Principles of Obesity Pharmacotherapy

As with other chronic diseases, the management of overweight and obesity emphasizes a foundation of nutritional, physical activity, and behavioral changes that have been shown to reduce weight and lower cardiometabolic risk. However, lifestyle interventions alone are often unsustainable or unfeasible for achieving long-term weight loss maintenance in most patients, with one-third to two-thirds of lost weight regained within one-year following end of treatment, and > 95% weight regained within 5 years (15).

Professional organizations including The Obesity Society, Obesity Medicine Association, the Endocrine Society, the American Association of Clinical Endocrinology, and the American Diabetes Association recommend adding OMs to lifestyle counseling for individuals with BMI ≥ 30 or BMI ≥ 27 with at least one ORCD, with thresholds adjusted for ethnicity and personalized metabolic risk, and recognizing that other anthropometric measures of fat mass can also be used as surrogates for BMI (16-20).

For health care professionals using pharmacotherapy for weight management, the following basic principles can be kept in mind:

• Lifelong treatment: Because obesity is a chronic disease, pharmacotherapy should be prescribed with the intent of lifelong use and as part of a comprehensive management plan that includes nutrition, physical activity, and behavioral counseling. Discontinuation of an OM often leads to weight regain and loss of metabolic benefits.
• OMs affect pathophysiological pathways that lead to obesity: Current obesity pharmacotherapy targets the underlying neurohormonal dysregulations that cause weight gain and prevent sustained weight loss through lifestyle alone. Changes in hormones in response to diet-induced weight loss, such as reduction in the anorexigenic hormone leptin and increase in the orexigenic hormone ghrelin, create a physiologic environment conducive to weight regain driven by the defense of the body’s “lipostat” or “body weight set point”(21,22). Additional adaptation responses to diet-induced weight loss affect energy expenditure, including reductions in daily energy expenditure that challenge a patient’s efforts to sustain weight loss maintenance (23,24).
• Treatments benefit both obesity and ORCDs: The goals of obesity treatment should be patient-centered and focused on primary, secondary, and tertiary prevention (17,25); that is, treating obesity also treats or prevents its co-morbidities and complications. For example, improvements in cardiometabolic risk factors and reduced incidence of diabetes have been consistently reported in the Phase 3 trials for OM’s. In addition to ORCDs, patient-centered goals may also include other measures of quality of life or non-weight scale victories.
• Expect heterogeneity in weight loss response: Phase 3 trials have consistently demonstrated that OMs achieve significantly greater weight loss than placebo when combined with lifestyle modifications (26-33). The mean weight loss efficacy in these studies ranges from 5-23% total body weight loss. However, as with any medical therapy, significant inter-individual response variability (34,35) have been reported, including the possibility of <5% weight loss (non-responders) to 25% or greater weight loss.

History of Obesity Medications

The development of modern OMs dates as far back as the 1940s, predating the standard FDA rules and regulations that are familiar today. Drug approval in the 1940s necessitated only proof of efficacy beyond placebo. Evaluation of benefit versus risk with controlled investigations was not a requirement until passage of the Kefauver-Harris amendment in 1962. Approval of the first OM, desoxyephedrine, in 1947 led to the development of a number of amphetamine derivatives for weight loss that have all since been removed from the market due to this amendment (36). A comprehensive narrative of the history of OMs covers the development of pharmacotherapy and the FDA’s role in regulation (37). Since the FDA’s adoption of stricter regulations and proof of clinical efficacy, only a couple of OMs have been removed from the U.S. market for safety concerns (Table 1).

Only two OMs have been removed from the market in recent history for safety concerns. The administration of sibutramine to individuals at high risk of CVD in the SCOUT trial was widely criticized by the medical community as it did not reflect real-life clinical practice; subgroup analysis of patients with T2D without CVD in SCOUT actually showed no increase in CVD events and a decrease in mortality with sibutramine compared to placebo (40). The voluntary recall of lorcaserin in 2020 occurred among significant confusion, as long-term data from the CAMELLIA-TIMI 61 trial did not demonstrate an imbalance in adverse events between treatment groups (41,42). The FDA has clarified their findings that led to this withdrawal recommendation. When all post-randomization adverse events were considered, not just those that occurred “on treatment” (i.e., those that occurred within 30 days of drug discontinuation) as analyzed in CAMELLIA-TIMI 61 (39), even though similar numbers of patients experienced cancers (n=462 out of 6000 on lorcaserin and n=423 out of 6000 on placebo), a greater number of participants who received lorcaserin compared to placebo were reported with multiple primary cancers (n=20 vs. 8), total cancers (n=520 vs. 470), metastases (n=34 vs. 19), and cancer deaths (n=52 vs. 33). The latency period to reach significance for differences in all cancers between the treatment groups was a little over 2 years, and although the overall cancer rates were low, the FDA felt that benefits of lorcaserin could not yet be judged to outweigh this potential adverse risk.

Gelesis100 (Plenity) is an oral, non-systemically absorbed hydrogel that expands in the stomach to promote fullness and aid weight loss. In clinical trials, it produced modest efficacy (6% mean weight loss at 6 months vs. 4% with placebo). It was FDA-approved for BMI ≥ 25 as a medical “device” because its primary mechanism of action was mechanical rather than pharmacologic, and it is now available as an over-the-counter obesity treatment agent.

FDA-Approved Medications for Obesity

Today, ten FDA-approved OMs remain on the market, with eight approved for long-term weight loss, of which one is indicated for specific monogenic or syndromic obesity (Table 2).

Efficacy

Several trials support orlistat’s efficacy for weight loss and maintenance. Rossner et al. found that subjects receiving orlistat lost significantly more weight in the first year of treatment, and fewer regained weight during the second year of treatment, than those taking placebo (55). Trials in Europe demonstrated similar results over a two-year period. Subjects in the orlistat group lost significantly more weight in the first year (10.2 vs. 6.1%) and regained half as much weight during the second year of treatment, as compared to the placebo group (56).

Effect on Metabolic Profile

In addition to promoting weight loss and maintaining lost weight, orlistat has been shown to improve insulin sensitivity and lower serum glucose levels. In a 2-year trial, Davidson et al. reported less weight regain rates and lower levels of serum glucose and insulin in patients maintained on a 120 mg three times per day dose of orlistat, as compared to those on placebo (57). In the 4-year XENDOS study conducted in Sweden, the cumulative incidence of T2D was 9.0% in the placebo plus diet and lifestyle group and 6.2% in the subjects receiving orlistat (26), corresponding to a relative risk reduction in development of T2D of 37.3%.

In patients with obesity and T2D with or without insulin treatment, orlistat resulted in improved glycemic control, determined via serum blood glucose levels and hemoglobin A1c (HbA1c) measurements, and reduced total cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and apolipoprotein B levels (58,59). In subjects with obesity and T2D, hypercholesterolemia, or hypertension, orlistat treatment also led to greater weight loss and reductions in HbA1c, LDL, and total cholesterol (60).

Safety and Side Effects

The gastrointestinal side effects of orlistat, including fatty/oily stool, fecal urgency, oily spotting, increased defecation, fecal incontinence, flatus with discharge, and oily evacuation (51), are the main reasons for discontinuation of therapy. These symptoms are usually mild to moderate and decrease in frequency the longer the medication is continued. Administration of orlistat with psyllium mucilloid reduced the incidence of GI side effects to 29% with psyllium vs. 71% without psyllium (61). Orlistat may reduce the absorption of fat-soluble vitamins A, D, E, and K, as well as beta-carotene, which can be mitigated with separate administration of vitamin supplementation.

Efficacy

Multiple Phase 1, 2, and 3 studies including more than 5000 subjects have evaluated the efficacy and safety of phentermine/topiramate combination therapy. The one-year EQUIP trial, a phase three 56-week RCT enrolled 1267 patients with obesity (mean BMI of 42.0 kg/m²) and showed 3.5% weight loss in the starting dose group (3.75 mg/23 mg) and 9.3% placebo-subtracted weight loss in the top treatment dose (15 mg/92 mg) group (29). The 52-week CONQUER trial randomized 2487 patients with obesity and a comorbidity (e.g. hypertension, dyslipidemia, prediabetes, diabetes, or abdominal obesity) to placebo, mid-dose treatment dose (7.5mg/46 mg), or maximum treatment dose (15/92 mg) and found 6.6% and 8.6% placebo-subtracted weight loss, respectively (28). A two-year extension of the CONQUER trial was published (SEQUEL) demonstrating mean placebo-subtracted weight loss of 7.5% in the mid-dose group and 8.7% in the maximum-dose group (65).

Effect on Metabolic Profile

Improvements in systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides, and high-density lipoprotein (HDL) cholesterol were reported in subjects treated with phentermine plus topiramate compared with placebo in both EQUIP and CONQUER (28,29). Improvements in fasting glucose and insulin levels were reported in the SEQUEL study, and a 54% and 76% reduction in progression to T2D in the two treatment groups was noted in subjects without diabetes at baseline (65).

Safety and Side Effects

Common side effects include paresthesias, dizziness, dry mouth, constipation, dysgeusia, insomnia, memory and word-finding difficulty, and anxiety or mood alternations. To mitigate these effects, a stepwise dosage titration is recommended. Phentermine-topiramate is initiated at the 3.75/23 mg dose daily for 14 days, followed by 7.5/46 mg daily thereafter. If after 12 weeks, a 3 percent loss in baseline bodyweight is not achieved, the dose can be increased to 11.25/69 mg for 14 days, and then to 15/92 mg daily. If an individual does not lose 5 percent of body weight after 12 weeks on the highest dose, phentermine-topiramate should be discontinued due to lack of response. Discontinuation should be performed gradually because rapid withdrawal of topiramate may provoke seizures.

Phentermine-topiramate is not recommended for patients with significant cardiac history such as coronary disease and uncontrolled hypertension (66). However, in individuals without coronary disease and with well-controlled hypertension, it is considered safe to use this drug along with regular blood pressure monitoring. Phentermine/topiramate exposure carries an increased risk of cleft lip/palate in infants exposed to the combination drug during the first trimester of pregnancy. Women of child-bearing age are recommended to have a pregnancy test prior to starting the medicine and to use contraception while taking it. This medication is also contraindicated in patients with hyperthyroidism, glaucoma, and in patients who have taken monoamine oxidase (MAO) inhibitors within 14 days. Topiramate can increase the risk of acidosis and renal stones so should be used cautiously in patients with a history of nephrolithiasis (67).

Efficacy

Four 56-week multicenter, double-blind, placebo-controlled trials (CONTRAVE Obesity Research: COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of bupropion/naltrexone in conjunction with lifestyle modification compared to a placebo-controlled cohort of 4536 patients. The COR-I, COR-II, and COR-BMOD trials enrolled patients with BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with at least one comorbidity (27,32,46). The COR-Diabetes trial enrolled patients with BMI greater than 27 kg/m² with T2D with or without hypertension or dyslipidemia (70). The primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight. In the 56-week COR-I trial, significantly greater mean weight loss (6.1%) occurred in patients assigned to naltrexone 32 mg/bupropion 360 mg dose compared with the placebo group (1.3%), and 48% of active treatment group achieved ≥5% weight loss compared to only 16% of placebo group (46). Similar weight loss efficacy was reported in COR-II (27) and COR-Diabetes (70) trials. Bupropion/naltrexone can be combined with intensive behavioral therapy (IBT) to achieve even greater weight loss (5.2% with placebo and 9.3% with bupropion/naltrexone) (32).

Effect on Metabolic Profile

In all the COR trials, secondary cardiovascular risk endpoints were met, including statistically significant greater improvements in waist circumference (WC), visceral fat, HDL cholesterol, and triglyceride levels in the participants treated with the bupropion 360 mg/naltrexone 32 mg dose compared with placebo-treated participants (27,32,46,70). Participants with diabetes in the COR-Diabetes trial using bupropion/naltrexone also showed a significantly greater 0.6% reduction in HbA1c from baseline, compared to a 0.1% reduction in placebo (70).

Safety and Side Effects

The most common side effects of bupropion/naltrexone include nausea/vomiting, constipation, headache, dizziness, insomnia, and dry mouth. Medication interactions include MAO inhibitors (use during or within 14 days of administration), opioids and opioid agonists (including partial agonists) that are inactive in the presence of naltrexone, and abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs that can increase risk for seizure. Bupropion/naltrexone should be avoided in patients with uncontrolled hypertension, history of seizures, history of bulimia or anorexia nervosa, and in individuals taking narcotics for pain control (71).

The FDA recommends monitoring patients for worsening or emergence of suicidal thoughts or behaviors.

Efficacy

SCALE Obesity and Prediabetes (n=3731) and SCALE Diabetes (n=846) evaluated the effect of liraglutide 3.0 mg on overweight and obesity with normoglycemia, prediabetes, and diabetes respectively (30,75). Both 56-week, randomized, placebo-controlled, double-blind clinical trials demonstrated significantly greater mean weight loss than placebo (8% vs. 2.6% in SCALE Obesity and Prediabetes (30) and 6.0% vs. 2% in SCALE Diabetes (75). The efficacy of liraglutide 3.0 in maintaining weight loss was examined in the SCALE Maintenance study. Four hundred and twenty-two subjects who lost ≥ 5% of their initial body weight on a low-calorie diet were randomly assigned to liraglutide 3.0 mg daily or placebo for 56 weeks. Mean weight loss on the initial diet was 6.0%. By the end of the study, participants in the liraglutide 3.0 group lost an additional 6.2% compared to 0.2% with placebo (76).

Effect on Metabolic Profile

Secondary endpoints in the SCALE Obesity and Prediabetes included waist circumference, lipids, HbA1c, and blood pressure, all of which showed significantly greater improvement than placebo (30). SBP dropped by 4.2 mmHg vs. 1.5 mmHg in the liraglutide 3.0 mg vs. placebo groups. Diastolic blood pressured was reduced by 2.6 mm Hg vs. 1.9 mm Hg. The most significant change in lipid profile was in the triglycerides that were reduced by 13.0 mg/dl in the liraglutide 3.0 mg group vs. 5.5 mg/dl in the placebo group. Participants assigned to liraglutide 3.0 had a lower frequency of prediabetes and were less likely to develop T2D than those assigned to placebo (30), an outcome that persisted in a 3-year extension analysis (77). For participants with obesity and moderate/severe obstructive sleep apnea, liraglutide 3.0 mg treatment resulted in significantly greater reductions than placebo in apnea-hypopnea index, body weight, SBP, and HbA1c levels (78).

In the SCALE Diabetes study, HbA1c levels were 0.93% lower in the liraglutide 3.0 vs. placebo treated group, and similar significant benefits on triglyceride (lower) and HDL cholesterol (higher) levels as in the SCALE Obesity study were reported (75).

Although liraglutide 3.0 mg was not evaluated in a cardiovascular outcomes trial (CVOT), the lower dose liraglutide 1.8 mg (Victoza), approved for T2D, was assessed in the LEADER trial (79). The primary outcome was a composite of major adverse cardiovascular events (MACE) including CVD death, nonfatal myocardial infarction (MI), and nonfatal stroke. Adults with T2D and baseline average BMI 32.5 kg/m² were randomized to liraglutide 1.8 mg vs. placebo. Approximately 81% of participants had established CVD. After a median of 3.8 years, individuals on liraglutide 1.8 mg demonstrated a 13% risk reduction in 3-point MACE compared to placebo. Analysis of additional outcomes showed a 22% reduction in CVD death and a 15% reduction in all-cause deaths. This risk reduction was driven primarily by a reduction in death from CV causes (p=0.01 for superiority) and all-cause mortality was reduced by 15%. Statistical significance was not achieved with individual endpoints of nonfatal MI or nonfatal stroke. Liraglutide 1.8 mg is now FDA-approved for secondary CV prevention in adults with T2D (80).

Safety and Side Effects

Gastrointestinal symptoms, such as nausea, vomiting and abdominal pain were the most common reason subjects withdrew from the SCALE trials. In a secondary analysis of these trials, treatment with liraglutide 3.0 resulted in dose-independent, reversible increases in amylase/lipase activity (7% for amylase and 31% for lipase) (81). Thirteen subjects (0.4%) in the liraglutide 3.0 group compared to one (0.1%) with placebo developed pancreatitis, but nearly half of these had evidence for gallstones as well (81). Even though liraglutide treatment showed improvements in blood pressure and lipids, it was found to increase heart rate by an average of 2 beats/min in SCALE Diabetes (75). Animal studies with liraglutide showing an association with medullary thyroid cancer. Even though the relevance of this observation to humans has not been determined, a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN 2) is considered a contraindication for treatment with this medication (82).

Efficacy

A single-arm, open-label, multicenter phase 3 trial of 21 participants aged 6 years and older evaluated the efficacy of setmelanotide for weight loss in patients with POMC deficiency (homozygous or compound heterozygous variants in POMC or PCSK1) or LEPR deficiency (85). After 12 weeks of treatment, those who lost at least 5 kg (or 5% if baseline weight was <100 kg) were then continued into an 8-week placebo-controlled withdrawal phase consisting of 4 weeks each of blinded setmelanotide or placebo treatment followed by an additional 32 weeks of open-label treatment. After approximately 1-year, mean weight loss was 25.6% among individuals with POMC deficiency and 12.5% among those with LEPR deficiency. Eight (80%) participants with POMC deficiency and 5 (45%) participants with LEPR deficiency achieved ≥ 10% weight loss.

Efficacy of setmelanotide 3.0 mg/d for children age ≥6 years with Bardet-Biedl or Alstrom syndrome was established in a 52-week, double-blind RCT that enrolled 38 participants. The trial was placebo-controlled only for the first 14 weeks, but the primary endpoint was defined as the proportion of participants ≥12 years old who achieved ≥10% weight loss from baseline after 52 weeks of setmelanotide. The primary endpoint was achieved among 32.3% of participants and with a mean weight loss of 5.2%. In the BBS cohort alone, mean weight loss was 9.5% (n=12) and change in BMI Z-score was -0.8 (n=14). The trial failed to establish efficacy in participants with Alstrom syndrome (n=6), however, potentially due to limited power.

Effect on Metabolic Profile

Individuals with POMC deficiency experienced an absolute reduction in HbA1c of -0.3%, and those with LEPR deficiency saw a reduction of -0.2%, neither of which were statistically significant. Lipid profiles improved among all participants: HDL increased by 45.0% and 19.6%, LDL decreased by -7.6% and -10.0%, and triglycerides decreased by -36.6% and -7.0% in POMC and LEPR deficiency groups, respectively.

Safety and Side Effects

The most common side effects included skin hyperpigmentation, injection site reactions, nausea, vomiting, headache, and diarrhea. No clinically significant changes in heart rate or blood pressure were observed. Spontaneous penile erections in males have occurred (83). Though the manufacturer warns of suicidal ideation and depression, the phase 3 trial reported one case of suicidal ideation not present at baseline and no treatment-related worsening in depression (85).

Efficacy

Semaglutide Treatment Effect in People with obesity (STEP) trials 1-4 evaluated the effect of semaglutide 2.4mg once weekly on weight loss in patients with overweight or obesity, with and without T2D (88-91). STEP 1-4 are 68-week, phase 3, double-blind, randomized, multicenter trials. STEP 1 (n=1961) was conducted in adult patients with obesity/overweight without T2D and demonstrated an average placebo-subtracted weight loss of 12.4% with 86.4% achieving ≥ 5% weight loss compared to 31.5% with placebo. STEP 2 (n=1210) was conducted in adults with obesity or overweight and T2D and found an average placebo-subtracted weight loss of 6.2%, with 68.8% achieving ≥ 5% weight loss compared to 28.5% with placebo. STEP 3 (n=611) treated adults with obesity or overweight with semaglutide 2.4 mg as an adjunct to intensive behavioral therapy (IBT) and found an average placebo-subtracted weight loss of 10.3%, with 86.6% achieving ≥ 5% weight loss compared to 47.6% with placebo plus IBT. STEP 4 (n=902) examined the efficacy of semaglutide 2.4mg weekly in maintaining weight loss achieved after a 20-week run-in period (16 weeks of dose escalation; 4 weeks of maintenance dose). Among the 803 patients who completed the run-in period with a mean weight loss of 10.6%, those continued on semaglutide from week 20 to 68 achieved further average weight loss of 7.9% versus an average weight gain of 6.8% in those randomized to placebo after the run-in period. The durability of semaglutide 2.4 mg for weight loss was established by STEP 5 (n=304), which reported mean weight change of -15.2% in the semaglutide group vs -2.6% in the placebo group over a period of 104 weeks (92). Conducted in Japan and South Korea, STEP 6 diversified the eligible population by enrolling adults with BMI ≥ 27 with at least two weight-related comorbidities or BMI ≥35 with at least one weight-related comorbidity. At 68 weeks, mean weight change was -13.2% with semaglutide 2.4 mg, -9.6% with semaglutide 1.7 mg, and -2.1% with placebo (93).

The maximum potential weight loss achievable with semaglutide was examined in the STEP UP trial, which randomized participants to semaglutide 7.2 mg/wk, 2.4 mg/wk, or placebo for 72 weeks (94). Weight losses were 18.7% with 7.2 mg, 15.6% with 2.4 mg, and -3.1% with placebo, The 7.2 mg dose conferred significantly greater benefit in diastolic blood pressure, HDL cholesterol, VLDL cholesterol, triglycerides, fasting plasma glucose, and fasting serum insulin as compared to the 2.4 mg dose; but no significant differences in improvements were seen for systolic blood pressure, LDL cholesterol, HbA1c, or high-sensitivity C-reactive protein (hs-CRP) as compared to the 2.4 mg arm. Adverse events leading to discontinuation were 5.4% with 7.2 mg and 4.0% with 2.4 mg. Gastrointestinal side effects were 70.8% in the 7.2 mg group vs. 61.2% in the 2.4 mg group. Notably, dysesthesias emerged as a new adverse event among incretin-therapy trials: 22.9% with 7.2 mg vs. 6.0% with 2.4 mg. STEP TEENS garnered semaglutide’s FDA-approval for treatment of obesity in pediatric and adolescents aged 12 years and older, demonstrating 16.1% weight loss with semaglutide vs 0.6% weight gain with placebo over 68 weeks (95).

Semaglutide 2.4 mg has been compared to liraglutide and semaglutide in several head-to-head clinical trials. In a 52-week multicenter phase 2 RCTs conducted in adults with obesity and without T2D, semaglutide (1.4-2.8 mg/week) demonstrated weight loss superiority compared to liraglutide 3.0 mg/d or placebo (96). The phase 3 RCT, STEP 8, randomized adults with obesity without T2D to liraglutide 3.0 mg/d or semaglutide 2.4 mg/wk or respective placebos (97). After 68 weeks, mean body weight change from baseline was significantly greater with semaglutide: -15.8% with semaglutide vs -6.4% with liraglutide.

In March 2024, semaglutide 2.4 mg received FDA-approval for the treatment of CVD in adults with preexisting CVD and obesity or overweight. In the SELECT trial, adults age 45 years or greater with BMI ≥ 27 and preexisting cardiovascular disease were randomized to semaglutide 2.4 mg vs placebo to investigate the primary endpoint of 3-point MACE: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (98). After a mean follow-up duration of 39.8± 9.4 months, the primary endpoint occurred in 6.5% of participants in the semaglutide group vs 8.0% in the placebo group, resulting in a relative risk reduction of 20%. The SELECT trial builds upon an established body of evidence in patients with diabetes (e.g., SUSTAIN-6) demonstrating the CV safety and benefits of semaglutide and is groundbreaking as the first CVOT to demonstrate secondary cardiovascular prevention with an obesity medication in a population without T2D.

In August 2025, semaglutide 2.4 mg received FDA-approval for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) in adults with moderate-to-advanced fibrosis (99). Providing the basis for this approval, the ESSENCE trial demonstrated resolution of steatohepatitis without worsening of fibrosis in 62.9% of the 534 patients in the semaglutide group vs. 34.3% of the 266 patients in the placebo group (100). In the semaglutide group, 36.8% of the patients compared to 22.4% of those in the placebo group experienced a reduction in liver fibrosis without worsening of steatohepatitis. The mean change in body weight was -10.5% with semaglutide and -2.0% with placebo over 240 weeks.

Oral semaglutide (trade name: Wegovy) was approved in December 2025 for the treatment of obesity or overweight with at least one ORCD. Due to sensitive absorption kinetics, the tablet must be taken alone, once a day on an empty stomach with 1-4 oz. of water, and the patient must wait 30 minutes before eating or drinking anything else. Efficacy for oral Wegovy was established with the OASIS-4 trial, which randomized 205 adults with overweight or obesity to semaglutide 25 mg/d vs. placebo for 64 weeks (101). Mean weight losses were 13.6% with oral semaglutide and 2.2% with placebo. Rate of gastrointestinal side effects and discontinuation due to AEs were comparable to prior semaglutide clinical trials. While a higher semaglutide dose of 50 mg/d was also examined in the clinical trial, OASIS-1, mean weight losses over 68 weeks were not noticeably greater than that of 25 mg/d: 15.1% with oral semaglutide 50 mg vs. 2.4% with placebo (102).

Effect on Metabolic Profile

Secondary endpoints in the STEP 1 trial included weight circumference, blood pressure, lipids, c-reactive protein, HbA1c, and physical functioning scores (SF-36, IWQOL-Lite-CT), all of which showed significantly greater improvement than placebo (133). SBP was reduced by -6.16 mmHg vs. -1.06 mmHg in the semaglutide 2.4 mg vs. placebo groups. Diastolic blood pressure decreased by -2.83 mmHg vs. -0.42 in the semaglutide 2.4 mg vs. placebo groups. HbA1c decreased by -0.52% vs. -0.17% in semaglutide 2.4 vs. placebo groups, with 84.1% of participants achieving normoglycemia at 68 weeks on semaglutide 2.4 vs. 47.8% of patients on placebo. In the STEP 2 trial, conducted in adults with obesity and T2D, HbA1c levels at 68 weeks were reduced by -1.6% in the semaglutide 2.4 vs. -1.5% in the semaglutide 1.0 vs. -0.4% in the placebo group, and 78.5%, 72.3%, and 26.5% achieved an HbA1c<7.0 (91). There were also significant improvements over placebo in SBP, triglycerides, C-reactive protein and physical functioning scores. A secondary analysis of the SELECT trial demonstrated semaglutide’s potential for the primary prevention of T2D and for the regression of T2D: only 1.5% vs 6.9% with placebo had biochemical diabetes by week 156, establishing a number needed to treat (NNT) of 18.5 to prevent one case of diabetes (103). Furthermore, 69.5% vs 35.8% achieved diabetes regression, defined biochemically as A1c <5.7 (i.e., normoglycemia).

The SELECT trial also examined the pre-specified main composite kidney endpoint of death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15, persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria) (104). This endpoint was observed in 1.8% of participants on semaglutide 2.4 mg vs 2.2% of participants on placebo, resulting in a relative risk reduction of 22%. No particular subgroup with respect to age, sex, race, ethnicity, baseline eGFR (<60 or ≥60), baseline UACR (<30, 30 to <300, ≥300), baseline body weight, baseline BMI, baseline A1c, or CVD inclusion criteria were found to have a statistically significant interaction with the treatment effect of semaglutide. The FLOW trial established renal benefit with semaglutide 1.0 mg in adults with T2D and CKD (105); after a median of 3.4 years, semaglutide resulted in a 24% relative risk reduction in the primary outcome defined as a composite of the onset of kidney failure (dialysis, transplantation, or eGFR <15 ), ≥50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes.

Additional cardiovascular protection has been proven in heart failure with preserved ejection fraction (HFpEF). Semaglutide 2.4 mg was demonstrated in the STEP HFpEF trial to significantly improve the Kansas City Cardiomyopathy Questionnaire clinical summary score by 16.6 points vs 8.7 points with placebo in adults with HFpEF and obesity (BMI ≥ 30) (106). Mean change in body weight was -13.3% with semaglutide and -2.6% with placebo over 52 weeks. The improvement in HFpEF symptoms may be mediated by weight-independent mechanisms and measurable via reductions in N-terminal pro–B-type natriuretic peptide (NT-proBNP) (107).

Safety and Side Effects

The most common side effects in phase 3 RCTs of semaglutide 2.4mg were nausea, diarrhea, vomiting and constipation. In the STEP 1 trial, these gastrointestinal side effects occurred more often in those receiving semaglutide vs. placebo (74.2% vs. 47.9%). However, most of these were mild-moderate in severity; serious adverse events occurred in 9.8% of those receiving semaglutide vs. 6.4% of those on placebo. Serious adverse events included serious gastrointestinal disorders (1.4% with semaglutide vs. 0% with placebo), hepatobiliary disorders (1.3% with semaglutide vs. 0.2% with placebo), gallbladder disorders (2.6% with semaglutide vs. 1.2% with placebo), and mild acute pancreatitis (0.2% with semaglutide vs. 0% placebo). Across all RCTs, participants experienced an average increase in heart rate of 1-4 beats per minute (bpm); 26% of individuals on semaglutide vs. 16% of those on placebo had increased heart rates by 20 bpm or more (87). Among patients with T2D, hypoglycemia occurred in 6.2% of patients treated with semaglutide vs. 2.5% of patients on placebo (91). Psychiatric side effects did not emerge as a treatment-related adverse event, and a real-world cohort study of over 200,000 patients found no evidence for increased risk of suicidal ideation (108).

Both liraglutide and semaglutide is contraindicated in the setting of a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. In rodents, semaglutide was found to cause thyroid C-cell tumors, but no human cases have been linked to semaglutide use. A narrative review of RCT and real-world data found no compelling link between semaglutide and thyroid cancer (109), and a systematic review and meta-analysis further concluded there was no increased risk of any cancer with semaglutide (110). Semaglutide 2.4mg should be discontinued at least 2 months prior to conception per manufacturer’s recommendation (87).

Efficacy

Two RCTs (ATTAIN 1 and ATTAIN MAINTAIN) have examined the effect of orforglipron in patients with obesity but not T2D (111). In ATTAIN 1, 3127 were randomized to placebo or 6, 12, and 36 mg of orforglipron with follow up for 72 weeks . Baseline to follow-up, the mean change in body weight from was -7.5%, -8.4%, -11.2%, and -2.1% in the 6 mg, 12 mg, 36 mg, and placebo assigned groups (P<0.001 for all comparisons with placebo). Among the patients in the orforglipron 36-mg group, categorical reductions of 10% or more, 15% or more, and 20% or more were seen in 54.6%, 36.0%, and 18.4%, respectively. In the ATTAIN MAINTAIN trial, a subset of participants from the SURMOUNT 5 trial (see below) assigned to maximum tolerated doses of tirzepatide (10 mg or 15 mg) and semaglutide (1.7 mg or 2.4 mg) for 72 weeks were then re-randomized to 36 mg or maximum tolerated dose of orforglipron versus placebo for another 52 weeks to determine efficacy of switching from the injectable to oral formulations on weight loss maintenance. The model-based estimate (MBE) of body weight reduction in those previously assigned to tirzepatide was 74.7% versus 49.2% with placebo; and 79.3% of body weight reduction in those previously assigned to semaglutide compared with 37.6% with placebo. Because the weight loss achieved in the SURMOUNT 5 trial was different between the tirzepatide and semaglutide arms (tirzepatide > semaglutide), an alternative analysis showed that while 85.9% of body weight reduction was maintained when semaglutide was switched to orforglipron, this number dropped to 74.4% maintaining body weight reduction when switched to orforglipron after tirzepatide treatment.

Effect on Metabolic Profile

In the ATTAIN 1 trial, significant improvements in waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol levels with orforglipron treatment compared with placebo were found. Estimated treatment differences were −6.1 cm (waist circumference), SBP −4.2 mmHg, TG −11.5%, non-HDL −4.9%. Among individuals with T2D, the ATTAIN 2 trial showed changes in A1c of −1.22, −1.50, and −1.66 for 6, 12, and 36 mg doses vs. −0.47 in placebo (112). T2D control (A1c<7%) was achieved by 64.6, 75.9, and 75.5% of orforglipron groups (6, 12, 36 mg) vs. 30.5% in placebo group.

Safety and Side Effects

Similar to other GLP-1RA drugs, the most common side effects with orforglipron were gastrointestinal effects and mostly mild to moderate. Rates of nausea, constipation, diarrhea and vomiting in active drug arms vs. placebo were 28.9-33.7 vs. 10.4%; 21.7-29.8 vs. 9.3%; 21.0-23.1 vs. 9.6%; and 13.0-24.0 vs. 3.5%. Discontinuation rates due to GI side effects were 3.5, 5.1, and 7.0% (6, 12, 36 mg, respectively) vs. 0.4% with placebo. As a small molecule, orforglipron has the potential for drug-drug interactions with respect to liver enzyme metabolism, specifically CYP3A4 inhibitors or inducers. Most relevant to patients with obesity and HLD, the maximum dose of simvastatin should be 20 mg/d while on orforglipron (113).

Efficacy

Tirzepatide has been investigated for the treatment of obesity in four phase 3 RCTs thus far: SURMOUNT-1, SURMOUNT-2, SURMOUNT-3, SURMOUNT-4, and SURMOUNT-5.

SURMOUNT-1 enrolled 2539 participants with BMI ≥ 30 kg/m² or ≥ 27 kg/m² with at least one weight-related comorbidity who were randomized to 5, 10, or 15 mg of tirzepatide or placebo for 72 weeks (118). Baseline weight was 104.8 kg and baseline BMI was 38.0 kg/m². The mean weight change was -15.0%, -19.5%, -20.9%, and -3.1% with tirzepatide 5 mg, 10 mg, 15 mg, and placebo, respectively. Categorical weight loss outcomes for tirzepatide 5 mg, 10 mg, 15 mg, and placebo were: 85%, 89%, 91%, and 35%, respectively.

In SURMOUNT-2, adults with BMI ≥ 27 kg/m² and A1c 7-10% on stable anti-diabetic therapy, either diet and exercise alone or oral antihyperglycemic medication for at least 3 months were randomized to tirzepatide 10 mg, 15 mg, or placebo for 72 weeks (119). Baseline weight was 100.7 kg, BMI 36.1, and A1c 8.02%. On average, duration of diabetes was 8.5 years. Change in weight was -12.8%, -14.7%, and -3.2% with tirzepatide 10 mg, 15 mg, and placebo, respectively. Participants who achieved ≥5% weight loss were 79%, 83%, and 32%, respectively. A1c was equally reduced by 2.1% with both tirzepatide 10 mg and 15 mg vs 0.5% with placebo. A post hoc analysis showed that the proportion of participants who increased anti-diabetic therapy intensity decreased in the tirzepatide arms and increased in the placebo arm.

SURMOUNT-3 investigated the effect of tirzepatide (10 mg or 15 mg) vs placebo after ≥5% weight loss with intensive lifestyle intervention (ILI) in adults with BMI ≥ 30 kg/m² or ≥ 27 kg/m² and at least one weight-related comorbidity (120). At baseline, weight was 110.1 kg and BMI was 38.7. After 72 weeks, participants on tirzepatide lost 18.4% of their baseline weight while those on placebo gained 2.5%. Significant more people on tirzepatide than placebo achieved ≥5% weight loss: 87.5% vs 16.5%. The numerically lower average weight loss achieved in SURMOUNT-3 compared to that in SURMOUNT-1 has called into question the role of lifestyle management in the era of highly effective OMs, but several potential areas of benefit have been identified, outside of weight: body composition and preservation of lean muscle mass, micronutrient adequacy, and cementation of behavior strategies associated with long-term weight loss maintenance (121).

SURMOUNT-4 examined the efficacy of tirzepatide (10 or 15 mg) vs placebo for weight loss maintenance in adults who completed a 36-week lead-in weight loss period (122). At the end of 36 weeks, average weight loss was 20.9% with tirzepatide vs --- with placebo. From week 36 to week 88, participants lost an addition 5.5% with tirzepatide and gained 14.0% with placebo. Overall, tirzepatide resulted in weight loss maintenance, defined as ≥ 80% of weight lost, for 89.5% of participants compared to only 16.6% of those on placebo. The total mean weight change from week 0 to 88 was -25.3% vs -9.9% in tirzepatide vs placebo arms.

In SURMOUNT-5, semaglutide at its maximum tolerated dose (MTD) of 1.7 or 2.4 mg was compared to tirzepatide’s MTD (10 or 15 mg) in adults with obesity. After 72 weeks, semaglutide resulted in 13.7% weight loss and tirzepatide caused 20.2% weight loss (p<0.001), demonstrating superiority of tirzepatide over semaglutide. Tolerability was comparable. Discontinuation rates due to adverse events were low (1.6% in each arm), and rates of nausea, constipation, and diarrhea were numerically comparable. For tirzepatide vs semaglutide, respective rates of vomiting (15.0% vs. 21.3%), gastroesophageal reflux disease (6.1% vs. 10.6%), and dyspepsia (5.9% vs. 7.4%) may have favored tirzepatide, while rates of injection site reactions (8.6% vs. 0.3%) may have favored semaglutide.

The SURMOUNT trials were notable for a few unique characteristics:

• New in-class mechanism of action incorporating GIP agonism.
• More balanced male-to-female recruitment approximating 50%, compared to prior obesity clinical trials.
• A new threshold achieved for average weight loss, greater than 20%, a milestone approaching and surpassing that of some bariatric surgeries.

In December 2024, the FDA approved the first medication for treatment of obstructive sleep apnea (OSA) based off of positive results of the SURMOUNT-OSA trial (123). The SURMOUNT-OSA trial (n=469) assessed the safety and efficacy of tirzepatide 10 or 15mg weekly on adults with moderate-to-severe OSA and a BMI ≥30 kg/m² (124). At 52 weeks, the trial showed a significant reduction in the apnea-hypopnea index (AHI) both in participants who were and were not receiving positive airway pressure (PAP) at baseline. In participants not receiving PAP therapy, those on tirzepatide had a reduction in AHI of 25.3 events/hr vs, a reduction of 5.3 events/hr in placebo and a placebo subtracted weight loss of -16.1%. Similarly, in participants receiving PAP therapy at baseline, those on tirzepatide had a reduction in AHI by 29.3 event/hr vs. a reduction of 5.5 events/hr in placebo and placebo subtracted weight loss of 17.3%. SURMOUNT-OSA effectively suggested that weight loss of >15% with tirzepatide could result in disease resolution of OSA.

Effect on Metabolic Profile

The benefits of tirzepatide on cardiometabolic risk factors were consistent across all trials. Participants on tirzepatide experienced significantly greater improvements in SBP, DBP, fasting insulin, fasting glucose, A1c, LDL cholesterol, HDL cholesterol, and triglycerides compared to placebo. In SURMOUNT-1, -2, and -3, SBP decreased by 5 to 7 mmHg with tirzepatide vs no change or increase in placebo groups. In SURMOUNT-4, during the weight loss maintenance phase, SBP increased by 2.1 mmHg with tirzepatide vs 8.4 mmHg with placebo. Insulin sensitivity improved among tirzepatide groups, with fasting insulin reduced by about 40% in SURMOUNT-1, -3, and -4. Among participants with obesity and T2D in SURMOUNT-2, A1c was reduced by about 2% with tirzepatide 10 or 15 mg vs 0.5% with placebo. The most dramatic improvements in lipid profiles remained the reduction of triglycerides of about 25% in SURMOUNT-1, -2, and -3, and up to 33% in SURMOUNT-4.

In a phase 2 study (SYNERGY-MASH) of participants with biopsy-confirmed metabolic-associated steatohepatitis (MASH) and stage F2 or F3 fibrosis, a significantly greater proportion of participants achieved resolution of MASH without worsening of fibrosis in tirzepatide groups compared to placebo after 52 weeks of treatment (125): 44% (5 mg), 56% (10 mg), 62% (15 mg) vs 10% (placebo).

While tirzepatide’s CVOT, SURMOUNT-MMO, is ongoing, its cardiac benefits have been established in HFpEF in the SUMMIT trial (126). The SUMMIT trial randomized adults with HFpEF (EF ≥50%) and BMI ≥30 kg/m² to tirzepatide 15 mg or placebo for 52 weeks. The primary endpoint, a composite of death from CV causes or worsening heart failure event, occurred in 9.9% of patients in the tirzepatide group vs. 15.3% of patients in the placebo group, conferring a 38% relative risk reduction (HR 0.62, 95% CI 0.41 to 0.95, p=0.026), primarily driven by a reduction in heart-failure events (HR 0.54, 95% CI, 0.34 to 0.85). The HR for CV death was 1.58 (95% CI 0.52 to 4.83). The change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) was another primary endpoint and increased by 19.5 points in the tirzepatide group and 12.7 points in the placebo group (HR 6.9, 95% CI 3.3 to 10.6, p<0.0001).

Safety and Side Effects

Across all five SURMOUNT obesity trials, the most common adverse events were gastrointestinal: nausea, vomiting, diarrhea, constipation. Treatment discontinuation rates due to adverse events were generally low (2-8%). No imbalances were noted for incidence of pancreatitis between tirzepatide groups and placebo. No cases of medullary thyroid carcinoma or pancreatic cancer occurred. In general, the incidence of gallbladder disease was numerically greater in tirzepatide groups compared to placebo though the overall incidences were low (<1%).

While all OMs are contraindicated in pregnancy, tirzepatide has been observed to affect absorption of estradiol-containing oral contraceptives and potentially reduce their efficacy as birth control, specifically during dose escalation phases of tirzepatide. For this reason, individuals of childbearing potential should be counseled to use a second form of birth control during dose escalation. The purported mechanism for this interference is a reduction in gastrointestinal motility and absorption, which may occur with other incretin therapies (i.e., semaglutide, liraglutide), but such interactions have not been reported.

Bupropion

Bupropion (trade name Wellbutrin or Zyban) is used for depression and smoking cessation and can also induce weight loss. A 48-week placebo-controlled trial randomized individuals with obesity to placebo, 300 mg, or 400 mg of bupropion sustained release (SR). Percentage losses of initial body weight for subjects completing 24 weeks were 5.0%, 7.2%, and 10.1% for placebo, bupropion SR 300, and 400 mg/d, respectively (127). In subjects with obesity and depressive symptoms, bupropion SR was more effective than placebo in achieving weight loss when combined with a 500 kcal deficit diet (4.6% vs.1.8% loss of baseline body weight, P<0.001) (128). Bupropion is contraindicated in patients with seizures, current or prior diagnosis of bulimia or anorexia nervosa, and concurrent use with MAOs (129). Caution should be used in patients with hypertension, mania/hypomania, psychosis, and angle-closure glaucoma. While the average weight loss seen with bupropion is small, it is a preferred alternative to most antidepressants, which commonly cause weight gain.

Metformin

Metformin (trade name Glucophage) is an antihyperglycemic agent that acts by suppressing gluconeogenesis and increasing peripheral insulin sensitivity (130). Potential weight loss mechanisms include:

• Activation of AMP-activated protein kinase (AMPK) to mimic an “energy deficient” state (131,132)
• Increasing anorexigenic hormones GLP-1 (133), growth/differentiation factor-15 (GDF-15) (134), neuropeptide Y (NPY), and agouti-related protein (AgRP) (135)
• Increasing leptin sensitivity (136)

In the landmark Diabetes Prevention Program (DPP), 3234 participants without T2D but with fasting and post-prandial hyperglycemia were randomized to intensive lifestyle intervention (ILI), metformin, or placebo (14). ILI included 150 minutes per week of physical activity, caloric deficit, and a low-fat diet with a weight loss goal of 7%. The mean age was 51 years and mean BMI was 34.0 kg/m². The metformin group was not offered ILI and was assigned to metformin 850 mg twice a day. After an average follow-up of 2.8 years, patients in the metformin group achieved greater weight loss than placebo but less than the ILI group: mean weight loss was 0.1 kg, 2.1 kg, and 5.6 kg in the placebo, metformin, and ILI groups, respectively (P<0.001, cross-group comparison) (14). The extended observational trial DPP Observation Study showed that the group on metformin maintained 3% weight reduction compared to placebo for 6-15 years after DPP ended (137). Short-term studies and meta-analyses in individuals with obesity and without prediabetes/diabetes consistently demonstrate ~2% weight loss beyond placebo, with a greater response in those with more insulin resistance (138). For this reason, metformin was considered a first line drug in treating patients with obesity and T2D. Recent updates to the American Diabetes Guidelines recommend GLP-1RA containing medications as initial therapy for patients with obesity and T2D because of the superior weight loss and confirmed cardiovascular benefits (139). The most common side effects of metformin are nausea, flatulence, diarrhea, and bloating (140). The most serious side effect is lactic acidosis, but this is rare (<1/100,000) and can be avoided by not initiating when estimated glomerular filtration rates (eGFR) are < 30 mL/min/1.73 m² (141). Monitoring for vitamin B12 deficiency is recommend as long-term use of metformin has been associated with low vitamin B12 levels and neuropathy (142).

Pramlintide

Pramlintide acetate (trade name Symlin) is an injectable agent that is FDA-approved for the treatment of type 1 diabetes and T2D. Pramlintide mimics the action of the pancreatic hormone amylin, which along with insulin regulates postprandial glucose control. Its effect on weight loss is thought to be mediated through brainstem receptors (143) that improve appetite control (144). In a pooled, post-hoc analysis of insulin-treated patients with T2D who were overweight and had obesity, pramlintide-treated patients (120 mcg twice daily) had a body weight reduction of -1.8 kg (P<0.0001) compared with placebo-treated patients (145). In this study, pramlintide-treated patients experienced a 3-fold increase in successfully achieving a total weight loss of ≥ 5%, when compared to those who received placebo. Subsequently, randomized trials combining pramlintide or placebo with a lifestyle intervention were undertaken in participants with obesity but not T2D. Treatment with pramlintide (up to 240 mcg three time daily) for 16 weeks resulted in a placebo-corrected reduction in body weight of 3.7% (P<0.001) and 31% of pramlintide-treated subjects achieved ≥5% weight loss vs. 2% with placebo (P<0.001) (146). In another study with one year follow-up, placebo-corrected weight loss in those taking 120 mcg three time daily and 360 mcg twice daily averaged 5.6% and 6.8% (147). Nausea was the most common adverse event with pramlintide treatment in these studies.

Sodium-Glucose Transporter-2 Inhibitors

Sodium-glucose transport-2 (SLGT2) inhibitors are a class of medications for T2D treatment. Inhibition of SGLT2 in the kidney lowers the renal threshold for glucose reabsorption, resulting in glucosuria and improved plasma glucose levels. As of 2024, there are five SLGT2 inhibitors approved in the U.S.: canagliflozin (Invokana), dapagliflozin (Farxiga), ertugliflozin (Steglatro), empagliflozin (Jardiance), and bexagliflozin (Brenzavvy). Pooled analyses of four phase 3 trials in adults with T2D showed about 2-3% placebo-subtracted weight loss with canagliflozin 100-300 mg/d at 26 weeks (148).

Canagliflozin has been uniquely examined in a phase 2 obesity RCT in combination with phentermine (149). A total of 334 adults with obesity/overweight with or without T2D were randomized to placebo, canagliflozin 300 mg/d monotherapy, phentermine 15 mg/d monotherapy, or combination canaglifozin/phentermine (cana/phen) for 26 weeks. All active drug arms demonstrated statistically greater weight loss vs. placebo: −1.9% (canagliflozin), −4.1% (phentermine), −7.5% (cana/phen) vs. −0.6% (placebo). Weight loss via combination vs. monotherapy arms was not a pre-specified endpoint, but an interaction term suggested at least additive effects (p=0.0624). Changes in cardiometabolic risk factors were generally reassuring: SBP changes were −3.1, −1.4, and −6.9 mmHg in canagliflozin, phentermine, and cana/phen arms, respectively vs. −2.7 mmHg (placebo); and mean heart rate changes were +0.7, +4.1, +3.5, respectively vs. −0.7 bpm (placebo).

Dapagliflozin on a background of metformin was found to result in a placebo-subtracted weight loss of 2.42kg at 102 weeks in adults with T2D and obesity (150). In the landmark EMPA-REG CVOT, average placebo-subtracted weight loss of about 2 kg was maintained out to 220 weeks with empagliflozin 25 mg (151). The SGLT2 inhibitor, ertugliflozin, also resulted in about 2kg weight loss over placebo in adults with T2D treated for 26 weeks (152). A meta-analysis of EMPA-REG, CANVAS (153,154), and DECLARE-TIMI 58 (155) found that SGLT2 inhibitors were associated with a 24% reduction in hospitalization for heart failure and CVD death in individuals with T2D and established CVD (156). This same meta-analysis concluded that SGLT2 inhibitors were also associated with nearly a 50% reduction in the composite outcome of end-stage renal disease, renal worsening, or renal failure in individuals with T2D and CVD or CVD risk factors. The reno-protective effect may be independent of baseline A1c given attenuated eGFR declines observed in CREDENCE and DAPA-HF trials with little change in A1c (157,158), suggesting a role of SGLT2 inhibitors in individuals with nephropathy without T2D. Dapagliflozin was recently approved by the FDA for the treatment of heart failure in individuals with or without T2D based on the results of the DAPA-HF trial (158). EMPEROR-Preserved and EMPEROR-Reduced established similar benefits of empagliflozin in heart failure irrespective of ejection fraction (159).

DAPA-CKD and EMPA-KIDNEY evaluated the effect of SGLT2 inhibitors in the broader CKD population (160,161). In DAPA-CKD, adults with eGFR 25-75 and urinary albumin-to-creatinine ratio (UACR) of 200-5000 were randomized to dapagliflozin 10 mg or placebo (162). The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. After a median of 2.4 years, the primary outcome occurred in 9.2% vs 14.5% in the dapagliflozin vs placebo groups, respectively, representing a 39% relative risk reduction. In EMPA-KIDNEY, adults with eGFR 20-45 or eGFR 45-90 with UACR ≥200 were randomized to empagliflozin 10 mg or placebo (163). The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. After a median of 2.0 years, the primary outcome occurred in 13.1% vs 16.9% in the empagliflozin and placebo groups, respectively, representing a 28% relative risk reduction.

Data for bexagliflozin is comparatively scarce to other members of its class. In a phase 3 RCT of adults with T2D and stage 3a/3b CKD, bexagliflozin resulted in A1c reduction of 0.59-0.65% vs 0.16-0.34% with placebo, depending on eGFR (164).

Due to the mechanism of action, all SGLT2 inhibitors may cause urinary tract infections, genital mycotic infections, and dehydration. They are contraindicated in end-stage renal disease and dialysis (165-168).

Topiramate

Topiramate (trade name Topamax) is an antiepileptic agent that has been found to reduce body weight in patients with a variety of disorders including epilepsy, bipolar disorder, and binge eating disorder (169). Randomized controlled trials have shown that when used as single drug (without phentermine), topiramate in doses of to 256 mg per day is both tolerable and effective in promoting weight loss (62). In addition to use for epilepsy, topiramate has received FDA approval for the prevention of migraine headaches. Topiramate can cause paresthesias and cognitive side effects, such as word-finding difficulty and memory loss. Caution should be taken if used in patients predisposed to renal stones, acute angle glaucoma, or metabolic acidosis (170).

Zonisamide

Zonisamide (trade name Zonegran) is another antiepileptic medication that has also been found to reduce body weight in patients. Short (16 weeks) and longer (one year) randomized-controlled studies in patients with obesity have shown that 400 mg of zonisamide daily is effective in promoting modest weight loss (~5 kg placebo-subtracted weight) (171,172). The most commonly reported side effects compared to placebo were gastrointestinal (nausea/vomiting), nervous system (headaches), and cognitive (anxiety, impaired memory, language problems) (172). Zonisamide should not be given to patients hypersensitive to sulfonamides (173).

Metreleptin

Metreleptin (trade name Myalept) is a leptin analog approved to treat the complications of leptin deficiency in individuals with congenital or acquired generalized lipodystrophy (174). It has been used off-label for the treatment of obesity and other endocrine complications in people with congenital leptin deficiency and hypothalamic amenorrhea (175). Metreleptin is administered as a once daily subcutaneous injection with dosages ranging from 0.06 mg/kg/d to 10 mg/d, depending on body weight and sex. Additional precautions should be implemented if it is being considered for individuals with T-cell lymphoma or autoimmune disorders. During therapy, patients should be tested for neutralizing anti-metreleptin antibodies if they develop severe infections or loss of efficacy. Common side effects include headache, hypoglycemia, decreased weight, and abdominal pain.