Determining the single 'number one' weight loss drug in America is a complicated question with no simple answer. The perception of which drug holds the top spot can vary depending on different factors, such as overall effectiveness, prescription volume, and media buzz. While newer, highly effective injectable medications like Zepbound and Wegovy have dominated headlines and demonstrated the most significant weight loss in clinical trials, older and less costly oral medications like phentermine remain widely prescribed. A patient's unique health profile, the amount of weight they need to lose, and potential side effects all influence a healthcare provider's final recommendation.
Understanding the Most Effective Injectables
For many looking for the most significant weight loss, the most effective medications are glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) agonists. These are typically administered as weekly injections and work by slowing digestion and increasing feelings of fullness, which helps reduce overall caloric intake.
Zepbound (Tirzepatide): The Highest Efficacy
As of mid-2025, Zepbound is often cited as the most effective weight loss medication. It contains the active ingredient tirzepatide, a dual-action agonist that mimics two different naturally occurring hormones (GIP and GLP-1). In clinical trials, adults on higher doses of Zepbound experienced an average weight loss of up to 22.5% over 72 weeks, surpassing the results of other similar medications. It was approved by the FDA for chronic weight management in November 2023.
Wegovy (Semaglutide): A Popular Contender
Another highly effective injectable is Wegovy, which contains the active ingredient semaglutide, a GLP-1 receptor agonist. It was approved for chronic weight management in June 2021 and has gained immense popularity. Studies show that patients on Wegovy can achieve an average weight loss of around 15%. Both Zepbound and Wegovy require a prescription and are generally used for long-term weight management in conjunction with diet and exercise.
The Role of Older Medications
Despite the rise of newer injectables, several older medications continue to be prescribed, often for their lower cost or specific applications.
Phentermine: A Long History
Phentermine is one of the oldest and most widely used weight loss medications, typically prescribed for short-term use. It is an appetite suppressant and, while effective, is a controlled substance due to its potential for abuse and dependence. Some studies suggest it can lead to about 5% weight loss.
Combination Pills: Qsymia and Contrave
- Qsymia (Phentermine-Topiramate): Combines the appetite suppressant phentermine with the anti-seizure medication topiramate, which together reduce appetite and increase feelings of fullness. Clinical trials indicate an average weight loss of 7% to 11%.
- Contrave (Naltrexone-Bupropion): Uses a combination of two drugs to target the brain's reward system, affecting cravings and appetite. It may help patients lose 5% to 10% of their body weight.
Orlistat: The Fat Inhibitor
Orlistat (brand names Xenical, and a lower-dose OTC version Alli) works differently by blocking the absorption of dietary fat. In studies, it has shown more modest weight loss results compared to other prescription options.
Comparison of Prominent Weight Loss Drugs
| Feature | Zepbound (Tirzepatide) | Wegovy (Semaglutide) | Phentermine | Qsymia (Phentermine/Topiramate) | Contrave (Naltrexone/Bupropion) |
|---|---|---|---|---|---|
| Drug Type | Dual GIP/GLP-1 Agonist | GLP-1 Agonist | Stimulant/Appetite Suppressant | Combination Pill | Combination Pill |
| Administration | Once-weekly injection | Once-weekly injection | Daily pill | Once-daily capsule | Twice-daily pill |
| Avg. Weight Loss | Up to 22.5% | Up to 15% | ~5% | 7%–11% | 5%–10% |
| FDA Status | Long-term weight mgmt. | Long-term weight mgmt. | Short-term weight loss | Long-term weight mgmt. | Long-term weight mgmt. |
| Common Side Effects | GI issues (nausea, diarrhea, vomiting) | GI issues (nausea, diarrhea, vomiting) | Increased heart rate, insomnia, dry mouth | Altered taste, numbness, dry mouth | Nausea, constipation, headache, dizziness |
| Insurance Coverage | Varies widely, can be very costly | Varies widely, can be very costly | Generally more accessible | Varies | Varies |
Considerations for Choosing a Medication
Choosing a weight loss medication is a highly individualized process that involves a comprehensive assessment by a healthcare provider. Key factors include BMI, coexisting health conditions, and a history of previous weight loss attempts. For instance, a patient with heart disease may be a strong candidate for Wegovy, which has proven cardiovascular benefits, while those with a lower BMI or who prefer an oral option may explore other medications. Eligibility for GLP-1 medications typically requires a BMI of 30 or higher, or a BMI of 27 or higher with at least one weight-related condition such as hypertension, type 2 diabetes, or sleep apnea.
It is also crucial to remember that no weight loss medication is a "magic bullet." For the most effective and sustainable results, these drugs must be used in combination with significant lifestyle changes, including a balanced, nutrient-dense diet and regular physical activity. A healthcare team, including a registered dietitian, can help tailor a nutritional plan to maximize the medication's effectiveness while managing potential side effects.
Conclusion: The Best Drug is a Personal Choice
Ultimately, there is no single number one weight loss drug in America for everyone. The best medication is the one that is most effective and safest for an individual's specific health needs and goals, as determined by a healthcare provider. While newer injectables like Zepbound and Wegovy have demonstrated unparalleled efficacy in recent years, older and more established medications continue to serve as viable options for many patients. The decision should always be made after a careful medical evaluation, considering effectiveness, side effects, cost, and a patient's commitment to accompanying lifestyle changes.
- Disclaimer: This information is for educational purposes only and is not medical advice. Consult with a qualified healthcare professional before starting or stopping any medication. For more information, visit the Obesity Medicine Association.*
