First approved by the U.S. FDA in 1994 for the treatment of type 2 diabetes (T2D), metformin works by lowering glucose production in the liver and by improving the body’s response to insulin. The drug demonstrated effectiveness in lowering blood glucose, and as it was also affordable and well-tolerated, the International Diabetes Foundation recommended it in 2005 as first-line treatment for T2D. Another goal of treating T2D is the limitation of the development or progression of complications, especially cardiovascular ones (the risk of cardiovascular-related death is 2-4 times greater in adults with all forms of diabetes compared to those without). Until recently, there was little data available on metformin’s impact on cardiovascular outcomes. But that situation changed in June with the presentation of new data at the 2022 American Diabetes Association (ADA) suggesting that while metformin is effective in lowering blood glucose and for helping to delay the progression from prediabetes to diabetes, the drug does not reduce cardiovascular risk in the absence of significant weight loss (data from the 3,200 patient, 21 year-long Diabetes Prevention Program Outcomes Study – DPPOS).
The DPPOS findings support the opinion of a growing number of endocrinologists that metformin should probably be replaced as first-line therapy in T2D by one or more newer agents that have exhibited clinically demonstrated cardiovascular benefit: GLP-1 receptor agonists and SGLT2 inhibitors.
GLP-1 receptor agonists slow digestion, lower blood sugar and blood pressure, and promote weight loss. SGLT2 inhibitors affect blood filtration through the kidneys, inhibiting the return of glucose to the bloodstream and leading to similar therapeutic benefits. Both classes of drugs have shown the ability to prevent serious cardiovascular events, and several, including the SGLT2 inhibitors empagliflozin (Lilly and Boehringer Ingelheim’s Jardiance), canagliflozin (Janssen’s Invokana), and the GLP-1 targeting drugs semaglutide (Novo Nordisk’s Ozempic) and liraglutide (Novo Nordisk’s Victoza), have been approved by the FDA for cardiovascular risk reduction in patients with T2D. In addition to lowering cardiovascular risk, semaglutide stimulates significant weight loss in many of those treated, achieving an average 15% loss at 18 months with a 2.5 mg weekly injection. This observation has led to a new case use for semaglutide, which was approved by the FDA in June 2021 as Wegovy for use in chronic weight management.
Enter Lilly’s tirzepatide (Moujaro), which has recently elicited even more excitement within the endocrinology community who see the drug as a significant breakthrough for weight loss. Tirzepatide combines agonist activity against both GLP-1 and a second receptor, glucose-dependent insulinotropic polypeptide (GIP), which enhances GLP-1-induced weight loss.
The Phase 3 SURMOUNT-1 study of tirzepatide tested once-weekly injections of the drug at one of three doses (5mg, 10mg, 15mg) versus placebo as a treatment for non-diabetic patients who were obese or who were overweight with at least one weight-related complication (e.g., high blood pressure, sleep apnea). Results of the study, presented at ADA and published in the New England Journal of Medicine, showed patients in each of the three dose groups to achieve a mean weight loss at 72 weeks of 15%, 19.5% and 20.9% respectively, with 85% of all tirzepatide-treated patients achieving at least a 5% weight reduction. In contrast, only 3% of patients in the placebo group achieved that weight loss goal. Improvements in cardiovascular and metabolic markers as well as significant reductions in blood pressure were also seen in the treated patients. The most common adverse reactions seen in the study were mild to moderate gastrointestinal events (transient nausea and diarrhea).
As was the case for semaglutide, weight loss is not the first indication for tirzepatide, which the FDA approved in May 2022 as an adjunct to diet and exercise to enhance glycemic control in adult patients with T2D. But it is the drug’s ability to elicit significant weight loss that has physicians and patients so enthused — an average of 35 to 52 pounds depending on dose. Experts are saying that the degree of weight loss achieved with tirzepatide is unprecedented for a drug therapy, and comparable to that seen with gastric bypass and other types of bariatric surgery. Moreover, at 72 weeks, the weight reduction curves for patients at the 10mg and 15mg doses had not yet reached a plateau, suggesting that those patients might achieve an even greater weight loss with a longer duration of treatment. Lilly plans to seek an expedited approval of the drug for obesity, but has not yet commented on when it may file. The FDA has typically required data on cardiovascular outcomes for the approval of anti-obesity medicines, and Lilly has additional SURMOUNT trials ongoing to look further at the cardiovascular effects of tirzepatide, with data expected in 2023.
If tirzepatide achieves marketing approval as a treatment for obesity, pricing and reimbursement remain possible obstacles to its broadest use, although Novo Nordisk announced about US $198 million in sales of Wegovy for the first quarter of 2022 despite facing similar challenges. Lilly has priced Mounjaro for the treatment of T2D at about $1,055 per month; in comparison, Novo Nordisk lists Ozempic at about $890 per month (and Wegovy at $1,350 per month). But while some insurers quickly covered Mounjaro for diabetes, it is not yet reimbursed by Medicare or Medicaid. The pricing situation in obesity is still more constrained. Not all insurers will cover weight loss drugs, and Medicare specifically excludes coverage for all anti-obesity treatments other than weight loss surgeries.