CAROLINA Reassures on CV Safety for Linagliptin, Glimepiride in Type 2 Diabetes

Miriam E. Tucker

June 11, 2019

SAN FRANCISCO — There are no major differences in cardiovascular outcomes between the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin (Tradjenta, Boehringer Ingelheim/Lilly) and the sulfonylurea glimepiride (Amaryl, Sanofi) among patients with early type 2 diabetes at increased cardiovascular risk, new research indicates.

Findings from the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA) were presented June 10 here at the American Diabetes Association (ADA) 2019 Scientific Sessions by Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, and several coauthors.

CAROLINA is the first cardiovascular outcomes trial to include an active comparator and it provides valuable information about both linagliptin and glimepiride.

On the one hand, it provides reassurance about the long-debated cardiovascular safety of sulfonylureas. But it also illustrates yet again the well-known risks of hypoglycemia and weight gain seen with that drug class.

At the same time, the study reaffirms the cardiovascular safety of linagliptin, first demonstrated in the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA) announced last September at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting.

The new findings don't change current treatment recommendations for use of a type 2 diabetes agent with proven cardiovascular benefit — a sodium-glucose cotransporter type 2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) agonist — after metformin in patients with established cardiovascular disease.

But for other patients with type 2 diabetes, they do inform the choice of a second-line agent when cost is an issue, Rosenstock stressed.

"Other than a cost consideration, CAROLINA supports the use of a DPP-4 inhibitor (linagliptin) before a sulfonylurea (glimepiride)," he said, adding that, at the same time, "cardiovascular safety should no longer be a consideration in the decision-making process for selecting between either of these two oral agents."

Cost the Only Reason to Use a Sulfonylurea, but They Are Safe

During a press briefing to discuss the findings, incoming ADA president Robert H. Eckel, MD, commented, "I've been taking patients off sulfonylureas for years, if their third-party payers allow it...This study has helped me know that I can continue sulfonylureas safely now."

But Eckel also said that, in terms of starting a patient on glucose-lowering therapy, "there's only one reason I would use a sulfonylurea: cost."

Concerns about the cardiovascular safety of sulfonylureas date back to the infamous 1970 publication by the University Group Diabetes Program (UGDP) study, which used the first-generation and long-discontinued sulfonylurea tolbutamide. In that study, conducted during the 1960s, there was an excess of cardiovascular deaths with the drug compared to placebo (26 vs 10; P = .005).

Subsequent studies with newer-generation sulfonylureas have not shown increased cardiovascular risk compared with placebo, but each of those had limitations in answering the cardiovascular safety question, CAROLINA coauthor Nikolaus Marx, MD, professor of cardiology, Aachen University, North Rhine-Westphalia, Germany, said during the ADA press briefing.  

"This study resolves the decades-long highly debated cardiovascular safety of sulfonylureas, specifically glimepiride, beginning 50 years ago with the UGDP study, then with other studies not confirming or showing neutrality for sulfonylureas...This resolves the ongoing discussion," Marx said.

Similar CV Safety, But Hypoglycemia Much Worse With Sulfonylurea

CAROLINA involved 6033 individuals with type 2 diabetes from 607 sites in 43 countries. All had relatively recent diabetes onset (median duration 6.3 years) and most had pre-existing cardiovascular disease (42%) or two or more defined cardiovascular risk factors (37%). Most (83%) were already taking metformin, but 9% were treatment naive at baseline. Those taking insulin were excluded.

Over a median of 6.3 years — the longest cardiovascular outcomes trial to date, note the researchers — there were no differences in the overall composite endpoint of cardiovascular death (fatal stroke and fatal myocardial infarction [MI]), nonfatal MI (excluding silent MI), or nonfatal stroke. Overall, the 3-point MACE occurred in 11.8% of the 3023 participants receiving linagliptin compared with 12.0% of the 3010 participants receiving glimepiride (hazard ratio [HR], 0.98; P = .7625).

Similarly, nonsignificant differences were seen between linagliptin and glimepiride for each individual component of CV death (HR 1.00; 5.6% vs 5.6%; P = .9863), nonfatal MI (HR, 1.01; 4.8% vs 4.7%; P = .9060), and nonfatal stroke (HR, 0.87; 3.0% vs 3.5%; P = .3352). 

The same was true for secondary endpoints including hospitalization for heart failure (HR, 1.21; 3.7% vs 3.1%; P = .1761), CV death (HR, 1.00), non-CV death (HR, 0.82), and all-cause mortality (HR, 0.91). 

No differences were seen in glycemic control. HbA1c levels dropped more quickly with glimepiride, but by the end of the trial both groups had returned to a baseline of around 7.0%. There were no differences in the proportion of patients for whom new glucose-lowering therapies, including insulin, were required (about 40% in both groups).

Those in the glimepiride group initially gained about 0.6 kg in weight while the linagliptin group lost about 1.0 kg. By the end of the trial, the glimepiride group weighed about 1.5 kg more than the linagliptin participants.

No differences were seen between the groups in systolic or diastolic blood pressure, or in LDL cholesterol, HDL cholesterol, or triglycerides.

Hypoglycemia occurred significantly more often in the glimepiride group, including hypoglycemia overall (37.7% vs 10.6%; P < .0001), moderate to severe hypoglycemia (30.9% vs 6.5%; P < .0001), severe hypoglycemia (2.2% vs 0.3%; P < .0001), and hospitalization due to hypoglycemia (0.9% vs 0.1%; P = .0004). 

"Based on our data, hypoglycemia remains the main concern with sulfonylureas," Marx observed.

Sulfonylureas Still Widely Used Around the World

However, Rosenstock noted during the briefing that sulfonylureas are still very widely used around the world.

"The reason is cost, especially in other countries. With this study, we provide very specific data for the magnitude of risk of hypoglycemia and of the weight changes, so people can decide whether to use it or not."

"There may be some patients who are at very low risk for hypoglycemia. Not everybody gets hypoglycemia. Not everybody gains 1 or 2 kilos. It may not be that important."

"It's the difference between a $10 pill and a $150 pill. The DPP-4 inhibitors make billions of dollars. So there are going to be cost considerations."

But at least, he said, their cardiovascular safety should no longer be in doubt.

"We think we've vindicated sulfonylureas, at least glimepiride specifically. Debate will come whether or not we can generalize this to other sulfonylureas. Most likely yes, but we can't say with certainty. But it certainly [eliminates] the stigma that sulfonylureas have had for more than 50 years."

Yet, he also noted, CAROLINA "reaffirms current clinical recommendations to choose an agent after metformin based on proven cardiovascular benefit, which none of those agents [DPP4 inhibitors or sulfonylureas] provide."

Rosenstock has served on scientific advisory boards and/or received honoraria, consulting fees, and/or grants/research support from Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim, Intarcia, Merck, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Janssen, and Lexicon. Marx has served as a speaker, received research grants, and/or served on advisory boards for Amgen, Bayer, Boehringer Ingelheim, Sanofi Aventis, MSD, BMS, AstraZeneca, Lilly, and Novo Nordisk. Eckel has received funding from the National Institutes of Health and ENDECE, and has served on scientific advisory boards for Merck, Sanofi/Regeneron, Novo Nordisk, and Kowa.

ADA 2019 Scientific Sessions. Presented June 10, 2019.

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