The Ultimate Guide to GLP-1 Medications for Weight Loss

Why have GLP-1 Drugs become so popular?

In a few short years, GLP-1 drugs like Ozempic, Wegovy,  Mounjaro and Zepbound have gone from relative obscurity to some of the most sought after medications in the US. What factors underlie their sudden popularity?

• Prevalence of obesity

With over 40% of American adults designated as obese (BMI of 30+) and rates continuing to climb, there is enormous demand for medical treatment, according to CDC data. At the current trajectory, nearly 50% of Americans are projected to have obesity by 2030, according to a New England Journal of Medicine study.(1)

• Limited success of lifestyle interventions

Diet, exercise and behavioral modifications alone have not proven successful long-term for most people with obesity. Many struggle to lose weight or keep it off through these approaches alone.

• Novel mechanism of action

GLP-1 drugs target appetite neurohormonal pathways in a way other weight loss drugs do not, providing a new avenue for treatment, according to ro.co.(2)

• Impressive weight loss results

In clinical trials, GLP-1 medications have helped patients lose on average 15-20% of their starting weight over 6-12 months. For many, this represents life-changing improvement.(3)

• Celebrity and social media hype

High profile figures attributing massive weight loss to these drugs have sparked intense public curiosity, with the resulting hype fueling demand.(4) Interest beyond medical necessity 
In addition to appropriate medical use, many people simply seeking cosmetic weight loss have added to the increased demand.(5)

In a short period, GLP-1s went from novel medications to the most sought after treatment for weight management.

How Effective Are GLP-1 Drugs For Weight Loss?

GLP-1 medications have shown dramatic effects in clinical trials, but how do they perform in the real world?

In randomized controlled trials of semaglutide, participants lost on average 14.9-17.6% of their baseline weight over 68 weeks, according to a study cited in Statnews.com.(6) For the GLP-1 tirzepatide, average losses reached 21.4% at the highest studied dose over 72 weeks.(7) All groups in the controlled trials also received counseling on diet and exercise.

Real world evidence also demonstrates substantial weight reduction, though to a lesser degree than research studies. An analysis of nearly 10,000 people taking semaglutide drugs found they lost on average 10.2-13.2% of baseline weight over 12 months.(8)

It’s important to note that GLP-1 clinical trials employ run-in periods where non-adherent participants are excluded.(9) Real world patients face many barriers to consistent adherence, including side effects, injection anxieties, medication costs and behavioral challenges.

While GLP-1s undeniably lead to significant weight loss in many patients, individual differences in dose, adherence and lifestyles result in variable outcomes.(10) Health care providers emphasize realistic expectations, as some may lose minimal weight while others lose over 20% body weight. Ongoing support improves adherence needed for optimal results.

What Are GLP-1 Drugs Approved to Treat?

GLP-1 receptor agonists are approved for multiple indications.

• Type 2 diabetes

Ozempic, Trulicity, Victoza and other GLP-1s are indicated as add-on treatments to help produce more insulin and lower blood sugar levels for patients with type 2 diabetes.(11)

• Obesity

Wegovy, Saxenda and Zepbound are specifically FDA-approved for chronic weight management in adults with obesity or who are overweight with an obesity-related health condition like diabetes or hypertension.

• Cardiovascular disease risk reduction

Studies show Ozempic and Victoza reduce cardiovascular events in type 2 diabetics at high CVD risk.(12)

Health care providers are permitted to prescribe drugs off-label, leading many to use GLP-1s like Ozempic for weight loss prior to Wegovy’s approval. These off-label prescriptions have driven shortages since they have been prescribed for both diabetes and weight management. Patients with obesity may be candidates if they meet specific body mass index (BMI) or body weight criteria.

Who is Eligible for GLP-1 Drug Therapy?

GLP-1s are FDA-approved for chronic weight management in adults with severe obesity or overweight with an obesity-related comorbidity like diabetes or hypertension. Criteria could expand as more safety data emerges but some experts argue eligibility should stay narrow for now. Those with certain gastrointestinal diseases or cancers may not be candidates.

What Are Risks and Side Effects of GLP-1 Drugs?

As with any medication, GLP-1 drugs have potential risks and adverse effects that must be considered before initiating treatment.

Common transient side effects:

• Nausea

Seen in up to 40% of patients, especially when starting treatment. Generally resolves over days to weeks with dose escalation.

• Diarrhea

Reported by ~12-15% of people starting GLP-1 drugs. Also tends to diminish over time.

• Vomiting

Around 10% experience vomiting when initiating. Usually improves with dose titration.

• Abdominal pain

Seen in up to 10% but typically resolves within days of treatment.

• Decreased appetite

This is expected on medications that suppress appetite, but the tendency for appetite to normalize while efficacy is maintained over longer term use in most patients.

• Fatigue

Reported by some patients when beginning treatment, lasting days to weeks.

Rarer adverse effects requiring prompt attention:

• Gallbladder disease

Increased risk of cholecystitis and cholelithiasis. Severe abdominal pain warrants evaluation.

• Acute pancreatitis

Rare cases reported. Patients should seek care for severe persistent abdominal pain.

• Kidney injury

Monitor renal function. Discontinue if acute impairment noted, recommends the FDA.(13)

• Hypoglycemia

This is only a risk in patients also taking insulin or sulfonylureas.(14)

• Hypersensitivity

Allergic reactions in rare cases.

• Suicidal ideation

Warn patients to alert health care providers about new or worsening mental health concerns, recommends the FDA. (16)

• Thyroid cancer

It is unknown if GLP-1s increase risk.

Providers should carefully screen candidates, counsel them on risks, and monitor for adverse events. Discontinue GLP-1 drugs if issues are severe or persistent.

How Costly Are GLP-1 Medications?

Published list prices for GLP-1 drugs range from around $900 to $1300 per month.(15) However, few patients actually pay these amounts. After undisclosed rebates and discounts negotiated by insurers and pharmacy benefit managers, the net cost is estimated to be 50-80% lower, according to analysis covered in The New York Times.(16)

For uninsured patients or those with high-deductible plans, out-of-pocket costs likely still approach the full list price.(17) Medicare enrollees also pay more since current federal law prohibits Medicare from covering medications for weight loss.

Manufacturing costs for GLP-1s are relatively low, but rebates, fees and other system factors influence pricing.(18) Increasing market competition may eventually help lower prices. Making the medications more affordable could greatly increase appropriate access for patients who medically qualify.

Is Insurance Coverage Available For GLP-1 Drugs?

Currently only about 25% of commercial health plans and employers cover GLP-1 drugs specifically prescribed for weight loss and obesity, according to a survey by Accolade cited in healthcaredive.com.(19) This is projected to reach 40% by 2024.

Most cite the high costs and unclear long-term cost-effectiveness for insurers as reasons for denying coverage. However, new research demonstrating cardiovascular benefits is putting pressure on payers to cover GLP-1 therapies more broadly, given the clear health benefits beyond just weight loss.

Medicare does not cover weight loss drugs due to an exclusion statute from the early 2000s. Some advocates say this should be revisited given modern medical understanding of obesity as a disease.

Until further changes, access will remain very limited for those without discretionary income or whose insurance excludes weight loss treatments. Increasing evidence-based coverage policies could greatly expand appropriate access.

How Do Prescribers Choose Between Different GLP-1 Options?

There is a growing list of FDA-approved GLP-1 receptor agonist medications, with more in development. This gives prescribers multiple options, but selecting the right choice for each patient can be complex.

Factors that influence prescribing decisions include:

• Dosing schedule

Some GLP-1 drugs only require one dose per week (semaglutide) while others need daily dosing (liraglutide).

• Weight loss efficacy

Average amounts of weight loss vary between specific GLP-1s based on clinical trial data. Newer options appear more potent.(20)

• Cardiovascular data

Only certain GLP-1s have proven cardiovascular benefits for at-risk diabetics thus far. These may be preferentially prescribed for such patients.

• Delivery method

Semaglutide is available as both a subcutaneous injection pen and oral pill, increasing choice.(21)

• Duration of Action

Shorter or longer activity profiles help match the drug to the patient’s needs.

• Insurance coverage

Formulary restrictions may mandate the use of one GLP-1over another.(22)

• Cost

Wholesale acquisition costs differ between brand nameGLP-1 drugs. Generics and biosimilars are also coming.(23)

• Patient preference

Frequency, delivery method, cost, lifestyle and other factors impact patient choice and likelihood of adherence.

While selection from among the available GLP-1 agonists is nuanced, the shared class benefits make any evidence-based option a reasonable choice if no drug-specific factors dictate otherwise.

Are GLP-1 Drugs Just Short-Term Fixes For Weight Loss?

GLP-1 receptor agonists alone do not represent cures for obesity.(24) The weight lowering effects appear to persist only as long as the medication is taken consistently and at the full therapeutic dose. Stopping treatment generally leads to weight regain.(25)

However, obesity is a chronic, relapsing disease. Some advocates argue GLP-1 drugs, when combined with lifestyle interventions, should be viewed as effective long-term medical management similar to medications for other lifelong conditions like diabetes or hypertension.

Maintaining initial weight loss will realistically require continued access to GLP-1 therapies for most patients, as well as ongoing adjunctive diet, exercise and behavioral modifications.(26) Sustained success necessitates ongoing, comprehensive treatment over the long term, not just short-term fixes.

While remission can occur in rare cases, the disease mechanisms underlying obesity often persist.(27) Framing GLP-1 medications as acute treatment risks undervaluing their potential for long-term medical management of a serious metabolic disease.

What Lifestyle Changes Optimize GLP-1 Treatment?

Most experts recommend combining GLP-1 drugs with improved nutrition, increased physical activity, reduced sedentary behavior, stress management and other healthy habit changes. Comprehensive lifestyle modification enhances GLP-1 efficacy and helps sustain results long-term. Health care providers often prescribe coaching to support necessary behavior changes.

What Happens When Patients Stop Taking GLP-1 Medications?

Discontinuing GLP-1 drug treatment leads to weight regain in a majority of patients.(28) Yet many stop using the medications even after losing significant weight. Surveys suggest that only 25-35% remain adherent at one year after starting treatment.(29)

Why do patients stop taking GLP-1s?

• Side effects

Gastrointestinal issues like nausea, constipation and diarrhea lead some to discontinue.(30)

• Cost

Out-of-pocket expenses make GLP-1 drugs unaffordable over the long run for some patients.

• Loss of effectiveness

GLP-1s appear less effective after ~2 years as the body adapts. Higher doses may be required to maintain effects.(31)

• Goals achieved

Some feel satisfied with weight lost and stop treatment, but regain is likely.(32)

• Behavioral factors

Inconsistent use, missing doses, injection anxieties and other behavioral hurdles impact adherence.(33)

• Coaching lapses

Lack of ongoing coaching on lifestyle modification contributes to recidivism.

Multifactorial support addressing side effects, costs, adherence barriers and lifestyle change is key to sustaining success long-term. Borrowing lessons from fields like addiction medicine may further optimize approaches for supporting maintenance after initial GLP-1-enabled weight loss, suggests a perspective in Nature Reviews Endocrinology.(34)

Can GLP-1 Medications Improve Cardiovascular Health?

Emerging but limited evidence suggests GLP-1 receptor agonists may reduce risk of major adverse cardiovascular events like stroke, myocardial infarction and cardiac death.

The most robust data comes from Novo Nordisk’s large cardiovascular outcomes trial SELECT, which found semaglutide reduced CV event risk by 26% in high risk type 2 diabetics. Other GLP-1s have also demonstrated heart benefits in diabetics, though to varying degrees.(35) It’s unknown whether positive cardiovascular effects extend to non-diabetics using GLP-1 drugs solely for weight loss, says a perspective published in JAMA Cardiology.(36)

Research points to potentially beneficial mechanisms that appear independent of weight loss alone. Experts hypothesize GLP-1s’ cardiovascular protection stems from direct effects on inflammation, atherosclerosis progression, cardiac remodeling, hypertension and other pathways.(37) But understanding remains incomplete.

If future research cements GLP-1s’ cardiovascular advantages, it would further strengthen the rationale for their use in at-risk patients beyond just encouraging weight reduction.(38) However, outcome trials in non-diabetic people taking GLP-1 drugs for obesity alone are still needed to clarify precise cardiovascular implications in this context.(39)

How Do GLP-1 Drugs Affect Type 2 Diabetes?

Alongside promoting weight loss, GLP-1 receptor agonists deliver key therapeutic benefits for patients with type 2 diabetes. They improve glycemic control through several mechanisms:

• Increasing insulin secretion from pancreatic beta cells in a glucose-dependent manner
• Suppressing inappropriately high glucagon secretion
• Slowing gastric emptying which stabilizes blood glucose excursions
• Supporting beta cell proliferation to help preserve insulin production over time
• Reducing appetite and calorie intake leading to weight loss

In patients with type 2 diabetes not meeting glycemic targets on other oral medications like metformin, adding a GLP-1 drug allows many to achieve hemoglobin A1c reductions of 0.7-1.6%.(40) This significantly improves diabetes control and lowers risks of long-term vascular complications.

However, GLP-1s pose some unique risks for diabetics. Costs are higher than many older agents. They require injection or oral ingestion. Gastrointestinal side effects may be limiting. Education on mitigating hypoglycemia from concurrent medications is imperative.(41)

Still, the efficacy of GLP-1 drugs makes them important options in the type 2 diabetes treatment paradigm, either alone or in combination with other classes like SGLT-2 inhibitors.

How are Digital Health Companies Tackling this Market?

A new wave of digital health companies aim to make prescription weight loss more accessible and effective by providing medications, coupled with virtual lifestyle coaching:

• Noom offers Noom Med, prescribing GLP-1s along with its health tracking app.
• WeightWatchers (WW) acquired telehealth platform Sequence to pair medication and coaching.
• Ro launched an integrated program that ships GLP-1 drugs to patients alongside personalized support.
• Omada, Lark and Found have also created combination medication and behavior change offerings.

By addressing biological and behavioral factors together, these companies seek to offer affordable, comprehensive weight management.

Could GLP-1 Medications Aid Smoking or Opioid Addiction Recovery?

Early research hints at intriguing potential for GLP-1 drugs to aid recovery from addictions beyond food cravings. Small studies suggest semaglutide may reduce cravings and withdrawal symptoms in people quitting smoking or recovering from opioid use disorder.

GLP-1 receptors are present in multiple brain regions implicated in addictive behaviors. Activating pathways involved in appetite may translate to diminishing other compulsive drives like substance cravings. However, this research is still in early stages.

Larger, rigorous human trials are needed to determine if GLP-1 therapies could become viable off-label treatments for nicotine, alcohol, opioid or other addictions. Currently, prescribing for addiction is neither evidence-based nor FDA-approved. If future research demonstrates efficacy, it would open a new frontier beyond metabolic disease. But effectiveness remains speculative pending further data.

Could Widespread GLP-1 Use Change How Society Functions?

The most transformative potential impact of GLP-1 receptor agonist medications is how they could reshape industries, markets, and social norms if adoption became extremely widespread. Some analysts speculate on seismic societal shifts occurring.

Broader population-level metabolic improvements could influence:

• Food industry

Greatly reduced food intake as appetite declines may restructure agriculture, manufacturing, restaurants, grocery stores and more.

• Healthcare

Lower prevalence of obesity should translate to reduced needs for associated care long-term, altering services required.

• Economy

Increased productivity from improved health may support economic growth. But costs born by public and private payers will be substantial near-term.

• Commerce

Demand could shift away from obesity-promoting products to new healthier alternatives, creating opportunities across sectors.

However, the extent of societal-level change depends on too many variables to predict confidently. Thus far GLP-1 utilization remains limited largely to higher income populations.
While already impacting some industries like soft drinks and pharmacies, broader ripples throughout society are very possible.

Conclusion

In just a few years, GLP-1 receptor agonists have risen from novel medications to the most promising option for enabling meaningful weight reduction in appropriate patients. However, their swift rise has outpaced insights into long-term impacts on individuals and society.

While not an obesity cure, optimally deployed GLP-1s represent a substantial advance for managing weight-related and metabolic disease through biochemical strategies. But questions remain regarding long-term safety, judicious prescribing, insurance access, costs, patient adherence and support models. Responsible practices and policies have yet to catch up to enthusiasm.

GLP-1 therapies are not for everyone. Diet, activity and behavioral change remain cornerstones of care. Still, amid complexity, the immense benefits to millions living with obesity are clear. This is only the beginning of learning how to most effectively harness the promise of GLP-1 drugs.

See Also

U.S. Food and Drug Administration 
reporting of medications containing semaglutide marketed for Type 2 diabetes or weight loss

Bariatric Surgery

Mechanisms Controlling Glucose-Induced GLP-1 Secretion in Human Small Intestine

Rybelsus

Exenatide

Bydureon

Dulaglutide

Sources