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 (12·7%) compared to 4·7% with placebo, 6.2% with fixed dose insulin and 5·9% 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 0·83 for glimepiride 1·13 for tolbutamide 1·34 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 score–matched 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 score–matched 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 (case–control 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 <0.01 vs all comparators Newer SU Safety: All-Cause Mortality In combination with metformin, Glimepiride is associated with lower mortality than other SUs having less selectivity for β-cell receptors Mortality with Glimepiride was significantly lower as compared to Gliclazide and Repaglinide

Do Gliclazide and Glimepiride have similar CV outcomes?

N Engl J Med Jun 4;372(23): N Engl J Med 2008;358: Recent Clinical Outcome Trials: Intensive vs Standard therapy VADT/FS: Glimepiride used in the intensive arm along with other OADs and insulin ADVANCE: Gliclazide MR used in Intensive arm along with 40% insulin, other OHA: 93% VADT – FS: Veteran's Affairs Diabetes Trial - Follow-up Study ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation

N Engl J Med Jun 4;372(23): Glimepiride used in intensive arm along with other OADs and insulin 17% RRR in CV events, effect on Microvascular complications were not studied HbA1c reached: 6.9% in intensive arm vs 8.4% in standard therapy arm VADT/FS: Clinical Outcome Results

Intensive vs Standard therapy: Effect on primary outcome of the time to the first major cardiovascular event N Engl J Med Jun 4;372(23): The intensive-therapy group (having glimepiride) had a significant 17% RRR in major CV events 2015 VADT/FS: Clinical Outcome Results

N Engl J Med 2008;358: ADVANCE: Gliclazide MR used in Intensive arm along with 40% insulin, other OHA: 93% HbA1c reached: 6.5% in intensive arm vs 7.3% in the standard therapy arm 10% RRR in combined Micro- and Macrovascular events  Due to a 16% RRR reduction in Microvascular events (nephropathy) No effect seen on Major Macrovascular events ADVANCE: Clinical Outcome Results

ADVANCE study: Is Gliclazide CV safe? Primary Endpoint: As compared with standard control, Intensive control Reduced the incidence of combined major macrovascular and microvascular events, mainly as a consequence of a reduction in nephropathy Resulted in a significant reduction in the incidence of major microvascular events (HR, 0.86; 95% CI, 0.77 to 0.97; P = 0.01) But not in the incidence of major macrovascular events (HR, 0.94) or death from cardiovascular causes (HR 0.88), or death from any cause (HR 0.93) The annual rate of macrovascular events was lower possibly due to the greater use of statins, BP lowering drugs and antiplatelet agents Thus, ADVANCE does not show that gliclazide MR was better than other OADs in terms of macrovascular events

Macrovascular outcome: Long term Cardiovascular outcome data StudyInterventionsCVD eventsMortality ADVANCE /ADVANCE ON) Intensive (Gliclazide MR+ combination) vs. Standard- control therapy VADT/VADT -FS Intensive (Glimepiride/met + rosiglitazone +/- insulin vs. Standard care Initial trial Long term follow up N Engl J Med Oct 9;371(15): N Engl J Med Jun 4;372(23): In terms of long term CV outcomes, Gliclazide or other contemporary SU would be the same

Summary Newer SUs are associated with a lower risk of all-cause and cardiovascular-related mortality Newer SUs are associated with a lower risk of CAD Newer SUs and especially Glimepiride may be preferred in patients with underlying CAD Among all SUs, risk of mortality is lower with Glimepiride In terms of long term CV outcomes, Glimepiride based combination therapy is better than Gliclazide