Effects of Linagliptin on Heart Failure and Related Outcomes: Observations from the CARMELINA Trial

By Darren K. McGuire, M.D., M.H.Sc.
Distinguished Teaching Professor of Internal Medicine 

Since 2008, the U.S. FDA and regulatory agen­cies around the world have required that all medications being developed for glucose control in type 2 dia­betes undergo formal clinical trial evaluation to prove cardiovascular (CV) safety. This has led to a series of interna­tional mega-trials over the past decade with the primary focus of CV assessment of such medications. These trials have focused primarily on three new classes of diabetes medications: the dipeptidyl peptidase (DPP) 4 inhibitors (DPP4is); glucagon-like peptide 1 receptor agonists (GLP1-RAs); and sodium-glucose cotransporter 2 inhibitors (SGLT2is). Four trials of four different GLP1-RAs (injectables) and four trials of three different SGLT2is (tablets) have not only demonstrated CV safety but also proved superiority versus placebo, each added to usual diabetes care, on reducing risk for major adverse CV outcomes including CV death, myocar­dial infarction (MI), stroke, and hospitalization for heart failure.

There are four DPP4is approved for use in the U.S., each administered as a once-daily tablet: sitagliptin, saxagliptin, alogliptin, and linagliptin. Three prior trials with three different DPP4is demonstrated CV safety but not incremental efficacy with saxagliptin, sitagliptin, and alogliptin. A major difference across the results from these trials was that saxagliptin increased risk of hospitalization for heart failure (hHF); alogliptin was associated with numerical excess of hHF events that did not achieve statistical significance; and sitagliptin had no effect on hHF. In this context, we analyzed hHF and related outcomes for the fourth such DPP4i trial, known as CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus). 

This trial enrolled 6,979 patients with type 2 diabetes and with preva­lent atherosclerotic CV disease and/or kidney dysfunction, randomizing participants to linagliptin 5 mg once daily versus placebo. The primary trial results demonstrated safety but not incremental efficacy on the outcomes of CV death/MI/stroke and for progression of kidney disease.

At the AHA, we reported results from the HF analyses of CARMELINA, demonstrating no difference in any HF-related outcome with linagliptin versus placebo, replicating the observations with sitagliptin and underscor­ing the heterogeneity across this class of medications for HF risk with lina­gliptin versus placebo (hHF HR 0.90; 95% CI 0.74-1.08). Importantly, unlike the other three DPP4is that are cleared renally and require dose adjustment with moderate kidney dysfunction and are contraindicated in severe kidney disease, linagliptin has minimal renal clearance and can be used at any level of kidney function, including for patients on dialysis. Thus, these results provide assurance of CV and renal safety in a very high-risk patient population, especially for patients with kidney dysfunction where therapeutic options to treat hyperglycemia in patients with type 2 diabetes are limited.