CAROLINA Published: Reaffirms Sulfonylurea Cardiovascular Safety

Miriam E. Tucker

September 20, 2019

BARCELONA — Publication of the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) reaffirms the cardiovascular safety of the sulfonylurea glimepiride, according to the study authors and outside experts.

Results from CAROLINA were presented September 19 in a symposium here at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting and simultaneously published in JAMA.

The data were first presented at the American Diabetes Association (ADA) 2019 Scientific Sessions in June, as reported by Medscape Medical News.

The randomized, double-blind, active-controlled, noninferiority CAROLINA trial showed no difference in cardiovascular outcomes over a mean of 6.3 years between the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Tradjenta, Boehringer Ingelheim/Lilly) and glimepiride (Amaryl, Sanofi) among a total of 6033 adults with relatively early type 2 diabetes who were at elevated risk of cardiovascular events.  

"Cardiovascular safety should no longer be a consideration in the decision-making process for selecting between either of these two oral agents," Julio Rosenstock, MD, chief of the Dallas Diabetes Research Center at Medical City, Texas, told delegates during the EASD symposium.

But, Rosenstock also said, because rates of hypoglycemia and weight gain were greater with the sulfonylurea, "Other than a cost consideration, CAROLINA supports the use of a DPP-4 inhibitor before a sulfonylurea."

Furthermore, CAROLINA also "reaffirms current clinical recommendations to choose an agent after metformin based on proven cardiovascular benefit, which none of those agents [DPP-4 inhibitor or sulfonylurea] provide."

CAROLINA coauthor Darren K. McGuire, MD, a cardiologist from UT Southwestern Medical Center, Dallas, Texas, also cautioned that it's not yet clear whether the study results can be extrapolated to different populations from those enrolled or the cardiovascular safety data extend to other modern sulfonylureas.

Nonetheless, he asserted, "the [US Food and Drug Administration] should revisit the glimepiride product-label warnings about CV mortality."

Clinicians Can Continue to Use Sulfonylureas

In an accompanying editorial to the JAMA publication, Deborah J. Wexler, MD, of the Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston, writes, "Clinicians can continue to use low-cost sulfonylureas added to metformin for management of hyperglycemia in type 2 diabetes with confidence in their effectiveness for reduction of microvascular complications as well as their cardiovascular safety."

"The adverse effect profile of sulfonylureas and their very low cost must be balanced against characteristics of other glucose-lowering medications, as clinicians consider the best approach for an individual patient," she added.

And at the EASD symposium, independent commentator Philip Home, MD, professor of diabetes medicine at Newcastle University, UK, called CAROLINA "a useful and well-done study, which will be much quoted and discussed."

However, he faulted the study for its duration, which "though relatively long, is however less than the time required to show differences from glucose lowering."

Like McGuire, Home said that it remains "uncertain" whether the CAROLINA findings apply to other sulfonylureas, but "perhaps yes" that they apply to other DPP-4 inhibitors.

Observational Data Still Implicate Sulfonylureas, but Are They Valid?

A second article published in the same issue of JAMA, of a retrospective cohort study of nearly 70,000 US veterans with diabetes and reduced kidney function, seems to show an advantage of metformin over sulfonylureas in terms of CV events.

The major adverse cardiovascular events (MACE) rates were 23.0 versus 29.2 events/1000 person-years for metformin versus sulfonylurea, respectively, which gave a significant cause-specific adjusted hazard ratio for metformin compared with sulfonylureas of 0.80.

These results "add to the limited observational evidence for the beneficial association of metformin, compared with sulfonylurea, and cardiovascular outcomes among those who develop reduced kidney function," say the researchers, led by Christianne L. Roumie, MD, of the Geriatric Research Education Clinical Center, VA Tennessee Valley Health Care System, Nashville.

In Wexler's editorial, which addresses both this trial and CAROLINA, she says the study by Roumie and colleagues is a "rigorously conducted retrospective cohort study," nonetheless, "even the most rigorous observational studies of the comparison between metformin and sulfonylureas may be limited by several significant biases." 

Specifically, she told Medscape Medical News by email: "In observational trials, medications are not randomly assigned. They are usually selected by physicians precisely because of patient characteristics that cause patients treated with different medications to be different in both measured and unmeasured ways which are likely related to the outcome of interest."

In contrast, "a large, well-conducted randomized controlled trial is the most valid way to determine whether a treatment causes an outcome in a given population."

"CAROLINA, as a randomized clinical trial, provides much higher quality evidence than even a very well-conducted observational trial," she stressed.

Different Strokes for Different Folks...

McGuire agreed, telling Medscape Medical News, "The patients who are prescribed metformin would be very different from the patients who are prescribed sulfonylureas. You can adjust for a lot of those differences, but you can't adjust all the way."

In addition, he noted, "There may be a reason they're not on metformin, either a contraindication or they're intolerant. They're just different patients."  

The concern about cardiovascular safety of sulfonylureas was initially triggered in 1970 with the publication of the controversial University Group Diabetes Program, despite very small event numbers (26 cardiovascular deaths among 204 individuals randomized to tolbutamide versus 10 of 205 with placebo).

Since then, Wexler notes that some, but not all, of the observational studies and meta-analyses of randomized clinical trials that attempted to evaluate the cardiovascular safety of sulfonylureas compared with metformin have supported the concern about sulfonylureas.

Wexler also points out that "all medications have adverse effects. In practice, the risk of hypoglycemia and weight gain with sulfonylureas may be mitigated with individualized glycemic targets and flexible dose adjustment for changes in meal size and physical activity, although these strategies have not been rigorously evaluated."

The Roumie study, she says, "further supports the use of metformin as the first-line treatment to which other diabetes medications are added, even as early chronic kidney disease develops."

In addition to CAROLINA, further randomized trial data to address the comparative effectiveness of glimepiride and a DPP-4 inhibitor, GLP-1 receptor agonist, and basal insulin, each added to metformin, is expected with the publication of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study in 2022.

Rosenstock has reported serving on scientific advisory boards and receiving honoraria and consulting fees from Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim, and Intarcia, and receiving grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Lexicon, Boehringer Ingelheim, and Intarcia. McGuire has reported receiving personal fees from Boehringer Ingelheim, Janssen Research and Development, Sanofi-Aventis, MSD, Eli Lilly USA, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon, Eisai, Esperion, Pfizer, Metavant, and Applied Therapeutics. Wexler has reported serving as a member of a data monitoring committee for Novo Nordisk. Home and/or his institution has received funding for lecturing, advisory, and/or research activities from all DPP-4 inhibitor manufacturers, including Boehringer Ingelheim, and from the manufacturer of glimepiride.

EASD 2019 Annual Meeting. Presented September 19, 2019.

JAMA. Published online September 19, 2019. Study 1, Study 2Editorial

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