Treat-to-target to improve cardiometabolic health with second-generation obesity drugs
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Semaglutide and other obesity medications that can induce weight loss of at least 10% can change the way providers approach the treatment of obesity, according to a speaker.
W. Timothy Garvey, MD, FACE, MABOM, professor of medicine at the University of Alabama (UAB) at Birmingham and director of the UAB Diabetes Research Center, described semaglutide (Wegovy, Novo Nordisk) as an agent that can produce a mean placebo-subtracted weight loss of 10% or more in randomized clinical trials or a 15% or greater weight loss in more than half of participants in conjunction with lifestyle intervention. Garvey said semaglutide and other second-generation obesity medications in the pipeline will allow providers to look beyond weight loss and treat other cardiometabolic and biomechanical complications of obesity.
“[Second-generation medications] allows us to think about obesity and treat it like we do other chronic diseases, a treat-to-target approach,” Garvey said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “When we have drugs that can actively manage body weight with this degree of competency, we can think about percent weight loss not as an endpoint, but as a biomarker ... where we can prevent or treat the complications of obesity, including diabetes, hypertension, nonalcoholic steatohepatitis, sleep apnea and osteoarthritis.”
Semaglutide changing obesity treatment
Data from the STEP 5 trial showed semaglutide can induce a significant decrease in weight for people with obesity, with the weight loss maintained over 2 years. Participants who took semaglutide and were treatment adherent had a 16.7% reduction in body weight at 2 years compared with a 0.6% reduction for placebo. In the semaglutide group, 83.3% had a mean weight loss of at least 5% at 2 years compared with 34.9% of placebo, and 67.4% of the semaglutide group lost at least 10% of their body weight at 2 years vs. 12.8% with placebo.
Semaglutide also had glycemic benefits for participants with prediabetes at baseline. In the semaglutide group, 80% of those with prediabetes achieved normal glycemia at 2 years compared with 37% in placebo.
“We have a pretty effective medicine here that we haven’t seen this level of efficacy before,” Garvey said.
More agents on the horizon
Semaglutide’s efficacy is sufficient to address a broad range of cardiometabolic diseases, according to Garvey, making it the first of what could become a series of second-generation obesity medications. Several agents currently in the pipeline have shown strong weight-loss efficacy similar to semaglutide.
Setmelanotide (Imcivree, Rhythm Pharmaceuticals), a medication for people with obesity caused by pro-opiomelanocortin deficiency, is the only second-generation obesity medication approved by the FDA other than semaglutide. In trial data, setmelanotide was associated with weight loss between 20% and 30%.
In phase 2 trial data published in The Lancet in November, 4.5 mg cagrilintide (Novo Nordisk), a long-acting, acylated amylin analogue, was associated with a 10.8% body weight reduction at 26 weeks. In a separate phase 1B trial in which 2.4 mg cagrilintide was combined with 2.4 mg semaglutide, participants had a mean weight loss of 17.1% at 20 weeks.
Bimagrumab (Novartis), an activin type II receptor blocking biologic, was effective in reducing fat mass in a phase 2 randomized clinical trial. Participants with obesity and type 2 diabetes taking bimagrumab had a 20.5% reduction in fat mass, with 77% of participants losing at least 15% of fat mass. Lean mass increased by 3.6% in the treatment group.
In the SURPASS 1 trial, 15 mg tirzepatide (Eli Lilly) was associated with an 11% reduction in body weight at 40 weeks and a decrease in mean HbA1c from 7.9% at baseline to 5.8% at 40 weeks. More than half of those taking 15 mg tirzepatide had an HbA1c of less than 5.7% at 40 weeks.
“We’re really thinking about weight loss becoming the primary therapeutic goal in patients who have both type 2 diabetes and overweight or obesity, because it not only lowers HbA1c and can put diabetes into remission, but also treats many other complications of obesity. I would argue that this is the first-line therapy in these patients,” Garvey said.
References:
- Clement K, et al. Long-term weight and hunger reduction with setmelanotide in individuals with POMC deficiency obesity. Presented at: ObesityWeek Interactive; Nov. 2-6, 2020 (virtual meeting).
- Enebo LB, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)00845-X.
- Heymsfield SB, et al. JAMA Netw Open. 2021;doi:10.1001/jamanetworkopen.2020.33457.
- Lau DCW, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)01751-7.
- Rosenstock J, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)01324-6.
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Garvey WT. A new era in obesity medicine: treat-to-target. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 2-4, 2021; Los Angeles (hybrid meeting).
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