Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes

Abstract

IMPORTANCE Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. OBJECTIVE This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. INTERVENTIONS Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. MAIN OUTCOMES AND MEASURES The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. RESULTS Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). CONCLUSIONS AND RELEVANCE Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior ri...

Emulation Differences vs. Biases When Calibrating Real‐World Evidence Findings Against Randomized Controlled Trials

“…The CAROLINA trial comparing linagliptin to glimepiride evaluated the risk of moderate or severe hypoglycemia. 8 An RWE prediction of this trial based on healthcare claims data could not directly mimic the definition from the trial, which captured many less severe events that did not require contact with the healthcare system. 9 Instead, hypoglycemia was defined as a primary inpatient or emergency department diagnosis PERSPECTIVES of hypoglycemia.…”

Latest Evidence on Sulfonylureas: What’s New?

“…While rates of hypoglycaemia were higher with glimepiride than with linagliptin ( Table 2), it is important to note that the absolute risk of hypoglycaemia was quite small, even in the SUtreated patients [18]. It is also important to highlight that the SU used in the CAROLINA study was glimepiride, and that there are differences among SUs in the risk of hypoglycaemia, as discussed later.…”

Importance of intensive blood pressure control in type 2 diabetes: Mechanisms, treatments and current guidelines

“…The special chemical structure of gliclazide, with its polycyclic ring able to capture free anions, may have clinical effects on systemic BP . In all, SUs can be considered as neutral with regard to BP and CV risk, as confirmed by the CAROLINA study, which compared CV outcomes between the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin and the SU glimepiride …”