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.


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)


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.


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, Metformin, Myocardial Infarction, Primary Prevention, Risk Factors, Smoking, Stroke, Sulfonylurea Compounds, Weight Gain

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