Trending Clinical Topic: Weight Loss Drugs

Ryan Syrek


December 02, 2022

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Excitement about "unprecedented" weight loss associated with tirzepatide, news about other injectable medications, and updated antiobesity recommendations resulted in this week's top trending clinical topic. In May, tirzepatide was approved by the US Food and Drug Administration (FDA) for glycemic control in patients with type 2 diabetes (T2D). In October, the FDA granted fast-track status for its use as an antiobesity drug. Now, findings presented at ObesityWeek suggest that the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist is remarkably and consistently effective (see Infographic).

SURMOUNT-1 compared the efficacy and safety of tirzepatide along with a reduced-calorie diet and increased physical activity. The study included 2539 adults without type 2 diabetes who had obesity or overweight with at least one obesity-related complication. The four BMI subgroups had similar results:

  • ≥ 27 to < 30 (overweight): Mean initial weight, 178 lb; mean weight reduction, 29-30 lb

  • ≥ 30 to < 35 (class 1 obesity): Mean initial weight, 198 lb; mean weight reduction, 33-43 lb

  • 35 to < 40 (class 2 obesity): Mean initial weight, 228 lb; mean reduction 34-56 lb

  • ≥ 40 (class 3 obesity): Mean initial weight, 280 lb; mean weight reduction, 44-64 lb

Patients with an initial BMI of ≥ 35 to < 40 who received the 15 mg/wk dose of tirzepatide had the most weight loss at 24.5%. That is approximately what is associated with bariatric surgeries (25%). Overall, 73%-90% of patients who received the 5- to 15-mg doses had ≥ 10% body weight reduction.

At the American Heart Association (AHA) Scientific Sessions 2022, a separate presentation involving the SURMOUNT-1 trial reported that treatment with tirzepatide led to significant cuts in 24-hour ambulatory blood pressure (BP). The substudy included 600 of the 2539 participants enrolled in SURMOUNT-1. Full results were available for 494 patients. The substudy included only those individuals who had a baseline BP of < 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded those with a BP of ≥ 160/100 mm Hg. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats/min. Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among controls. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms; it rose by an average 0.5 mm Hg among the controls. Experts expressed optimism that these findings will translate into tangible benefits at a clinical level.

Also at ObesityWeek 2022, presenters described "impressive" weight loss associated with a novel GLP-1/glucagon dual receptor agonist (BI 456906), albeit in early research. Patients were aged 18-75 years, had T2D, a BMI of 25-50, an A1c of 7%-10%, and were stable on metformin therapy. At the highest tested dose of BI 456906 (1.8 mg twice-weekly subcutaneous injections), 57% of patients lost ≥ 5% of their initial body weight and 35% lost ≥ 10% of their initial body weight at 16 weeks. Among the patients who received a 1-mg semaglutide dose as a comparator, only 38% lost ≥ 5% of their initial body weight and only 16% lost ≥ 10% of their initial body weight. Patients had a mean initial weight of 214 lb (97 kg). After 4 months, on average, patients who received the highest tested dose of BI 456906 lost 9% of their initial weight, or roughly 8.7 kg (19 lb). Patients who received semaglutide lost 5.4% of their initial weight, or roughly 5.2 kg (11.5 lb). Patients who received placebo lost only 1.2% of their initial weight.

At the American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting, a new study showed several factors that appear to influence the risk for acute pancreatitis among patients who start taking GLP-1 receptor agonist medications for weight loss. Of the 2245 patients in the study, 49 (2.2%) developed acute pancreatitis after starting a GLP-1. A history of T2D made acute pancreatitis twice as likely (95% CI, 1.04-3.96; P = .04). Stage 3 or higher chronic kidney disease increased risk 2.3 times (95% CI, 1.18-4.55; P = .01), whereas tobacco use upped it 3.3 times (95% CI, 1.70-6.50; P < .001). In contrast, researchers found that those with a BMI of 36-40 were 88% less likely to develop acute pancreatitis (95% CI, 0.07-0.67; P = .007) compared with patients with a BMI of ≤ 30. Patients with a BMI of > 40 had a 73% lower risk (95% CI, 0.10-0.73; P = .01).

The American Gastroenterological Association (AGA) recently released recommendations for weight loss medications among patients with obesity who do not respond adequately to lifestyle interventions alone. Four medications are suggested as first-line options: semaglutide, liraglutide, phentermine-topiramate extended-release (ER), and naltrexone-bupropion ER. Also recommended, albeit based on lower-certainty evidence, were phentermine and diethylpropion. The guidelines suggest avoiding use of orlistat. Evidence was insufficient regarding Gelesis100 superabsorbent hydrogel.

In other guideline news, a new comprehensive joint consensus report from the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) recommended that weight loss should be a co-primary management goal for T2D in adults. The new "Management of Hyperglycemia in Type 2 Diabetes" statement was simultaneously published in Diabetologia and Diabetes Care incorporates recent clinical trial data for cardiovascular and kidney outcomes for sodium–glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 agonists to broaden recommendations for cardiorenal protection. The document also places increased emphasis on social determinants of health.

The remarkable weight loss associated with newly developed and approved medications continues to be of interest to clinicians tackling the widespread obesity epidemic. As new information about efficacy, risk factors, and recommendations becomes available, attention is likely to remain focused on these potentially game-changing drugs.

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