Progress in Pharmacotherapy for Obesity

The obesity epidemic in the US continues unabated. The elevated risk for severe disease and death from COVID-19 associated with obesity and its comorbidities underscores the urgency to develop and implement effective prevention and treatment strategies. Multicomponent behavior-based weight-management interventions are recommended for adults with obesity; however, some patients do not respond to even the highest-quality programs. Medications are well-accepted in the treatment of other disorders that potentially respond to dietary interventions, such as the use of statin drugs for hypercholesterolemia. However, many clinicians, payors, and patients are hesitant to prescribe, reimburse for, or use anti-obesity medications respectively.

There are numerous reasons for such hesitancy. Anti-obesity medications have a problematic safety history, with several drugs removed for adverse events. Weight losses with available anti-obesity medications rarely meet patient expectations. Physicians also prescribe anti-obesity medications infrequently relative to the numbers of adults who are potentially eligible for their use. According to national estimates, only 3% of adults trying to lose weight reported taking prescription anti-obesity medications between 2012-2016. Many private and public payors do not cover anti-obesity medications at all or require prior authorization, and a majority of patients taking prescription obesity medications pay out-of-pocket.

Currently Approved Anti-Obesity Medications

In 2021, 5 medications (orlistat, phentermine plus topiramate, naltrexone plus bupropion, liraglutide and semaglutide) are currently approved by the Food and Drug Administration for long-term weight management in adults with a Body Mass Index (kg/m²) ≥30 or ≥27 with comorbid conditions (Table 1); the notable additions to the medications that were approved by 2015^1,2 are daily subcutaneous (SQ) liraglutide 3.0 mg, a glucagon-like peptide-1 receptor agonist (GLP1-RA) that reduces body weight by approximately 5 kg (~5% of body weight) more than placebo in adults ^3,4 and adolescents ≥12y⁵ and weekly SQ semaglutide 2.4 mg.^6-9 In addition, setmelanotide, a melanocortin agonist, was approved in 2020 for treatment of syndromes of genetic obesity affecting the proximal leptin-signaling pathway in adults and children ≥6y. Because of the rarity of such syndromes, setmelanotide was approved without long-term placebo-controlled trials but with evidence of substantial effects on body weight.

Table 1:

Food and Drug Administration-Approved Medications for Long-term use

	Year approved	Generic Drug	Route of Administration, Frequency and Dose	Mechanism of Action	Wholesale Price per Month*	1-Year Weight Change Relative to Placebo (kg)**
Adults Adolescents age ≥12y	1999 2003	Orlistat	PO, 3 times/day, 60 or 120mg, within 1 hr of fat-containing meals, plus a daily multi-vitamin	Gastrointestinal lipase inhibitor	$300-$600	For nonprescription 60mg TID: −2.5 kg (−1.5 to −3.5) For 120mg TID: −3.4 kg (−3.2 to −3.6) in adults and −2.6 kg in adolescents
Adults only	2012	Phentermine plus topiramate-ER	PO, once daily, start 3.75/23mg /d, then 7.5/46mg/d, escalating to a maximum of 15/92mg/d	Noradrenergic + GABA-receptor activator, kainite/AMPA glutamate receptor inhibitor	$125-$150	For 7.5/46mgd: −6.7 kg (−5.9 to −7.5) For 15/92mg/d: −8.9 kg (−8.3 to −9.4)
Adults only	2014	Naltrexone-bupropion-ER	PO, once or twice daily; start 8-mg naltrexone/90-mg bupropion tablet per day escalating to a maximum of two 8-mg/90-mg tablets twice daily, for a total daily dose of 32 mg/360 mg	Opioid receptor antagonist + dopamine/norepinephrine reuptake inhibitor	$200	−4.9 kg (−4.6 to −5.1)
Adults and adolescents age ≥12y	2014 2020	Liraglutide	SQ, once daily, start 0.6 mg, increase weekly by 0.6 mg to a maximum of 3 mg	GLP1 receptor agonist	$1,500	For adults: −5.2 kg (−4.9 to −5.6) For adolescents: −4.5 kg (−7.2 to −1.8)
Adults only	2021	Semaglutide	SQ, once-weekly, start 0.25 mg escalating to a maximum of 2.4 mg	GLP1 receptor agonist	N/A	−6.1kg to −12.7kg

Weight Loss Medications. GABA: gamma-aminobutyric acid, GLP1: glucagon-like peptide 1, SQ: subcutaneous injection. NA: Not available

^*Reference prices found in February and March 2021.

^**Weight changes relative to placebo (95 percentile confidence interval) using intent-to-treat analyses for each medication at 1 year for orlistat, phentermine-topiramate, naltrexone-bupropion-ER and liraglutide are found in prior reports that performed meta-analyses.^1-3 At present there is only 1 large, placebo-controlled trial for adolescents using liraglutide.⁵ Semaglutide weight change is described in the papers as occurring at week 68, after 52 weeks at full dose.^6-8 Total weight losses (not relative to placebo) are somewhat greater and generally reflect the intensity of the lifestyle modification program offered.

Mean placebo-subtracted 1y weight loss for prescription medications for non-syndromic obesities approved prior to 2021 ranged from 3.4 to 8.9kg, with high-dose phentermine plus topiramate showing the largest weight loss. All medications show a greater proportion of responders losing ≥5% initial weight than with placebo, ranging from an odds ratio (OR) of 2.70 [95% Credible Interval 2.34-3.09] with orlistat to 9.22 [95% Credible Interval 6.63-12.85] with phentermine/topiramate.³ Monotherapy with the noradrenergic drug phentermine is still the most prescribed anti-obesity medication, despite approval for short-term use, and is often used off-label for indefinite treatment.

Semaglutide is a GLP1-RA that was previously approved for treatment of T2DM at a 1.0 mg weekly s.c. dose and approved for chronic weight management at a 2.4mg weekly s.c. dose on June 4, 2021. Four double-blind, randomized placebo-controlled trials that tested semaglutide 2.4mg SQ once weekly for obesity treatment have recently been published.^6-9 In the STEP-1 trial,⁶ among 1961 adults with overweight plus comorbid conditions or obesity, those randomized to receive semaglutide lost 15.3kg (14.9% of initial weight), which was 12.7kg (12.4%) more weight loss than those randomized to receive placebo. The percent of participants with ≥5%, ≥10%, ≥15%, and ≥20% weight losses with semaglutide were 86.4%, 69.1.8%, 50.5%, and 32.0, much higher than with placebo (31.5%, 12.0%, 4.9%, and 1.7% respectively). The STEP-2 trial of weight management in 1210 participants with type 2 diabetes ⁷ (who typically lose less weight than those without diabetes) found those randomized to receive semaglutide 2.4mg lost 9.7kg (9.6%), which was 6.1kg (6.2%) more weight loss than those randomized to placebo. 25.8% of semaglutide-treated (versus 3.2% of placebo-treated) participants lost ≥15% of their body weight. STEP-3⁸ assessed the additional contribution of semaglutide to intensive behavioral treatment in 611 adults with overweight/obesity. Participants in the semaglutide group lost 16.8kg (16.0%), which was 10.6kg (10.3%) more weight loss than participants in the placebo group, with 55.8% of semaglutide-treated (versus 13.2% of placebo-treated) participants losing ≥15%.⁸ Importantly, the retention rates in the semaglutide studies were much higher than in most anti-obesity medication trials, with >90% of participants having a body weight assessment at week 68 and/or attending the week 75 final study visit, providing confidence in the validity of the findings. The STEP-4 trial ⁹ of 803 adults without diabetes, which examined the effect of continued semaglutide 2.4mg for 68 weeks vs. switch to placebo at 20 weeks, found an additional 7.9% weight loss among those who continued drug treatment, compared with a weight gain of +6.9% among those switched to placebo, for a final placebo-subtracted weight loss of 14.8%. This study confirmed the necessity of continued anti-obesity pharmacotherapy for sustained benefit. Adverse events with semaglutide were primarily gastrointestinal, and similar to other GLP1-RA. An increased incidence of gallbladder-related disorders was observed, as is typical whenever large, rapid weight losses are induced. Reductions in cardiovascular risk factors, including systolic blood pressure, lipids, and glycated hemoglobin, also were observed. Semaglutide 2.4mg is now being tested in a large multisite cardiovascular outcomes trial (CVOT) in participants without diabetes but at high CVD risk (ClinicalTrials.gov Identifier: NCT03574597).

Anti-Obesity Medications in Phase 3 Trials

Most people with obesity seek weight loss of 15% or more, typically attained only with bariatric surgery, and greater weight loss leads to greater improvements in many obesity-related outcomes. Thus, there continues to be a need to develop non-surgical therapies with greater clinical effectiveness.

Another medication in late-stage trials is tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and GLP1R dual-agonist that takes advantage of GIP-GLP1R synergism and also appears to have substantial beneficial effects on body weight and glucose homeostasis in patients with type 2 diabetes, for whom published phase 2¹⁰ and company-reported phase 3 placebo-subtracted weight losses at 26-40 weeks exceeded 10kg. Adverse consequences were mainly gastrointestinal, and generally did not lead to discontinuation. Longer, large Phase 3 clinical trials of efficacy for weight management (e,g. NCT04660643) as well as cardiovascular outcomes in patients with diabetes (NCT04255433) are ongoing.

Conclusions:

Use of medications for obesity has been limited by perceived modest efficacy, safety concerns, patient and clinician reluctance, and lack of reimbursement by both public and private insurers. Newer medications, including those with novel “twincretin” mechanisms of action, offer the potential for greater weight loss efficacy with an acceptable safety profile. Ongoing CVOT should provide evidence for any salutary or adverse effects on cardiovascular outcomes in populations at high risk. The recent approval of liraglutide for adolescents with obesity provides an additional non-surgical option for teenagers who have not responded to lifestyle interventions alone. The approval of setmelanotide for children and adults with some rare monogenic obesities, provides a glimpse of the potential of precision treatments targeted to underlying mechanisms. Although no modality for obesity treatment is universally successful, if potent agents in development show benefit for important clinical and patient-reported outcomes without unacceptable safety risks and barriers to their use can be addressed, clinicians and patients will have additional options for successful management of obesity and its comorbidities.