New CV Outcomes Trials Examine Linagliptin and Glimepiride Among Patients With High CVD Risk

The CAROLINA and CARMELINA Trials offer further information regarding the CV safety of linagliptin and glimepiride among patients with T2DM, high CVD risk, and decreased renal function.  

Patients with diabetes carry an increased risk of cardiovascular disease. Since the development of diabetes drugs, there has been attention to the impact that medications can have on diabetes patients’ cardiovascular health. One of the most popular diabetes drug classes that carry an increased risk for cardiovascular disease is the class of thiazolidinediones (TZDs). Treatment with TZDs is accompanied by a significantly increased risk for heart failure and exacerbation of existing heart failure, leading to its significant decrease in use.  Over the past decade, the FDA has emphasized the importance of the CVD risk that glucose-lowering medications may cause. Since 2008, evaluation of cardiovascular safety of new diabetes drugs through extensive non-inferiority studies compared to placebo has been mandated. Several cardiovascular outcomes trials have proven SGLT2 inhibitors and GLP1 receptor agonists to be of the most significant benefit to patients with particularly increased risk for cardiovascular disease. DPP4 inhibitors have previously demonstrated a non-inferior risk of a composite CV outcome vs. placebo. Two recent significant studies analyzed the CV effect of the DPP4 linagliptin in patients already at high cardio-renal and cardiovascular risk.  

The CAROLINA trial analyzed 6,033 adults aged 40-85 years old with T2DM and established CVD or increased risk for CVD. Participants were randomly assigned linagliptin 5 mg once daily or the sulfonylurea glimepiride 4 mg, both in addition to other diabetes medications previously prescribed, for an average of 6.3 years. The primary outcome was a composite of CV death, nonfatal MI, and nonfatal stroke. Concerning CV events, there were no between-group differences between the two groups. There were also no between-group differences for HbA1c. The significant differences found were the incidence of hypoglycemia. These results sparked researchers to “debunk” the long-standing debate regarding sulfonylureas, especially glimepiride, and increased CV harm.  

The CARMELINA trial analyzed 6,979 adults with T2DM with a history of vascular disease and urinary albumin to creatinine ratio of ≥200 mg/g; participants had a broad range of kidney function. This trial had the most participants with reduced kidney function compared to any other DPP4 inhibitor cardiovascular outcomes trial. Participants were randomly assigned linagliptin 5 mg once daily or placebo once daily for an average of 2.2 years. The primary outcome was the time to the first occurrence of a composite of CV death, nonfatal MI or nonfatal stroke. Secondary results were the incidence of end-stage renal disease or a sustained decrease of 40% or more in eGFR. Participants in the linagliptin and placebo groups experienced CV outcomes at similar rates; this indicates that linagliptin did not have a negative effect on cardiovascular risk. No difference was observed for hospitalization for heart failure or severe renal events.  

What these trials can help us to understand is that linagliptin, a DPP4 inhibitor anti-diabetic drug, does not have a negative effect on cardiovascular risk in patients with T2DM. Also, glimepiride, of the sulfonylurea class, has comparable CV outcome risk to linagliptin. It is important to note that glimepiride carries an increased risk for hypoglycemia and weight gain, whereas linagliptin and DPP4 inhibitors do not. Linagliptin also is safe for patients with reduced renal function; it is the only DPP4 inhibitor that does not require renal adjustments for low eGFR. While these drugs are not found to improve cardiovascular outcomes, we can observe from these large trials that they do not worsen CV risk for patients with type 2 diabetes.  

Practice Pearls: 

• Linagliptin and glimepiride were compared to assess CV risk in patients with T2DM, and results showed similar results. 
• Linagliptin and placebo showed similar outcomes for patients with kidney function and a history of vascular disease for CV and renal risk. 
• Linagliptin is a safe option for T2DM patients with CVD and compromised renal function. 

• Glimepiride has shown comparable CV outcomes to linagliptin and, therefore, may be safe for high–risk CVD patients, although it carries other disadvantages, including hypoglycemia, weight gain and beta-cell burnout.  

“CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes – Full–Text View.” Full–Text View – ClinicalTrials.gov, clinicaltrials.gov/ct2/show/NCT01243424. 

Rosenstock, Julio, et al. “Effect of Linagliptin vs. Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk.” Jama, vol. 321, no. 1, 2019, p. 69., doi:10.1001/jama.2018.18269. 

Amber Satz, PharmD Candidate, LECOM School of Pharmacy 

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