE	1
Ali, F	1
Sholley, C	1
Worrall, C	1
Kelman, JA	1
Gamboa, J	1
Blankenship, DA	1
Niemi, JP	1
Landreth, GE	1
Karl, M	1
Hilow, E	1
Sundararajan, S	1
Shinohara, Y	1
Doehner, W	1
Erdmann, E	3
Cairns, R	1
Clark, AL	1
Dormandy, JA	2
Ferrannini, E	1
Anker, SD	1
Gallagher, AM	1
Smeeth, L	1
Seabroke, S	1
Leufkens, HG	1
van Staa, TP	1
Bravata, DM	1
Shulman, GI	1
McVeety, JC	1
Horwitz, RI	1
Belcher, G	1
Lambert, C	1
Goh, KL	1
Edwards, G	1
Valbuena, M	1
Diep, QN	1
Amiri, F	1
Benkirane, K	1
Paradis, P	1
Schiffrin, EL	1
Yki-Järvinen, H	1
Charbonnel, B	1
Eckland, DJ	1
Massi-Benedetti, M	1
Moules, IK	1
Skene, AM	1
Tan, MH	1
Lefèbvre, PJ	1
Murray, GD	1
Standl, E	1
Wilcox, RG	1
Wilhelmsen, L	1
Betteridge, J	1
Birkeland, K	1
Golay, A	1
Heine, RJ	1
Korányi, L	1
Laakso, M	1
Mokán, M	1
Norkus, A	1
Pirags, V	2
Podar, T	1
Scheen, A	1
Scherbaum, W	1
Schernthaner, G	2
Schmitz, O	1
Skrha, J	1
Smith, U	1
Taton, J	1
Fonseca, V	1
Jawa, A	1
Asnani, S	1
Guillausseau, PJ	1
Yoshiuchi, I	1
Itoh, N	1
Nakano, M	1
Tatsumi, C	1
Yokoyama, K	1
Matsuyama, T	1
Robinson, JG	1
Wilcox, R	2
Bousser, MG	1
Betteridge, DJ	1
Kupfer, S	2
Dormandy, J	1
Culman, J	1
Zhao, Y	1
Gohlke, P	1
Herdegen, T	1
Nakamura, T	2
Yamamoto, E	2
Kataoka, K	2
Yamashita, T	2
Tokutomi, Y	2
Dong, YF	2
Matsuba, S	2
Ogawa, H	2
Kim-Mitsuyama, S	2

Trial	Phase	Enrollment	Study Type	Start Date	Status
Insulin Resistance Intervention After Stroke (IRIS) Trial[NCT00091949]	Phase 3	3,876 participants (Actual)	Interventional	2005-02-28	Completed
TECOS: A Randomized, Placebo Controlled Clinical Trial to Evaluate Cardiovascular Outcomes After Treatment With Sitagliptin in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control[NCT00790205]	Phase 3	14,671 participants (Actual)	Interventional	2008-12-10	Completed
Preventive Effects of Ginseng Against Atherosclerosis and Subsequent Ischemic Stroke: A Randomized Controlled Trial[NCT02796664]		58 participants (Actual)	Interventional	2016-06-23	Completed
The Effect of Acupuncture on Insulin Sensitivity of Women With Polycystic Ovary Syndrome and Insulin Resistance: a Randomized Controlled Trial[NCT02491333]	Phase 3	342 participants (Actual)	Interventional	2015-08-31	Completed
PROspective PioglitAzone Clinical Trial In MacroVascular Events: A Macrovascular Outcome Study in Type 2 Diabetic Patients Comparing Pioglitazone With Placebo in Addition to Existing Therapy[NCT00174993]	Phase 3	4,373 participants (Actual)	Interventional	2001-05-31	Completed
The Effect of Liraglutide Treatment on Postprandial Chylomicron and VLDL Kinetics, Liver Fat and de Novo Lipogenesis - a Single-center Randomized Controlled Study[NCT02765399]	Phase 4	23 participants (Actual)	Interventional	2015-02-01	Completed
A Prospective, Randomized, Parallel-group, Adaptive Design Phase IIb/III, Multicenter Study, to Assess the Efficacy of Polychemotherapy for Inducing Remission of Newly Diagnosed Type 2 Diabetes.[NCT04271189]	Phase 2/Phase 3	180 participants (Anticipated)	Interventional	2020-09-01	Active, not recruiting
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Fatal or non-fatal acute myocardial infarction or unstable angina (NCT00091949)
Timeframe: 5 years

All Cause Mortality

Composite Outcome of Fatal or Non-fatal Stroke, Fatal or Non-fatal MI or Episode of Serious Congestive Heart Failure

Decline in Cognitive Status

Intervention	participants (Number)
Pioglitazone	206
Placebo	249

Intervention	participants (Number)
Pioglitazone	136
Placebo	146

Intervention	participants (Number)
Pioglitazone	206
Placebo	249

Change in modified mental status examination (3MS) score from baseline to exit. Theoretical range of 3MS scores is 0-100. Baseline scores ranged from 22-100. (NCT00091949)
Timeframe: Annual measures from baseline to exit (up to 5 years)

Development of Overt Diabetes

Fatal or Non-fatal Stroke Alone

Recurrent Fatal or Non-fatal Stroke, or Fatal or Non-fatal Myocardial Infarction

Percent Incidence of All-cause Mortality (Intent to Treat Population)

Intervention	units on a scale (Mean)
Pioglitazone	0.27
Placebo	0.29

Intervention	participants (Number)
Pioglitazone	73
Placebo	149

Intervention	participants (Number)
Pioglitazone	127
Placebo	154

Intervention	participants (Number)
Pioglitazone	175
Placebo	228

Percent incidence of all-cause mortality is reported as the percentage of participants who died due to any cause. (NCT00790205)
Timeframe: Up to 5 years

Percent Incidence of All-cause Mortality (Per Protocol Population)

Intervention	Percentage of participants (Number)
Sitagliptin	7.5
Placebo	7.3

Percent incidence of all-cause mortality is reported as the percentage of participants who died due to any cause. (NCT00790205)
Timeframe: Up to 5 years

Percent Incidence of CHF Requiring Hospitalization (Intent to Treat Population)

Intervention	Percentage of participants (Number)
Sitagliptin	4.7
Placebo	4.3

Percent incidence of CHF requiring hospitalization was reported as the percentage of participants who were admitted to the hospital for CHF. (NCT00790205)
Timeframe: Up to 5 years

Percent Incidence of Congestive Heart Failure (CHF) Requiring Hospitalization (Per Protocol Population)

Intervention	Percentage of participants (Number)
Sitagliptin	3.1
Placebo	3.1

Percent incidence of CHF requiring hospitalization was reported as the percentage of participants who were admitted to the hospital for CHF. (NCT00790205)
Timeframe: Up to 5 years

Percentage of Participants Who Initiated Chronic Insulin Therapy (Intent to Treat Population)

Intervention	Percentage of participants (Number)
Sitagliptin	2.8
Placebo	2.8

Chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months. (NCT00790205)
Timeframe: Up to 5 years

Percentage of Participants Who Initiated Chronic Insulin Therapy (Per Protocol Population)

Intervention	Percentage of participants (Number)
Sitagliptin	9.7
Placebo	13.2

Chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months. (NCT00790205)
Timeframe: Up to 5 years

Percentage of Participants With First Confirmed Cardiovascular (CV) Event of Major Adverse Cardiovascular Event (MACE) Plus (Per Protocol Population)

Intervention	Percentage of participants (Number)
Sitagliptin	8.6
Placebo	11.9

Primary composite CV endpoint of MACE plus which includes CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. (NCT00790205)
Timeframe: Up to 5 years

Percentage of Participants With First Confirmed CV Event of MACE (Intent to Treat Population)

Intervention	Percentage of participants (Number)
Sitagliptin	9.6
Placebo	9.6

CV composite endpoint of MACE which includes CV-related death, nonfatal MI, or nonfatal stroke. (NCT00790205)
Timeframe: Up to 5 years

Percentage of Participants With First Confirmed CV Event of MACE (Per Protocol Population)

Intervention	Percentage of participants (Number)
Sitagliptin	10.2
Placebo	10.2

CV composite endpoint of MACE which includes CV-related death, nonfatal MI, or nonfatal stroke. (NCT00790205)
Timeframe: Up to 5 years

Percentage of Participants With First Confirmed CV Event of Major Adverse Cardiovascular Event (MACE) Plus (Intent to Treat Population)

Intervention	Percentage of participants (Number)
Sitagliptin	8.4
Placebo	8.3

Primary composite CV endpoint of MACE plus which includes CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. (NCT00790205)
Timeframe: Up to 5 years

Percentage of Participants With Initiation of Co-interventional Agent (Intent to Treat Population)

Intervention	Percentage of participants (Number)
Sitagliptin	11.4
Placebo	11.6

In participants not receiving insulin at baseline, time to addition of first co-interventional agent (i.e., next oral AHA or chronic insulin, where chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months.) (NCT00790205)
Timeframe: Up to 5 years

Percentage of Participants With Initiation of Co-interventional Agent (Per Protocol Population)

Intervention	Percentage of participants (Number)
Sitagliptin	21.7
Placebo	27.9

In participants not receiving insulin at baseline, time to addition of first co-interventional agent (i.e., next oral antihyperglycemic agent [AHA] or chronic insulin, where chronic insulin therapy is defined as a continuous period of insulin use of more than 3 months.) (NCT00790205)
Timeframe: Up to 5 years

Change From Baseline in HbA1c Over Time (Intent to Treat Population)

Intervention	Percentage of participants (Number)
Sitagliptin	18.9
Placebo	24.5

HbA1c is a measure of the percentage of glycated hemoglobin in the blood. Estimated mean difference between sitagliptin and placebo controlling for baseline HbA1c and region. (NCT00790205)
Timeframe: Baseline and up to 4 years

Change From Baseline in HbA1c Over Time (Per Protocol Population)

Intervention	Percentage of HbA1c (Mean)
	Month 4: Sitagliptin, n= 6772; Placebo, n= 6738	Month 8: Sitagliptin, n= 6478; Placebo, n= 6414	Month 12: Sitagliptin, n= 6448; Placebo, n= 6384	Month 24: Sitagliptin, n= 6105; Placebo, n= 5975	Month 36: Sitagliptin, n= 3521; Placebo, n= 3439	Month 48: Sitagliptin, n= 1432; Placebo, n= 1383	Month 60: Sitagliptin, n= 123; Placebo, n= 128
Placebo	0.1	0.1	0.1	0.1	0.1	0.1	0.0
Sitagliptin	-0.3	-0.2	-0.2	-0.1	-0.1	0.0	0.0

Change From Baseline in Renal Function Over Time (Intent to Treat Population)

Intervention	Percentage of HbA1c (Mean)
	Month 4; Sitagliptin, n=6632, Placebo, n=6588	Month 8; Sitagliptin, n=6294, Placebo, n=6197	Month 12; Sitagliptin, n=6217, Placebo, n=6092	Month 24; Sitagliptin, n=5668, Placebo, n=5475	Month 36; Sitagliptin, n=3227, Placebo, n=3083	Month 48; Sitagliptin, n=1271, Placebo, n=1224	Month 60; Sitagliptin, n=106, Placebo, n=108
Placebo	0.1	0.1	0.1	0.2	0.1	0.1	0.0
Sitagliptin	-0.3	-0.3	-0.2	-0.1	-0.1	0.0	-0.1

Change in renal function based on eGFR using the MDRD method. (NCT00790205)
Timeframe: Baseline and up to 5 years

Change From Baseline in Renal Function Over Time (Per Protocol Population)

Intervention	mL/min/1.73 m^2 (Mean)
	Month 4; Sitagliptin, n=3949; Placebo, n=3977	Month 8; Sitagliptin, n=3687; Placebo, n=3648	Month 12; Sitagliptin, n=5082; Placebo, n=5015	Month 24; Sitagliptin, n=5157; Placebo, n=5071	Month 36; Sitagliptin, n=3037; Placebo, n=2942	Month 48; Sitagliptin, n=1237; Placebo, n=1210	Month 60; Sitagliptin, n=93; Placebo, n=106
Placebo	-0.8	-0.9	-0.5	-1.7	-1.6	-2.8	-5.7
Sitagliptin	-1.8	-2.4	-1.8	-3.2	-3.8	-4.0	-4.2

Change in renal function based on estimated glomerular filtration rate [eGFR] using the Modification of Diet in Renal Disease [MDRD] method. (NCT00790205)
Timeframe: Baseline and up to 5 years

Change From Baseline in Urine Albumin:Creatinine Ratio Over Time (Intent to Treat Population)

Intervention	mL/min/1.73 m^2 (Mean)
	Month 4; Sitagliptin, n= 3859; Placebo, n= 3864	Month 8; Sitagliptin, n= 3562; Placebo, n= 3501	Month 12; Sitagliptin, n=4912, Placebo, n=4778	Month 24; Sitagliptin, n=4782, Placebo, n=4637	Month 36; Sitagliptin, n=2776, Placebo, n=2614	Month 48; Sitagliptin, n=1096, Placebo, n=1056	Month 60; Sitagliptin, n=79, Placebo, n=88
Placebo	-0.8	-0.9	-0.5	-1.7	-1.6	-2.8	-6.4
Sitagliptin	-1.9	-2.5	-1.8	-3.1	-3.7	-3.7	-3.5

Change from baseline reflects the difference between the urine albumin:creatinine ratio reported time point and baseline value. (NCT00790205)
Timeframe: Baseline and up to 5 years

Change From Baseline in Urine Albumin:Creatinine Ratio Over Time (Per Protocol Population)

Intervention	g/mol Creatinine (Mean)
	Month 4; n=677, n=713	Month 8; n=658, n=624	Month 12; n=1167, n=1115	Month 24; n=1011, n=964	Month 36; n=537, n=553	Month 48; n=265, n=256	Month 60; n=14, n=18
Placebo	-1.4	0.5	1.2	3.1	3.9	1.6	6.4
Sitagliptin	-2.1	2.1	1.3	0.5	2.6	1.9	-2.5

Change from baseline reflects the difference between the urine albumin:creatinine ratio reported time point and baseline value. (NCT00790205)
Timeframe: Baseline and up to 5 years

Drug Compliance

Intervention	g/mol Creatinine (Mean)
	Month 4; Sitagliptin, n=664; Placebo, n=688	Month 8; Sitagliptin, n=635; Placebo, n=597	Month 12; Sitagliptin, n=1126; Placebo, n=1059	Month 24; Sitagliptin, n=930; Placebo, n=892	Month 36; Sitagliptin, n=488; Placebo, n=513	Month 48; Sitagliptin, n=238; Placebo, n=233	Month 60; Sitagliptin, n=13; Placebo, n=17
Placebo	-1.4	0.2	1.2	3.2	4.0	1.5	4.8
Sitagliptin	-2.2	1.7	0.8	0.7	2.5	1.3	-2.7

We calculated average drug compliance based on the number of remained drugs at each follow-up. (NCT02796664)
Timeframe: At twelve months after randomization.

Modified Rankin Scale

Intervention	percentage of drug compliance (Mean)
Ginseng	97.4
Placebo	97.8

Presence of other cerebro-cardiovascular morbidity or mortality assessed by aggravation of patient status (modified Rankin Scale). The modified Rankin Scale is ranging from 0 to 5. The higher scale indicates the worse outcome. (NCT02796664)
Timeframe: Twelve months after randomization.

The Composite of Cerebral Ischemic Stroke and Transient Ischemic Attack

Intervention	Participants (Count of Participants)
	mRS 0	mRS 1	mRS 2	mRS 3	mRS 4	mRS 5
Ginseng	21	5	0	2	0	0
Placebo	22	1	0	1	0	0

The 1-year composite of cerebral ischemic stroke and transient ischemic attack downstream to an atherosclerotic lesion (NCT02796664)
Timeframe: Twelve months after randomization.

The Changes in Volumetric Blood Flow (ml/Sec) in Intracranial Vessels.

Intervention	Participants (Count of Participants)
	Ischemic stroke	Transient ischemic attack
Ginseng	0	0
Placebo	0	1

The changes in volumetric blood flow (ml/sec) in intracranial vessels assessed by quantitative magnetic resonance angiography with noninvasive optimal vessel analysis. (NCT02796664)
Timeframe: At randomization and twelve months after randomization.

The Changes of White Matter Hyperintensities.

Intervention	Participants (Count of Participants)
	The flow change in steno-occlusive lesion72501839	The flow change in steno-occlusive lesion72501838	The flow change in collateral vessel72501838	The flow change in collateral vessel72501839
	Improved	No change	Aggravated
Ginseng	4
Placebo	5
Ginseng	17
Placebo	18
Placebo	1
Ginseng	7
Placebo	7
Placebo	9
Placebo	8

The changes of white matter hyperintensities, assessed by the Fazekas scale using brain magnetic resonance imaging. The Fazekas scale is a 4 point white matter disease severity scale with values ranging from 0 to 3. It quantifies the amount of white matter T2 hyperintense lesions each in periventricular white matter and deep white matter. Higher scales mean a worse white matter status. In the region of the periventricular white matter, 0 means absence of the lesion; 1, caps or pencil-thin lining lesion; 2, smooth halo lesion; 3, irregular high intense signal extending into the deep shite matter. In the region of the deep white matter, 0 means absence of the lesion; 1, punctate foci lesions; 2, beginning confluence; 3, large confluent hyperintense areas. (NCT02796664)
Timeframe: At randomization and twelve months after randomization.

Body Weight

Intervention	Participants (Count of Participants)
	Periventricular white matter72501836	Periventricular white matter72501837	Deep white matter72501837	Deep white matter72501836
	Fazekas scale 3	Fazekas scale 0	Fazekas scale 1	Fazekas scale 2
Placebo	11
Placebo	10
Ginseng	2
Ginseng	9
Placebo	6
Ginseng	15
Placebo	15
Ginseng	3
Placebo	2
Ginseng	1
Placebo	1

Before vs after intervention (Liraglutide or placebo): Change in body weight. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in ApoCIII Level

Intervention	kg (Mean)
	Baseline	16 weeks
Liraglutide	98.6	96.1
Placebo	92.0	89.8

Before vs after intervention (Liraglutide or placebo): apolipoprotein CIII concentration in plasma measured by using turbidimetric immunoassay. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in Direct CM-apoB48 Clearance

Intervention	mg/dL (Mean)
	Baseline	16 weeks
Liraglutide	12.0	9.9
Placebo	9.7	8.6

Before vs after intervention (Liraglutide or placebo): Direct apoB48 clearance rates in isolated chylomicrons and measured by liquid chromatography - mass spectrometry and calculated by multicompartmental modeling assay. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (1979). So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. 2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. 2021. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in fP-glucose Level

Intervention	mg/day (Mean)
	Baseline	16 weeks
Liraglutide	106	3.8
Placebo	20	17

Before vs after intervention (Liraglutide or placebo): concentration of fasting plasma glucose measured using the hexokinase method. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in HbA1c Level

Intervention	mmol/L (Mean)
	Baseline	16 weeks
Liraglutide	8.3	6.4
Placebo	6.5	6.4

Before vs after intervention (Liraglutide or placebo): Change in B -Hemoglobiini-A1c level in plasma. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in Hepatic de Novo Lipogenesis

Intervention	HbA1c % (Mean)
	Baseline	16 weeks
Liraglutide	7.0	6.4
Placebo	6.3	6.4

Before vs after intervention (Liraglutide or placebo): Hepatic DNL is calculated from enrichment of deuterated water ingested during the kinetic study at specified time points (0, 4 and 8 hrs.). Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in Insulin Level

Intervention	μmol/L (Mean)
	Baseline	16 weeks
Liraglutide	15.4	19.1
Placebo	12.6	13.8

Before vs after intervention (Liraglutide or placebo): Concentration of insulin level in plasma measured using electrochemiluminescence. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after16 weeks

Change in Liver Fat Content

Intervention	μU/mL (Mean)
	Baseline	16 weeks
Liraglutide	13.9	14.5
Placebo	13.8	14.1

Before vs after intervention (Liraglutide or placebo): mean liver fat content was measured by magnetic resonance imaging. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in Matsuda Index

Intervention	fat % (Mean)
	Baseline	16 weeks
Liraglutide	14.8	10.7
Placebo	16.1	13.9

Before vs after intervention (Liraglutide or placebo): Matsuda index was calculated for assessment of insulin sensitivity in plasma at time points 0, 30, 60 and 120 minutes using formula 10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during oral glucose tolerance test]. The Matsuda index is considered to be the gold standard to determine insulin sensitivity without glucose clamp studies (Matsuda M, DeFronzo RA. Diabetes Care. 22:1462-70). Subjects who don't have insulin resistance have values of Matsuda Index of 2.5 or higher (Kerman WN et al. Stroke 34:1431;2003). Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in SAT Area

Intervention	index (Mean)
	Baseline	16 weeks
Liraglutide	2.5	3.5
Placebo	3.1	3.1

Before vs after intervention (Liraglutide or placebo): subcutaneous adipose tissue area measured by magnetic resonance imaging (MRI). Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in Systolic RR

Intervention	cm3 (Mean)
	Baseline	16 weeks
Liraglutide	4043	3792
Placebo	5400	5161

Before vs after intervention (Liraglutide or placebo): systolic blood pressure measurements. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Change in VAT Area

Intervention	mm Hg (Mean)
	Baseline	16 weeks
Liraglutide	135	139
Placebo	145	137

Before vs after intervention (Liraglutide or placebo): visceral adipose tissue area measured by magnetic resonance imaging (MRI). Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Mean apoB48 FTR to VLDL1 Particles

Intervention	cm3 (Mean)
	Baseline	16 weeks
Liraglutide	3403	3185
Placebo	2710	2600

Before vs after intervention (Liraglutide or placebo): Change in apoB48 chylomicron fractional transfer rate to VLDL1 isolated from plasma by ultracentrifugation and by liquid chromatography/mass spectrometry and calculated with multicompartmental modeling assay. So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. JIM 2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. 2021. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Mean CM FDC of apoB48

Intervention	pools/day (Mean)
	Baseline	16 weeks
Liraglutide	12	26
Placebo	34	30

Before vs after intervention (Liraglutide or placebo): Change in chylomicron fractional direct clearance rates of apoB48 measured from plasma by liquid chromatography - mass spectrometry with multicompartmental modeling assay. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (1979). So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. 2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. 2021. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Mean CM-apoB48 Transfer Rates to VLDL1

Intervention	pools/day (Mean)
	Baseline	16 weeks
Liraglutide	9	0.8
Placebo	4.4	3.2

Before vs after intervention (Liraglutide or placebo): Change in chylomicron-apoB48 transfer rates to VLDL1 isolated from plasma by ultracentrifugation and measured using multicompartmental modeling. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (1979). So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. 2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. 2021. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Mean Fractional Catabolic Rate of VLDL2-apoB100

Intervention	mg/day (Mean)
	Baseline	16 weeks
Liraglutide	127	110
Placebo	170	150

Before vs after intervention (Liraglutide or placebo): Change in VLDL2-apoB100 fractional catabolic rates measured from isolated VLDL2 from plasma by ultracentrifugation and measured using mathematical modeling. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (JCI 1979). So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. JIM 2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. DOM 2021. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Mean Production Rate of apoB48 in CM

Intervention	pools/day (Mean)
	Baseline	16 weeks
Liraglutide	6.7	5.6
Placebo	4.5	5.1

Before vs after intervention (Liraglutide or placebo): Change in mean production rate of ApoB48 in chylomicrons isolated from plasma samples and measured by multicompartmental modeling assay. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (JCI 1979). So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. JIM 2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Mean TG Fractional Catabolic Rates in CM

Before vs after intervention (Liraglutide or placebo): Change in triglycerides fractional catabolic rates in isolated chylomicrons from plasma samples measured by multicompartmental modeling assay. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (JCI 1979). So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. JIM 2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. DOM 2021. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Mean Total Production of apoB48

Before vs after intervention (Liraglutide or placebo): ApoB48 total production in plasma measured by using multicompartmental modeling. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (JCI 63:1262;1979) and have been widely used over 30yrs. So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. JIM 285:562;2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. Diabetes Obes Metab. 23:1191; 2021. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Mean VLDL1-TG Production Rates

Before vs after intervention (Liraglutide or placebo): Change in VLDL1 production rates measured from isolated VLDL from plasma samples by ultracentrifugation and measured using mathematical modeling. The power of mathematical modelling to describe the metabolic pathways of lipid and lipoprotein metabolism was demonstrated by Zech L et al (JCI 1979). So far few studies have focused on the modelling of apo B48 and apo B100 after a meal that is more physiological than the fasting state (Björnson E et al. JIM 2019). Production rates for apo B48, apo B100 and triglycerides in chylomicrons, VLDL1 and VLDL2 were derived from samples taken before and after the tracer injection and after the meal at 0, 30, 45, 60, 75, 90,120, 150 min and at 3, 4, 5, 6, 8, 10, 24 hrs and averages for 24 hrs. Analysis of tracer/ tracee curves of stable isotopes was used to derived the estimates of kinetic parameters using a new mathematical modeling per day. Results from Taskinen et al. DOM 2021. (NCT02765399)
Timeframe: Baseline and after16 weeks

Plasma Triglyceride (TG) Area Under Curve (AUC)

Before vs after intervention (Liraglutide or placebo): postprandial plasma TG summary measured using the trapezoidal rule and expressed as AUC (at fasting and at 0.5, 1, 2, 3, 4, 6 and 8 hours) after oral fat tolerance test. Results from Matikainen et al. Diabetes Obes Metab 21:84-94; 2019. (NCT02765399)
Timeframe: Baseline and after 16 weeks

Article	Year
Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance. Diabetes, obesity & metabolism, 2022, Volume: 24, Issue:6 Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Insulin Re	2022
In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome. Diabetes, obesity & metabolism, 2023, Volume: 25, Issue:11 Topics: Brain Ischemia; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Hypoglycemic Agents; Insul	2023
Recent advances in preventing recurrent stroke. F1000Research, 2020, Volume: 9 Topics: Aged; Blood Pressure; Diet; Endarterectomy, Carotid; Humans; Hypertension; Pioglitazone; Recurrence;	2020
Stroke prevention in patients with type 2 diabetes or prediabetes. Recommendations from the Cerebrovascular Diseases Study Group, Spanish Society of Neurology. Neurologia, 2021, Volume: 36, Issue:4 Topics: Diabetes Mellitus, Type 2; Humans; Neurology; Pioglitazone; Prediabetic State; Stroke	2021
Diabetes, stroke, and neuroresilience: looking beyond hyperglycemia. Annals of the New York Academy of Sciences, 2021, Volume: 1495, Issue:1 Topics: Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Insuli	2021
Antidiabetic drugs and stroke risk. Current evidence. European journal of internal medicine, 2018, Volume: 48 Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Metfo	2018
Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in people with stroke or transient ischaemic attack. The Cochrane database of systematic reviews, 2017, 12-02, Volume: 12 Topics: Cardiovascular Diseases; Carotid Artery Diseases; Humans; Hypoglycemic Agents; Insulin Resistance; I	2017
Updates in Stroke Treatment. Rhode Island medical journal (2013), 2018, 03-01, Volume: 101, Issue:2 Topics: Acute Disease; Atrial Fibrillation; Brain Ischemia; Glucose Intolerance; Humans; Hypoglycemic Agents	2018
Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. The Cochrane database of systematic reviews, 2014, Jan-08, Issue:1 Topics: Cardiovascular Diseases; Humans; Hypoglycemic Agents; Ischemic Attack, Transient; Myocardial Infarct	2014
Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. The Cochrane database of systematic reviews, 2015, Oct-29, Issue:10 Topics: Cardiovascular Diseases; Humans; Hypoglycemic Agents; Ischemic Attack, Transient; Myocardial Infarct	2015
Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies. BMC cardiovascular disorders, 2016, Jan-15, Volume: 16 Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Myocardi	2016
Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis. Stroke, 2017, Volume: 48, Issue:2 Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Pioglitazone; Prediabeti	2017
[Japanese Guidelines for the Management of Stroke 2009 : important revised points necessary for the neurologist]. Rinsho shinkeigaku = Clinical neurology, 2010, Volume: 50, Issue:11 Topics: Aspirin; Atorvastatin; Cilostazol; Diabetes Complications; Dyslipidemias; Evidence-Based Medicine; H	2010
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
Update on PPAR agonists: the clinical significance of FIELD and PROACTIVE. Current atherosclerosis reports, 2007, Volume: 9, Issue:1 Topics: Coronary Disease; Fenofibrate; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Peroxisome Prolife	2007
PPAR-gamma: therapeutic target for ischemic stroke. Trends in pharmacological sciences, 2007, Volume: 28, Issue:5 Topics: Animals; Brain Ischemia; Diabetes Mellitus, Type 2; Drug Administration Routes; Drug Delivery System	2007

Article	Year
Central vs site outcome adjudication in the IRIS trial. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 2022, Volume: 31, Issue:9 Topics: Double-Blind Method; Humans; Hypoglycemic Agents; Ischemic Attack, Transient; Pioglitazone; Stroke;	2022
Pioglitazone attenuates ischaemic stroke aggravation by blocking PPARγ reduction and inhibiting chronic inflammation in diabetic mice. The European journal of neuroscience, 2022, Volume: 56, Issue:6 Topics: Animals; Brain Ischemia; Diabetes Mellitus, Experimental; Inflammation; Ischemic Stroke; Mice; NLR F	2022
Pioglitazone Use and Reduced Risk of Dementia in Patients With Diabetes Mellitus With a History of Ischemic Stroke. Neurology, 2023, 04-25, Volume: 100, Issue:17 Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Ischemic Stroke; Myocardial Ischemia; Piogli	2023
Lobeglitazone, a novel thiazolidinedione, for secondary prevention in patients with ischemic stroke: a nationwide nested case-control study. Cardiovascular diabetology, 2023, 05-05, Volume: 22, Issue:1 Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Insulin	2023
Pioglitazone and PPAR-γ modulating treatment in hypertensive and type 2 diabetic patients after ischemic stroke: a national cohort study. Cardiovascular diabetology, 2020, 01-07, Volume: 19, Issue:1 Topics: Aged; Antihypertensive Agents; Brain Ischemia; Databases, Factual; Diabetes Mellitus, Type 2; Female	2020
Pioglitazone for primary stroke prevention in Asian patients with type 2 diabetes and cardiovascular risk factors: a retrospective study. Cardiovascular diabetology, 2020, 06-20, Volume: 19, Issue:1 Topics: Aged; Asian People; Brain Ischemia; Databases, Factual; Diabetes Mellitus, Type 2; Female; Humans; H	2020
Pioglitazone in patients with insulin resistance after ischemic stroke or transient ischemic attack: A comment on the IRIS trial. Journal of diabetes and its complications, 2017, Volume: 31, Issue:1 Topics: Brain Ischemia; Humans; Insulin Resistance; Ischemic Attack, Transient; Pioglitazone; Stroke	2017
Letter by Castilla-Guerra et al Regarding Article, "Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis". Stroke, 2017, Volume: 48, Issue:5 Topics: Humans; Pioglitazone; Secondary Prevention; Stroke; Thiazolidinediones	2017
Response by Lee and Ovbiagele to Letter Regarding Article, "Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis". Stroke, 2017, Volume: 48, Issue:5 Topics: Humans; Pioglitazone; Secondary Prevention; Stroke; Thiazolidinediones	2017
New Hope For People With Dysglycemia and Cardiovascular Disease Manifestations: Reduction of Acute Coronary Events With Pioglitazone. Circulation, 2017, 05-16, Volume: 135, Issue:20 Topics: Brain Ischemia; Cardiovascular Diseases; Diabetes Mellitus; Humans; Insulin Resistance; Ischemic Att	2017
Letter by Iguchi and Nango Regarding Article, "Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis". Stroke, 2017, Volume: 48, Issue:7 Topics: Humans; Pioglitazone; Secondary Prevention; Stroke; Thiazolidinediones	2017
Response by Lee et al to Letter Regarding Article, "Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis". Stroke, 2017, Volume: 48, Issue:7 Topics: Humans; Pioglitazone; Secondary Prevention; Stroke; Thiazolidinediones	2017
Which Patients With Ischemic Stroke and Insulin Resistance May Benefit From Pioglitazone Hydrochloride? JAMA neurology, 2017, 11-01, Volume: 74, Issue:11 Topics: Brain Ischemia; Humans; Insulin Resistance; Ischemic Attack, Transient; Myocardial Infarction; Piogl	2017
Letter by Musso et al Regarding Article, "Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus". Circulation, 2017, 10-17, Volume: 136, Issue:16 Topics: Brain Ischemia; Diabetes Mellitus; Humans; Insulin Resistance; Ischemic Attack, Transient; Pioglitaz	2017
Letter by Jin-Shan and Xue-Bin Regarding Article, "Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus". Circulation, 2017, 10-17, Volume: 136, Issue:16 Topics: Brain Ischemia; Diabetes Mellitus; Humans; Insulin Resistance; Ischemic Attack, Transient; Pioglitaz	2017
Response by Young et al to Letters Regarding Article, "Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus". Circulation, 2017, 10-17, Volume: 136, Issue:16 Topics: Brain Ischemia; Diabetes Mellitus; Humans; Insulin Resistance; Ischemic Attack, Transient; Pioglitaz	2017
Distance from Home to Research Center: A Barrier to In-Person Visits but Not Treatment Adherence in a Stroke Trial. Neuroepidemiology, 2018, Volume: 50, Issue:3-4 Topics: Aged; Aged, 80 and over; Clinical Trials as Topic; Female; Health Services Accessibility; Humans; Ma	2018
Impact of treatment with pioglitazone on stroke outcomes: A real-world database analysis. Diabetes, obesity & metabolism, 2018, Volume: 20, Issue:9 Topics: Cohort Studies; Databases, Factual; Diabetes Mellitus, Type 2; Female; Hospitalization; Humans; Hypo	2018
Pioglitazone Use After Stroke: Story of Hearts, Minds, and Bones. Circulation, 2018, 09-18, Volume: 138, Issue:12 Topics: Brain Ischemia; Heart Failure; Humans; Hypoglycemic Agents; Insulin; Ischemic Attack, Transient; Pio	2018
Detecting pioglitazone use and risk of cardiovascular events using electronic health record data in a large cohort of Chinese patients with type 2 diabetes. Journal of diabetes, 2019, Volume: 11, Issue:8 Topics: Case-Control Studies; China; Diabetes Mellitus, Type 2; Electronic Health Records; Female; Follow-Up	2019
Potential New Horizons for the Prevention of Cerebrovascular Diseases and Dementia. JAMA neurology, 2019, 05-01, Volume: 76, Issue:5 Topics: Cerebrovascular Disorders; Dementia; Humans; Pioglitazone; Prediabetic State; Stroke	2019
Effect of pioglitazone in acute ischemic stroke patients with diabetes mellitus: a nested case-control study. Cardiovascular diabetology, 2019, 05-31, Volume: 18, Issue:1 Topics: Aged; Brain Ischemia; Databases, Factual; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Ag	2019
Comparing pioglitazone to insulin with respect to cancer, cardiovascular and bone fracture endpoints, using propensity score weights. Clinical drug investigation, 2013, Volume: 33, Issue:9 Topics: Aged; Aged, 80 and over; Cohort Studies; Female; Fractures, Bone; Humans; Hypoglycemic Agents; Insul	2013
Risk of stroke with thiazolidinediones: a ten-year nationwide population-based cohort study. Cerebrovascular diseases (Basel, Switzerland), 2013, Volume: 36, Issue:2 Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cohort Studies; Diabetes Mellitus, Type 2; Female; Heart	2013
Litigation seeking access to data from ongoing clinical trials: a threat to clinical research. JAMA internal medicine, 2014, Volume: 174, Issue:9 Topics: Access to Information; Biomedical Research; Connecticut; Diabetes Mellitus, Type 2; Humans; Hypoglyc	2014
The Yin and the Yang of CV risks in patients with diabetes. The American journal of managed care, 2014, Volume: 20, Issue:8 Spec No. Topics: Adamantane; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides	2014
Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study. PloS one, 2015, Volume: 10, Issue:5 Topics: Adult; Aged; Cardiovascular Diseases; Cardiovascular System; Cohort Studies; Diabetes Mellitus, Type	2015
Time-Dependent Protection of CB2 Receptor Agonist in Stroke. PloS one, 2015, Volume: 10, Issue:7 Topics: Animals; Behavior, Animal; Brain Ischemia; Calcium-Binding Proteins; Cannabinoid Receptor Agonists;	2015
Pioglitazone may reduce cardiovascular events in high risk patients with prediabetes. BMJ (Clinical research ed.), 2016, Feb-18, Volume: 352 Topics: Humans; Hypoglycemic Agents; Myocardial Infarction; Pioglitazone; Prediabetic State; Stroke; Thiazol	2016
The IRIS (Insulin Resistance Intervention after Stroke) trial: A new perspective on pioglitazone. Journal of diabetes, 2016, Volume: 8, Issue:5 Topics: Humans; Hypoglycemic Agents; Insulin Resistance; Ischemic Attack, Transient; Multicenter Studies as	2016
Insulin Resistance Intervention After Stroke Trial of Pioglitazone: Is This Perhaps the End of the Beginning? Stroke, 2016, Volume: 47, Issue:7 Topics: Humans; Hypoglycemic Agents; Insulin Resistance; Pioglitazone; PPAR gamma; Prediabetic State; Stroke	2016
Pioglitazone: Good news for diabetic patients with stroke? European journal of internal medicine, 2017, Volume: 39 Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Pioglitazone; Randomized Controlled Trials a	2017
Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Archives of internal medicine, 2008, Nov-24, Volume: 168, Issue:21 Topics: Aged; Diabetes Complications; Diabetes Mellitus; Female; Heart Failure; Humans; Hypoglycemic Agents;	2008
Relationship between thiazolidinedione use and cardiovascular outcomes and all-cause mortality among patients with diabetes: a time-updated propensity analysis. Pharmacoepidemiology and drug safety, 2009, Volume: 18, Issue:6 Topics: Acute Disease; Cardiovascular Diseases; Cohort Studies; Data Interpretation, Statistical; Diabetes M	2009
Thiazolidinediones and clinical outcomes in type 2 diabetes. Lancet (London, England), 2009, Jun-20, Volume: 373, Issue:9681 Topics: Cholesterol, LDL; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Hospitalization; Humans; Hyd	2009
Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA, 2010, Jul-28, Volume: 304, Issue:4 Topics: Aged; Aged, 80 and over; Cohort Studies; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; H	2010
Extension of the neuroprotective time window for thiazolidinediones in ischemic stroke is dependent on time of reperfusion. Neuroscience, 2010, Oct-27, Volume: 170, Issue:3 Topics: Animals; Behavior, Animal; Blood Pressure; Brain; Brain Ischemia; Cell Adhesion Molecules; Disease M	2010
Risk of death and cardiovascular outcomes with thiazolidinediones: a study with the general practice research database and secondary care data. PloS one, 2011, Volume: 6, Issue:12 Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; Databases	2011
Long-term effects of the PPAR gamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats. Canadian journal of physiology and pharmacology, 2004, Volume: 82, Issue:11 Topics: Animals; Hypertension; Hypertrophy, Left Ventricular; Male; Myocarditis; Pioglitazone; PPAR gamma; R	2004
The PROactive study: some answers, many questions. Lancet (London, England), 2005, Oct-08, Volume: 366, Issue:9493 Topics: Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Myocardial Infarction; Pio	2005
Commentary: the PROactive study--the glass is half full. The Journal of clinical endocrinology and metabolism, 2006, Volume: 91, Issue:1 Topics: Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Progression; Hum	2006
PROactive study. Lancet (London, England), 2006, Jan-07, Volume: 367, Issue:9504 Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Pioglitazone; Stroke; Thiazolidinediones	2006
PROactive study. Lancet (London, England), 2006, Mar-25, Volume: 367, Issue:9515 Topics: Clinical Trials as Topic; Endpoint Determination; Humans; Hypoglycemic Agents; Myocardial Infarction	2006
Case report of Klinefelter's syndrome with severe diabetes, dyslipidemia, and stroke: The effect of pioglitazone and other anti-inflammatory agents on interleukin-6 and -8, tumor necrosis factor-alpha, and C-reactive protein. Diabetes care, 2006, Volume: 29, Issue:8 Topics: Adult; Anti-Inflammatory Agents; C-Reactive Protein; Diabetes Mellitus; Dyslipidemias; Humans; Inter	2006
[Pioglitazone protects the type-2-diabetes patient from myocardial infarction and stroke]. MMW Fortschritte der Medizin, 2007, Aug-02, Volume: 149, Issue:31-32 Topics: Cholesterol, HDL; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Th	2007
Pioglitazone exerts protective effects against stroke in stroke-prone spontaneously hypertensive rats, independently of blood pressure. Stroke, 2007, Volume: 38, Issue:11 Topics: Animals; Blood Glucose; Blood Pressure; Cerebral Arteries; Cytokines; Diabetes Complications; Diseas	2007
Beneficial effects of pioglitazone on hypertensive cardiovascular injury are enhanced by combination with candesartan. Hypertension (Dallas, Tex. : 1979), 2008, Volume: 51, Issue:2 Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressur	2008

pioglitazone and Apoplexy