Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes - CAROLINA

Contribution To Literature:

The CAROLINA trial showed that the DPP-4 inhibitor linagliptin was noninferior to glimepiride; however, it was not superior.


Description:

The goal of the trial was to evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin compared with the sulfonylurea glimepiride among patients with type 2 diabetes and elevated cardiovascular risk.


Study Design

  • Randomized
  • Parallel
  • Blinded
  • Stratification

Patients with type 2 diabetes and elevated cardiovascular risk were randomized to linagliptin 5 mg daily (n = 3,028) versus glimepiride 4 mg daily (n = 3,014).

  • Total number of enrollees: 6,042
  • Duration of follow-up: median 6.3 years
  • Mean patient age: 64 years
  • Percentage female: 40%
  • Percentage with diabetes: 100%

Inclusion criteria:

  • Type 2 diabetes (glycated hemoglobin 6.5-8.5%)
  • Elevated cardiovascular risk (established cardiovascular risk, ≥2 cardiovascular risk factors [diabetes duration >10 years, systolic blood pressure >140 mm Hg, current smoker, low-density lipoprotein cholesterol ≥135 mg/dl or on lipid-lowering therapy], ≥70 years of age, or microvascular complications)

Exclusion criteria:

  • On insulin therapy
  • Previous exposure to DPP-4 inhibitors, glucagonlike peptide-1 receptor agonists
  • New York Heart Association class III or IV heart failure

Principal Findings:

The primary outcome of cardiovascular death, myocardial infarction, or stroke occurred in 11.8% of the linagliptin group compared with 12.0% of the glimepiride group (p for noninferiority < 0.001, p for superiority = 0.76).

Secondary outcomes:

  • Cardiovascular death: 4.3% with linagliptin vs. 4.2% with glimepiride  
  • Myocardial infarction: 4.7% with linagliptin vs. 4.6% with glimepiride  
  • Stroke: 2.8% with linagliptin vs. 3.4% with glimepiride  
  • Hypoglycemia: 10.6% with linagliptin vs. 37.7% with glimepiride (p < 0.001)
  • Weighted average mean difference in body weight: -1.54 kg for linagliptin vs. glimepiride (p < 0.05)

Interpretation:

Among patients with type 2 diabetes and elevated cardiovascular risk, the DPP-4 inhibitor linagliptin was noninferior to the sulfonylurea glimepiride on prevention of major adverse cardiovascular events over a median of 6.3 years. Linagliptin was not superior to glimepiride on prevention of major adverse cardiovascular events; however, it was associated with a lower frequency of hypoglycemia and less weight gain compared with glimepiride.

Metformin remains the first-line agent for treatment of type 2 diabetes. Options for a second-line agent include a sulfonylurea or a DPP-4 inhibitor. Lower cost would favor the former category, while less hypoglycemia and weight gain would favor the latter category.

References:

Rosenstock J, Kahn SE, Johansen OE, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA Randomized Clinical Trial. JAMA 2019;322:1155-66.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Nonstatins, Heart Failure and Cardiac Biomarkers, Smoking

Keywords: Blood Pressure, Cholesterol, LDL, Diabetes Mellitus, Type 2, Dipeptidyl Peptidase 4, Dipeptidyl-Peptidase IV Inhibitors, Hypoglycemia, Metabolic Syndrome X, Metformin, Myocardial Infarction, Primary Prevention, Risk Factors, Smoking, Stroke, Sulfonylurea Compounds, Weight Gain


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