Advances in Pharmacological Treatment of Obesity: A Comprehensive Review for the Practicing Internist

Dr Neeraj Manikath , claude.ai

Abstract

The landscape of obesity pharmacotherapy has undergone a revolutionary transformation in recent years, moving from modest weight loss agents to highly effective medications achieving weight reductions comparable to bariatric surgery. This review examines the current evidence base for anti-obesity medications, with particular emphasis on GLP-1 receptor agonists, dual and triple incretin receptor agonists, and emerging therapeutic approaches. We provide practical guidance for patient selection, treatment optimization, and management of common challenges encountered in clinical practice.

Introduction

Obesity affects over 650 million adults globally and represents one of the most significant public health challenges of our era. Despite decades of research, the medical community has historically struggled to achieve meaningful, sustained weight loss through pharmacological interventions. The 2020s have witnessed an unprecedented paradigm shift with the development of incretin-based therapies that achieve weight reductions of 15-25%, fundamentally altering our therapeutic approach to obesity management.

For the practicing internist, understanding these advances is no longer optional—obesity-related comorbidities constitute a substantial proportion of our daily clinical encounters, and we now possess tools that can meaningfully alter disease trajectories.

Historical Context and the Evolution of Anti-Obesity Pharmacotherapy

Pearl: The history of obesity pharmacotherapy is littered with withdrawn medications (fenfluramine, sibutramine, rimonabant), teaching us that efficacy must never compromise cardiovascular safety. Current agents have undergone rigorous cardiovascular outcome trials—a standard that should inform our confidence in prescribing.

The early 2010s offered limited options: orlistat (modest 3% placebo-subtracted weight loss, poorly tolerated), phentermine (short-term use only), and lorcaserin (withdrawn 2020 due to cancer concerns). The approval of liraglutide 3.0 mg in 2014 marked the beginning of the incretin era, though its 5-6% weight loss seemed unremarkable at the time.

GLP-1 Receptor Agonists: The Current Standard

Semaglutide

Semaglutide, a long-acting GLP-1 receptor agonist, represents the most extensively studied anti-obesity medication currently available. The STEP (Semaglutide Treatment Effect in People with obesity) trial program demonstrated:

STEP 1: 68 weeks of semaglutide 2.4 mg weekly achieved 14.9% weight loss versus 2.4% with placebo (mean difference 12.5 kg)
STEP 2: In patients with type 2 diabetes, 9.6% weight loss versus 3.4% with placebo
STEP 5: Sustained weight loss of 15.2% at 104 weeks

Hack: Many patients experience nausea during titration. Counsel patients to eat slowly, stop when comfortable (not full), avoid high-fat meals, and stay upright after eating. Starting metoclopramide 10 mg before meals for 2-3 weeks during dose escalation can improve tolerability in selected patients, though this is off-label.

The SELECT cardiovascular outcomes trial (2023) demonstrated a 20% reduction in major adverse cardiovascular events in patients with established cardiovascular disease, independent of weight loss—a finding that elevates semaglutide beyond purely metabolic therapy.

Liraglutide

Liraglutide 3.0 mg daily (Saxenda) produces approximately 8% weight loss but requires daily subcutaneous injection. While less effective than semaglutide, it remains a viable option with established safety data and may suit patients requiring more gradual weight loss.

Oyster: Don't overlook liraglutide for patients who have had previous pancreatitis or strong family history. While all GLP-1 agonists carry theoretical pancreatitis risk, liraglutide has the most extensive real-world safety data spanning over a decade.

Dual and Triple Incretin Receptor Agonists: The Next Frontier

Tirzepatide (GIP/GLP-1 Co-agonist)

Tirzepatide represents a significant advancement, co-activating both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors. The SURMOUNT clinical trial program demonstrated:

SURMOUNT-1: 72 weeks of tirzepatide 15 mg weekly achieved 20.9% weight loss versus 3.1% with placebo—the highest weight loss ever recorded in a phase 3 obesity trial
Approximately 50% of patients achieved ≥20% weight loss
SURMOUNT-2: In type 2 diabetes, 15.7% weight loss versus 3.2% placebo

Pearl: The superior efficacy of tirzepatide over semaglutide (head-to-head comparison in SURMOUNT-5 pending full publication) appears related to GIP co-agonism enhancing lipolysis and potentially reducing the compensatory metabolic adaptation that limits weight loss with GLP-1 monotherapy.

Clinical experience suggests tirzepatide may be better tolerated than semaglutide at equipotent doses, though robust comparative data are limited. The mechanism underlying improved tolerability remains uncertain but may relate to GIP's effects on gastric motility.

Retatrutide (GIP/GLP-1/Glucagon Triple Agonist)

Phase 2 data (2023) for retatrutide demonstrated 24.2% weight loss at 48 weeks with the 12 mg dose—the highest pharmaceutical weight loss recorded to date. Glucagon receptor activation increases energy expenditure and hepatic fat oxidation, potentially explaining the incremental benefit over dual agonism.

Hack: When discussing emerging therapies with patients, frame the conversation around mechanism rather than "better" versus "worse." This educational approach helps patients understand their current therapy while managing expectations about future options.

Combination Therapies and Adjunctive Approaches

Phentermine-Topiramate ER

This combination (Qsymia in the US) produces approximately 10% weight loss through complementary mechanisms—phentermine's noradrenergic appetite suppression and topiramate's mechanisms including modulation of GABA and glutamate receptors. While effective, concerns about teratogenicity, cognitive effects, and cardiovascular safety in specific populations limit widespread use.

Naltrexone-Bupropion SR

Contrave combines opioid antagonism with dopamine-norepinephrine reuptake inhibition, yielding approximately 5-6% weight loss. The modest efficacy and tolerability issues (nausea in 30%) position this as a third-line option, though it may suit patients with concurrent depression or substance use disorders.

Patient Selection and Treatment Individualization

Pearl: The patient most likely to succeed is not the one with the highest BMI, but the one who understands this is chronic disease management requiring indefinite therapy. Initial counseling should emphasize that discontinuation typically results in weight regain—patients must make an informed choice about long-term commitment.

Appropriate Candidates

Current guidelines support pharmacotherapy for:

BMI ≥30 kg/m² OR
BMI ≥27 kg/m² with weight-related comorbidities (type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease)

Matching Patient to Medication

For maximal weight loss: Tirzepatide > semaglutide 2.4 mg > liraglutide 3.0 mg

For established cardiovascular disease: Semaglutide (proven cardiovascular benefit) or tirzepatide (cardiovascular outcomes trial ongoing)

For type 2 diabetes: Tirzepatide or semaglutide (superior glycemic control with weight loss)

For cost-sensitivity: Generic phentermine-topiramate or naltrexone-bupropion where available; patient assistance programs for brand medications

Oyster: Don't prescribe incretin-based therapies for "cosmetic" weight loss in normal-weight individuals. Beyond ethical concerns and lack of indication, these patients are at higher risk of excessive weight loss, muscle loss, and may develop disordered eating patterns.

Practical Management Pearls

Titration Strategies

Hack: Slower titration reduces discontinuation. For semaglutide, consider extending each dose level to 3-4 weeks rather than the standard 4-week escalation if patients experience persistent nausea. Clinical trials used fixed titration, but individualized approaches improve real-world persistence.

Managing Common Adverse Effects

Nausea/Vomiting: Usually transient during titration. Small, frequent meals; ginger supplementation; temporary dose reduction; antiemetics if severe.

Constipation: Adequate hydration (2-3 L daily), fiber supplementation, polyethylene glycol as needed. Under-recognized and undertreated—proactive counseling improves adherence.

Hypoglycemia: Rare with GLP-1 monotherapy; reduce sulfonylurea/insulin doses by 30-50% when initiating in type 2 diabetes.

Gallbladder disease: Rapid weight loss increases cholelithiasis risk. Consider ursodeoxycholic acid in high-risk patients (though evidence is limited).

Gastroparesis symptoms: Profound gastric emptying delay can mimic gastroparesis. Usually improves within weeks of discontinuation. Consider holding medication before elective procedures requiring anesthesia.

Monitoring

Baseline: CBC, CMP, lipid panel, HbA1c, TSH, lipase (if history suggestive)

Follow-up:

Monthly initially for adverse effects and dose escalation
Every 3 months once stable for weight, blood pressure, metabolic parameters
Annual lipid panel, HbA1c (if diabetic)

Pearl: Weight loss plateaus are inevitable and don't necessarily indicate treatment failure. Patients typically lose 5-10% in the first 3-4 months, then more gradually. Setting realistic expectations prevents premature discontinuation. The weight curve is logarithmic, not linear.

Emerging Therapies and Future Directions

Oral GLP-1 Agonists

Oral semaglutide (Rybelsus) is approved for type 2 diabetes but produces less weight loss (~5-6%) than injectable formulations due to lower bioavailability. Ongoing trials are evaluating higher doses specifically for obesity.

Amylin Analogs

Cagrilintide, a long-acting amylin analog, is being studied in combination with semaglutide (CagriSema), with phase 3 data suggesting ~25% weight loss—potentially exceeding monotherapy through complementary satiety mechanisms.

Small Molecule Approaches

Oral small molecule GLP-1 receptor agonists in development may improve accessibility and adherence, though achieving injectable-equivalent efficacy remains challenging.

Special Populations

Chronic Kidney Disease

Semaglutide and tirzepatide are safe across CKD stages and provide nephroprotective benefits beyond weight loss. Dose adjustment is not required.

Elderly Patients

Oyster: Aggressive weight loss in older adults risks sarcopenia and frailty. Consider lower target doses, emphasize resistance training, ensure adequate protein intake (1.2-1.5 g/kg), and monitor for excessive lean mass loss.

Pregnancy

All current anti-obesity medications are contraindicated in pregnancy. GLP-1 agonists should be discontinued 2 months before conception attempts due to long half-lives.

Cost and Access Considerations

The elephant in the room: annual costs of $12,000-15,000 for branded incretin therapies create significant access barriers. Insurance coverage varies dramatically by region and policy.

Hack: Many pharmaceutical companies offer patient assistance programs. Maintain an updated list of program contacts and eligibility criteria. For uninsured patients, compounded semaglutide from reputable pharmacies may offer temporary solutions, though quality concerns and legal uncertainties exist.

Duration of Therapy and Weight Maintenance

The STEP 4 trial unequivocally demonstrated that semaglutide discontinuation results in substantial weight regain—patients regained two-thirds of lost weight within one year of cessation. This confirms that obesity pharmacotherapy is chronic disease management, not a time-limited intervention.

Pearl: Frame this conversation early: "These medications help your body regulate weight at a healthier set point, but your biology will try to return you to your previous weight if we stop. Think of this like treating hypertension—we don't stop medications once blood pressure normalizes."

Contraindications and Precautions

Absolute contraindications (GLP-1 agonists):

Personal or family history of medullary thyroid carcinoma
Multiple endocrine neoplasia type 2
Previous severe hypersensitivity reaction
Pregnancy

Relative contraindications:

History of pancreatitis (carefully weigh risks/benefits)
Severe gastroparesis
Diabetic retinopathy (semaglutide may transiently worsen; ophthalmologic monitoring advised)

Conclusion

The advances in obesity pharmacotherapy over the past five years represent a genuine paradigm shift in our ability to treat this chronic disease. Incretin-based therapies, particularly semaglutide and tirzepatide, achieve clinically meaningful weight loss with acceptable safety profiles and cardiovascular benefits. As internists, we must embrace these tools while maintaining realistic expectations, ensuring appropriate patient selection, and committing to long-term management partnerships with our patients.

The future promises even more effective therapies—triple agonists, novel combination approaches, and oral formulations—but the fundamental principle remains unchanged: obesity is a chronic disease requiring chronic treatment, and our role is to guide patients through evidence-based management with compassion, clinical expertise, and realistic goal-setting.

Key References

Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002.
Garvey WT, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022;28(10):2083-2091.
Lincoff AM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232.
Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216.
Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526.
Rubino D, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021;325(14):1414-1425.
Pi-Sunyer X, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373(1):11-22.
Garvey WT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Endocr Pract. 2016;22(Suppl 3):1-203.