Demystifying Cardiovascular Safety of Sulfonylurea UGDP: The Genesis of Sulfonylurea CV controversy The University Group Diabetes Program (UGDP) study was initiated in 1960 and patients were treated with the sulfonylurea tolbutamide alone, or placebo, fixed dose insulin or variable dose insulin. Surprisingly, an excess of cardiac deaths was found in the tolbutamide group (127%) compared to 47% with placebo, 6.2% with fixed dose insulin and 59% with variable dose insulin; the tolbutamide arm of the study was prematurely terminated This led some experts to conclude that SUs, as a class, were associated with increased cardiovascular mortality while others criticized the design and analysis of the UGDP study and questioned its conclusions First Generation Tolbutamide Chlorpropamide Second Generation Glibenclamide Gliclazide Third Generation Glimepiride Gliclazide MR Sulfonylureas: How are they defined? Older SUs Newer SUs A therapy should demonstrate that it will not result in an unacceptable increase in: Cardiovascular mortality Myocardial infarction and stroke Hospitalization for acute coronary syndrome, urgent revascularization procedures Other endpoints Are all Sulfonylureas CV unsafe?? Is there a difference in risk for different SUs? Lets see what evidence has to say? Sulfonylurea and CV safety: Few unanswered questions Cardiovascular mortality Myocardial infarction and stroke Hospitalization for acute coronary syndrome, urgent revascularization procedures Other endpoints To compare mortality and adverse CV events among SUs Systematic review & network meta-analysis of studies reporting the Risk of all cause mortality CV related mortality or MI for SUs 28 studies ( patients) included in the main analysis Relative risk of death compared with glibenclamide was Lancet Diabetes Endocrinol Jan;3(1): 65 for gliclazide 083 for glimepiride 113 for tolbutamide 134 for chlorpropamide Comparison of cardiovascular-related mortality between SUs using direct and indirect evidence Lancet Diabetes Endocrinol Jan;3(1):43-51 Newer SUs (Gliclazide and Glimepiride) were associated with a lower risk of all- cause and cardiovascular-related mortality compared with glibenclamide 178341metformin monotherapy patients, 2948 added insulin and added a sulfonylurea Propensity score matching yielded 2436 metformin + insulin and metformin + sulfonylurea patients JAMA Jun 11;311(22): Cardiovascular Events and Mortality: Met+SU vs Met+insulin A, Cumulative incidence of cardiovascular disease (acutemyocardial infarction, stroke) or death among a propensity scorematched cohort of patients taking metformin + sulfonylurea vs patients taking metformin + insulin B, Cumulative incidence of fatal and nonfatal cardiovascular events (acute myocardial infarction, stroke, or cardiovascular deaths) among a propensity scorematched cohort of patients taking metformin + sulfonylurea vs patients taking metformin + insulin Sulfonylureas are CV safe when it comes to diabetes treatment JAMA Jun 11;311(22): Comparison of various CV outcome trials which had sulfonylurea in control group Trial Type of patients enrolled Primary event: Placebo Primary event: Study Drug % patients on SU in placebo group % patients on SU in study drug group TECOS T2DM with cardiovascular disease 11.6%11.4%45%45.6% SAVOR TIMI T2DM patients with a H/o or were at risk for CV events 7.2%7.3%40.2%39.8% EXAMINE T2DM patients with either an AMI or unstable angina requiring hospitalization 11.8%11.3%46.2%46.9% In all the recent CV outcome trials, the control group having SU as the major drugs, did not show worse CV outcomes Cardiovascular mortality Myocardial infarction and stroke Hospitalization for acute coronary syndrome, urgent revascularization procedures Other endpoints Significance of Ischemic preconditioning NO ISCHEMIC PRECONDITIONING Prolonged occlusion of a major coronary artery leads to myocardial infarction ISCHEMIC PRECONDITIONING Repeated and brief occlusion of the same vessel preconditions the myocardium such that subsequent prolonged occlusion leads to a smaller infarct SULFONYLUREAS Sulfonylureas other than Glimepiride/Gliclazide abolish ischemic preconditoning, resulting in large infarction size J Am Coll Cardiol Apr;31(5): Klepzig et al. Eur Heart J 1999;20: 76 T2DM cases who developed CAD were compared retrospectively with 152 controls that did not The hazard of developing CAD associated with initial treatment increased by 2.4-fold with glibenclamide 2.9-fold with either The hazard decreased 0.3-fold with glimepiride, 0.4-fold with gliclazide, and 0.4- fold with either Initiating treatment of T2DM with the older SUs (glibenclamide) is associated with increased risk of CAD as compared to the newer SUs (glimepiride or gliclazide) Diabetes Res Clin Pract Dec;82(3):391-5 6738 cases of first-time MI and 67,374 matched controls Odds ratios (ORs) of MI (casecontrol study) were estimated Risk of MI: Higher among users of old SUs (adjusted OR, 2.07) than among users of new SUs (adjusted OR, 1.36) New SUs (Glimepiride/Gliclazide) may be associated with a lower risk of MI than old SUs (Glibenclamide) Am J Ther Mar-Apr;13(2): Meta-analysis comparing a SU with a non-SU agent in T2DM End points: Major cardiovascular events (MACE) and mortality An overall OR for MACE with SU treatment vs comparators was 1.08 thus detecting no signal for cardiovascular risk Use of SU was not associated with any significant difference in the incidence of MI with respect to comparators (OR: 0.88) Diabetes Obes Metab Oct;15(10):938-53 Cardiovascular mortality Myocardial infarction and stroke Hospitalization for acute coronary syndrome, urgent revascularization procedures Other endpoints 1310 diabetic patients with Acute STEMI and Non-STEMI Mortality was lower in patients previously treated with SUs (3.9%) vs. those on other OHAs (6.4%), insulin (9.4%), or no medication (8.4%) Among SU-treated patients, in-hospital mortality was lower in patients receiving newer SUs (gliclazide or glimepiride) Arrhythmias and ischemic complications were also less frequent in patients receiving gliclazide/glimepiride J Clin Endocrinol Metab Nov;95(11): Effect of Newer vs Older SU on CV risk J Clin Endocrinol Metab Nov;95(11): Effect of Newer vs Older SU on CV risk: Subgroup analysis J Clin Endocrinol Metab Nov;95(11): Patients on newer SUs have fewer early complications and lower mortality than those on glibenclamide All SUs do not have the same impact on cardiac outcomes and should therefore not be considered a single pharmacologic entity Effect of Newer vs Older SU on CV risk: Subgroup analysis A retrospective cohort study patients with T2DM 18 years of age, with and without a history of CAD who initiated monotherapy with Metformin (N = ) Glipizide (N = 4325) Glyburide (N = 4279) Glimepiride (N = 2537) Diabetes Obes Metab Sep;14(9):803-9 Glimepiride: Preferred SU in patients with underlying CAD If a SU is required to obtain glycaemic control, glimepiride may be the preferred SU in those with underlying CAD Survival probability in T2DM patients treated with SU or metformin monotherapy and a documented h/o CAD Diabetes Obes Metab Sep;14(9):803-9 Cardiovascular mortality Myocardial infarction and stroke Hospitalization for acute coronary syndrome, urgent revascularization procedures Other endpoints 47 RCTs were included, totalizing patients SU were not associated with total (OR 1.12, 95% C.I to 1.30; I2 = 0%, p = 0.67) or cardiovascular mortality (OR 1.12, 95% C.I to 1.42; I2 = 12%, p = 0.30) SU were also not associated with increased risk of myocardial infarction(OR 0.92, 95% CI ; I2 = 3% p = 0.42) or stroke (OR 1.16, 95% CI ; I2 = 30% p = 0.09) Rados DV, Pinto LC, Remonti LR, et al. Sulfonylureas are not associated with increased mortality: Meta-analysis and trial sequential analysis of randomized clinical trials. American Diabetes Association 2015 Scientific Sessions; June 6, 2015; Boston, MA. Abstract 16-OR SU does not increase the risk of all-cause or CV mortality: A meta-analysis Sulfonylureas are not associated with increased Cardiovascular Mortality Monami M, et al. Diabetes Metab Res Rev 2006; 22(6): Kaplan-Meier survival analysis Glimepiride or gliclazide Repaglinide Glibenclamide Time (months) Cumulative survival Glimepiride Gliclazide Repaglinide Glibenclamide Yearly mortality 0.4% 2.1%* 3.1%* 8.7%** * P < 0.05 vs Glimepiride **P