• CAROLINA: No Added Heart Risk With Sulfonylureas

     

    BARCELONA -- Investigators in the long-awaited Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes (CAROLINA) trial said their findings, reported here, should finally put concerns about sulfonylureas' cardiovascular safety to rest.

    Rates of major adverse cardiovascular events (MACE) did not differ significantly between the sulfonylurea glimepiride (Amaryl) and the DPP-4 inhibitor linagliptin (Tradjenta) in CAROLINA, with a hazard ratio of 0.98 (95.47% CI 0.84-1.14, P<0.001 for noninferiority), according to Julio Rosenstock, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues.

    Findings from the randomized trial were presented at the European Association for the Study of Diabetes (EASD) 2019 annual meeting and simultaneously published in JAMA.

    Fears surroundings the cardiovascular safety of sulfonylureas initially stemmed from the University Group Diabetes Program conducted in the 1960s and continued to linger until present day, despite wide global use of sulfonylureas due to their low cost.

    Back in 2012, Steven Nissen, MD, of the Cleveland Clinic in Ohio penned an editorial about this controversy, in part stating: "With more than two thirds of diabetic patients dying of CV causes and millions of patients currently receiving sulfonylureas, this question must be resolved with high-quality evidence. Continued darkness is not an acceptable option."

    With the CAROLINA trial underway at the time of Nissen's publication, Rosenstock's group responded with a letter of their own, promising the findings would "mak[e] the dark ages brighter."

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    Investigators Nikolaus Marx, MD (left), and Julio Rosenstock, MD (right), speak at the EASD press conference

    "The elevated risk that we were concerned about with sulfonylureas -- this is vindicated," underscored study co-author Nikolaus Marx, MD, of the University Hospital Aachen in Germany during a press conference of the findings.

    "[CAROLINA is] the only DPP-4 active comparator versus a sulfonylurea," Rosenstock pointed out during the press conference. He then referenced findings of the placebo-controlled sister trial CARMELINA, presented at last year's EASD meeting, which confirmed long-term cardiovascular and renal safety for linagliptin.

    Over 6,000 individuals with type 2 diabetes were included in the CAROLINA trial, with a median 6-year duration of diabetes, 83% of whom were on metformin and none on insulin. All patients had either cardiovascular risk factors or established atherosclerotic cardiovascular disease at the time of study entry. "It's important to note here that the participants are reflecting a patient population typically seen in clinical practice," Marx stated, adding that this wasn't a "highly selective population."

    Half of the patients were randomized to 5 mg of once-daily linagliptin, while the other half of the cohort received 1-4 mg of once daily glimepiride (mean dose of 2.9 mg), both therapies added to standard of care.

    Among the individual MACE components, none differed significantly between treatment groups:

    • CV death: HR 1.00 (95% CI 0.81-1.24, P=0.99)
    • Nonfatal MI: HR 1.01 (95% CI 0.80-1.28, P=0.91)
    • Nonfatal stroke: HR 0.87 (95% CI 0.66-1.15, P=0.34)

    Risk for heart failure also wasn't significant difference between the two treatments (HR 1.21, 95% CI 0.92-1.59, P=0.18), nor was time to death by any cause (HR 0.91, 95% CI 0.78-1.06, P=0.23).

    As expected, there was some weight gain with the sulfonylurea (weighted average mean difference -3.4 lb for linagliptin vs glimepiride, 95% CI -4.0 to -2.82 lb; –1.54 kg, -1.80 to –1.28 kg) -- differences that also reflected some weight loss with linagliptin. However, there were no significant differences noted in regard to HbA1c, fasting plasma glucose, blood pressure, or lipid levels.

    Notably, however, hypoglycemic events were more common with the sulfonylurea. Overall, those on the DPP-4 inhibitor saw an 82% reduced risk for experiencing moderate or severe hypoglycemia versus glimepiride (HR 0.18, 95% CI, 0.15-0.21, P<0.001). Those on the sulfonylurea not only saw an increased risk for a first hypoglycemic event, but also for recurrent episodes. This risk of hypoglycemia "is not new -- we've known this for over 50 years," noted Marx.

    In the context of choosing the best agent for a patient in clinical practice, Rosenstock highlighted the need for the regimen to be tailored to the patient's individual needs.

    "In the decision-making process of selecting a medication ... they can decide whether or not weight gain is an issue, whether hypoglycemia is an issue, cost is an issue. But they should not involve concerns of increased cardiovascular disease when they chose not to use a sulfonylurea," he concluded.

     

    The study was sponsored by Boehringer Ingelheim and Eli Lilly and Company.

    Rosenstock reported relationships with Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim, Intarcia, Merck, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, and Lexicon.

    Marx reported funding by the German Research Foundation, and relationships with Amgen, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Lilly, and Novo Nordisk.

    — LAST UPDATED 

    Source:

    JAMA

    Source Reference: Rosenstock J, 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; DOI: 10.1001/jama.2019.13772.

     


    Read the original article on Medpage Today: CAROLINA: No Added Heart Risk With Sulfonylureas

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