The US Food and Drug Administration (FDA) has approved an additional indication ― reduction of cardiovascular (CV) disease risk — for the injectable formulation of the GLP-1 agonist semaglutide (Ozempic, Novo Nordisk) in the treatment of type 2 diabetes and has added new trial data information to the label of the oral version (Rybelsus, Novo Nordisk) pertaining to CV safety.
On January 16, the FDA expanded the once-weekly injectable semaglutide's label to include an indication for reducing the risk for major adverse cardiovascular events (MACE), including CV death, nonfatal myocardial infarction (MI), or nonfatal stroke, in adults with type 2 diabetes who have established CV disease.
Initially approved for the treatment of type 2 diabetes in adults in December 2017, once-weekly subcutaneously injectable semaglutide comes in 0.5-mg and 1.0-mg doses in a dedicated prefilled pen device.
The approval for the new indication was based on data from the 2-year randomized Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN 6), in which injectable semaglutide or placebo was added to standard of care in 3297 adults with type 2 diabetes and established CV disease.
As reported by Medscape Medical News in September 2016, patients who underwent treatment with one of the two doses of semaglutide had a significant 26% lower risk for the primary composite outcome of first occurrence of CV death, nonfatal MI, or nonfatal stroke compared with those who received placebo.
The reduced CV risk was driven primarily by significant reductions in nonfatal stroke and nonfatal MI (39% and 26%, respectively). There was no difference in CV death between drug and placebo groups. Gastrointestinal adverse events were more frequent with semaglutide than placebo, with the majority occurring during the first 30 weeks.
The oral semaglutide formulation, taken daily in 7-mg or 14-mg doses, was approved for the treatment of type 2 diabetes in September 2019, the first orally available GLP-1 agonist.
Now, the FDA has updated the prescribing information in the clinical studies section (section 14) to include results from the randomized, placebo-controlled, 3183-subject Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes (PIONEER 6), reported in June 2019, which found a nonsignificant 21% reduction in three-component MACE with oral semaglutide. The addition to the label for Rybelsus is with regard to CV safety, not benefit.
SOUL: Large Ongoing CVOT for Oral Semaglutide
In June 2019, Novo Nordisk initiated a larger CV outcomes trial of oral semaglutide, A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL). The trial, which includes 9642 adults with type 2 diabetes and established CV disease, is further investigating the drug's effects on the incidence of MACE. The estimated completion date is July 2024.
Semaglutide joins a growing list of drugs approved for treating type 2 diabetes that have been granted additional label indications for benefits beyond the lowering of glucose.
These include Novo Nordisk's other injectable GLP-1 agonist, liraglutide (Victoza), additionally approved for reducing CV events in high-risk patients with type 2 diabetes, and the sodium-glucose transport protein 2 inhibitors empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), for reducing CV death, canagliflozin (Invokana, Janssen), for reducing major adverse CV events, kidney disease, CV death, and heart failure hospitalization, and dapagliflozin (Farxiga, AstraZeneca), for reducing heart failure hospitalization.
Recently, in an exclusive Medscape Medical News article, some experts questioned the design of these CV outcomes trials, suggesting that imbalances in glycemic control, blood pressure, and diuretic use between treatment and placebo arms could have biased the CV and renal outcomes of the trials in favor of the study drugs
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Cite this: FDA Approves CVD Benefit for Once-Weekly Semaglutide - Medscape - Jan 17, 2020.