GLP-1 receptor agonists & weight Loss

Background

Glucagon-like peptide 1 (GLP-1) is an incretin peptide that stimulates glucose-dependent insulin secretion while inhibiting glucagon release and gastric emptying.

GLP-1 receptor agonist (GLP1RA) medications increase glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, and slow gastric emptying. They also act in the areas of the brain involved in the regulation of appetite and caloric intake.

All GLP1RAs have been found to have weight loss effects, although at this time only two drugs (both injectable) have FDA approval for the treatment of obesity in patients over 12 years of age: semaglutide (Wegovy) and liraglutide (Saxenda).

• Other brand names of semaglutide (Ozempic, Rybelsus) and liraglutide (Victoza) do not have FDA approval for weight loss in the presence of obesity, although are frequently used for this purpose
• Other GLP1RAs include dulaglutide (Trulicity), exenatide (Byetta, Bydureon ER), lixisenatide (Adlyxin), and tirzepatide (Mounjaro), which is a combined GLP1RA and glucose-dependent insulinotropic peptide (GIP)

Evidence

The Semaglutide Treatment Effect in People with Obesity (STEP) program is a series of trials testing semaglutide specifically for promoting weight loss, regardless of the presence of type 2 diabetes mellitus. Here’s a quick summary:

• STEP 1
  • Double-blind trial of 1961 adults with BMI ≥30 (or ≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, randomly assigned in a 2:1 ratio to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention
  • Findings revealed an average 14.9% reduction in bodyweight from baseline during 68 weeks of treatment with semaglutide 2.4 mg plus a lifestyle intervention, compared with just a 2.4% reduction in the placebo plus lifestyle intervention group. In total, 86.4% of the semaglutide group lost at least 5% of their bodyweight, and adverse effects were in line with those expected for the medication class
• STEP 2
  • Double-blind trial of 1210 participants with type 2 diabetes and overweight/obesity, randomized to semaglutide 1.0 mg dose versus the higher 2.4 mg dose and matched placebos over 68 weeks
  • Findings revealed average bodyweight reductions of 9.64%, 6.99%, and 3.42% with semaglutide 2.4 mg, 1.0 mg, and placebo, respectively. The higher dose also achieved slightly better glycemic control, reductions in cardiometabolic risk, and improved physical function relative to the standard dose
• STEP 3
  • Double-blind trial of 611 adults with BMI ≥30 (or ≥27 in persons with ≥1 weight-related coexisting condition), without diabetes, randomized to semaglutide 2.4 mg or placebo, both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (30 counseling visits) during 68 weeks
  • Findings revealed the average weight reduction after 68 weeks of treatment was 16.0% with semaglutide versus 5.7% with placebo. The co-primary endpoint of at least a 5% reduction in bodyweight was met by 86.6% versus 47.6%
• STEP 4
  • Double-blind trial of 902 participants who all received semaglutide 2.4 mg for the first 20 weeks, after which they were randomized to receive either semaglutide or placebo for the remaining 48 weeks
  • Findings revealed that participants who continued to take semaglutide after randomization lost an additional 7.9% of their bodyweight, on average, to give a total 17.4% weight loss over the whole trial, whereas those who switched to placebo regained an average 6.9%, giving a total weight loss of 5.0%

And what about semaglutide versus liraglutide?

• STEP 8
  • Double-blind trial of 338 participants with BMI ≥30 (or ≥27 in persons with ≥1 weight-related coexisting condition), without diabetes, randomized to semaglutide 2.4 mg or liraglutide 3.0 mg
  • Findings revealed a significantly greater average bodyweight reduction of 15.8% with semaglutide compared with 6.4% with liraglutide

Adverse Drug Effects

GLP1RAs have a black box warning for medullary thyroid carcinoma based on animal studies. Specifically, in the early stages of drug development, thyroid C-cell tumors were noted in animal studies with semaglutide and liraglutide. But it is unknown whether these drugs cause thyroid C-cell tumors in humans.

Other significant ADEs:

• Acute kidney injury (mostly in patients who experience nausea, vomiting, diarrhea, or dehydration)
• Diabetic retinopathy 
  • Noted during the SUSTAIN-6 study, a clinical trial evaluating the impact of subcutaneous semaglutide on cardiovascular outcomes in patients with type 2 diabetes; complications included vitreous hemorrhage, onset of diabetes-related blindness, and the need for treatment with an intravitreal agent or retinal photocoagulation
• Gallbladder disease (cholelithiasis and cholecystitis)
  • Resolution of biliary stones following discontinuation has been documented with liraglutide
• GI symptoms (e.g., abdominal pain, constipation, diarrhea, nausea, and vomiting)
  • GI effects tend to occur during dose escalation and decrease over time
• Pancreatitis
• Other: headache, fatigue, nasopharyngitis

Dosing

Semaglutide

Liraglutide

Monitoring

Monitoring parameters in patients on GLP1RAs for weight loss include weight, triglycerides, and kidney function.

• Weight: Baseline and 16-20 weeks 
• Triglycerides: Baseline or within one year of therapy initiation
• Renal function: Recheck patients with CKD reporting severe GI effects

Discontinuation should be considered in patients not meeting expected weight loss goals (i.e., not achieving at least 5% weight loss after adequate use).

Blog post based on Med-Peds Forum talk by Katie Owens, PharmD