What Is Semaglutide Good For?

FDA-Approved Indications

Semaglutide has two primary FDA-approved uses, each supported by extensive clinical trial data involving tens of thousands of participants. These approvals represent the culmination of rigorous phase 3 clinical development programs that demonstrated both efficacy and safety across diverse patient populations.

Type 2 Diabetes Management

Semaglutide received FDA approval for type 2 diabetes in December 2017 (injectable Ozempic) and September 2019 (oral Rybelsus), establishing it as a cornerstone therapy for glycemic control. The approval was based on the SUSTAIN clinical trial program, which enrolled over 8,000 participants across 10 major trials comparing semaglutide to placebo, other GLP-1 receptor agonists, SGLT2 inhibitors, and insulin.

Glycemic Control

The primary benefit of semaglutide in diabetes is its robust glucose-lowering effect. Across the SUSTAIN trials, semaglutide consistently reduced HbA1c by 1.5-1.8% from baseline, with many participants achieving HbA1c levels below 7% (the general target for diabetes management). In SUSTAIN-1, which compared semaglutide to placebo, 72% of participants on 1 mg weekly achieved HbA1c below 7%, compared to 25% on placebo. The glucose-lowering effect appears within the first few weeks of treatment and reaches maximum effect by 12-16 weeks.

What distinguishes semaglutide from many other diabetes medications is its glucose-dependent mechanism of action. It stimulates insulin secretion only when blood glucose is elevated, substantially reducing the risk of hypoglycemia compared to sulfonylureas or insulin. In the SUSTAIN trials, severe hypoglycemia was rare (occurring in less than 1% of participants) and primarily occurred in those also taking insulin or sulfonylureas. This safety profile makes semaglutide particularly valuable for patients at high risk of hypoglycemia, including older adults and those with hypoglycemia unawareness.

Weight Management in Diabetes

Unlike many diabetes medications that cause weight gain (insulin, sulfonylureas, thiazolidinediones), semaglutide promotes weight loss. In the SUSTAIN trials conducted at diabetes doses (0.5-1 mg weekly), participants lost an average of 4-6 kg over 30-56 weeks. This weight loss is clinically meaningful because excess weight is a major driver of insulin resistance and diabetes progression. The weight loss with semaglutide appears to be primarily fat mass, with preservation of lean muscle mass better than with caloric restriction alone.

SUSTAIN-8 directly compared semaglutide 1 mg to canagliflozin 300 mg (an SGLT2 inhibitor also associated with weight loss) in 788 participants with inadequately controlled type 2 diabetes. Semaglutide produced superior HbA1c reduction (1.5% vs 1.0%) and greater weight loss (5.3 kg vs 4.2 kg). These results established semaglutide as one of the most effective glucose-lowering agents available, particularly for patients with obesity.

Cardiovascular Benefits in Diabetes

The SUSTAIN-6 cardiovascular outcomes trial enrolled 3,297 participants with type 2 diabetes at high cardiovascular risk and followed them for 2 years. Semaglutide reduced the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 26% compared to placebo (6.6% vs 8.9%, HR 0.74, p=0.02). This benefit was driven primarily by reductions in non-fatal stroke (39% reduction) and non-fatal myocardial infarction (26% reduction), though these individual components did not reach statistical significance.

Importantly, semaglutide also reduced the risk of new or worsening nephropathy by 36%, suggesting kidney protective effects beyond glucose control. The mechanisms underlying these cardiovascular and renal benefits likely involve multiple pathways including weight loss, blood pressure reduction, improvements in lipid profiles, and direct effects on endothelial function and inflammation. These findings have positioned semaglutide as a preferred agent for patients with diabetes and established cardiovascular disease or high cardiovascular risk.

Blood Pressure Reduction

Across the SUSTAIN trials, semaglutide consistently reduced systolic blood pressure by 3-5 mmHg, an effect that appears independent of weight loss. In SUSTAIN-6, the blood pressure reduction was evident within weeks of treatment initiation, before significant weight loss occurred. The mechanism remains incompletely understood but may involve natriuresis (increased sodium excretion), improved endothelial function, reduced sympathetic nervous system activity, and direct effects on vascular smooth muscle.

This blood pressure reduction is clinically meaningful. Meta-analyses suggest that each 5 mmHg reduction in systolic blood pressure reduces cardiovascular event risk by approximately 10%. For patients with diabetes, who often have hypertension as a comorbidity, the dual benefit of glucose control and blood pressure reduction makes semaglutide particularly attractive. Some patients may be able to reduce or discontinue antihypertensive medications after starting semaglutide, though this should only be done under medical supervision.

Lipid Profile Improvements

Semaglutide produces modest but consistent improvements in lipid profiles. Total cholesterol typically decreases by 2-4%, LDL cholesterol by 3-5%, and triglycerides by 10-15%. HDL cholesterol may increase slightly or remain unchanged. These effects are smaller than those achieved with statins but contribute to overall cardiovascular risk reduction. The lipid improvements appear to result from both weight loss and direct effects on hepatic lipid metabolism.

Beta Cell Function Preservation

Preclinical studies suggest GLP-1 receptor agonists may preserve or even enhance pancreatic beta cell function, potentially slowing diabetes progression. In animal models, GLP-1 agonists increase beta cell mass through enhanced proliferation and reduced apoptosis. Human studies using measures of beta cell function (HOMA-B, C-peptide levels) show improvements with semaglutide treatment, though whether this translates to long-term preservation of beta cell function remains uncertain. Nonetheless, the possibility that semaglutide might slow diabetes progression, rather than simply treating symptoms, is an exciting prospect.

Chronic Weight Management

In June 2021, semaglutide received FDA approval for chronic weight management at a higher dose (2.4 mg weekly, marketed as Wegovy). This approval was based on the STEP (Semaglutide Treatment Effect in People with obesity) clinical trial program, which enrolled over 4,500 participants and demonstrated unprecedented weight loss for a pharmaceutical intervention.

Substantial Weight Loss

The STEP-1 trial enrolled 1,961 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity, but without diabetes. Participants received either semaglutide 2.4 mg weekly or placebo, both combined with lifestyle intervention (reduced-calorie diet and increased physical activity). After 68 weeks, the semaglutide group lost an average of 14.9% of body weight compared to 2.4% with placebo—a difference of 12.5 percentage points.

Even more impressive, 86% of semaglutide participants lost at least 5% of body weight (vs 32% placebo), 69% lost at least 10% (vs 12% placebo), and 50% lost at least 15% (vs 5% placebo). Nearly one-third (32%) of semaglutide participants lost 20% or more of their body weight. These results approach those typically seen with bariatric surgery, previously considered the gold standard for substantial, sustained weight loss.

The weight loss trajectory follows a predictable pattern. Weight loss is most rapid during the first 20 weeks of treatment, averaging approximately 0.5-1% of body weight per week. The rate of loss gradually slows but continues through week 60, after which weight typically stabilizes. Individual variation is substantial—some people lose 25-30% of body weight while others lose only 5-10%. Factors associated with greater weight loss include higher baseline BMI, younger age, and better adherence to lifestyle modifications.

Body Composition Changes

DEXA scan analyses from the STEP trials show that approximately 75% of weight lost with semaglutide is fat mass, with 25% being lean mass (primarily muscle). This ratio is actually favorable compared to weight loss through caloric restriction alone, which typically results in 60-70% fat loss and 30-40% lean mass loss. The preservation of lean mass with semaglutide may result from its effects on protein metabolism and the fact that appetite suppression allows people to maintain adequate protein intake while reducing overall calories.

Visceral adipose tissue (the metabolically harmful fat surrounding internal organs) appears to be preferentially reduced with semaglutide. MRI studies show reductions in visceral fat of 30-40%, greater than the reduction in subcutaneous fat. This preferential loss of visceral fat likely contributes to the metabolic improvements seen with semaglutide, as visceral fat is strongly associated with insulin resistance, inflammation, and cardiovascular risk.

Cardiometabolic Risk Factor Improvements

The weight loss achieved with semaglutide translates into improvements across multiple cardiometabolic risk factors. In STEP-1, semaglutide reduced waist circumference by 9.4 cm (vs 4.1 cm placebo), systolic blood pressure by 6.2 mmHg (vs 1.1 mmHg placebo), and improved lipid profiles with reductions in triglycerides and increases in HDL cholesterol. Inflammatory markers including C-reactive protein decreased by approximately 40%.

For participants with prediabetes at baseline, semaglutide reduced progression to type 2 diabetes by 61% over 68 weeks. Among those with prediabetes, 84% reverted to normoglycemia with semaglutide compared to 48% with placebo. These findings suggest semaglutide may be valuable for diabetes prevention in high-risk individuals, though it is not currently approved for this indication.

Quality of Life Improvements

Beyond objective health measures, semaglutide significantly improves quality of life. In STEP-1, participants reported improvements in physical functioning (ability to perform daily activities, exercise tolerance), reductions in bodily pain, and improvements in general health perceptions. Mental health measures also improved, with reductions in depression and anxiety symptoms. These quality of life improvements appear to result from both the physical effects of weight loss (reduced joint pain, improved mobility, better sleep) and psychological effects (improved body image, increased self-efficacy).

Weight Loss Maintenance

The STEP-4 trial specifically examined weight loss maintenance. Participants first received open-label semaglutide for 20 weeks, losing an average of 10.6% of body weight. They were then randomized to continue semaglutide or switch to placebo for an additional 48 weeks. Those continuing semaglutide lost an additional 7.9% of body weight (total 17.4% from baseline), while those switched to placebo regained 6.9% (net loss of only 5.6% from baseline).

These results demonstrate that semaglutide's weight loss benefits are maintained with continued treatment but largely disappear when treatment is stopped. This has led to discussions about whether obesity should be viewed as a chronic disease requiring long-term pharmacotherapy, similar to hypertension or diabetes. The alternative view is that semaglutide should be used as a tool to achieve weight loss, after which intensive lifestyle modification can maintain the loss. Real-world data will be needed to determine optimal treatment duration and strategies for maintaining weight loss after semaglutide discontinuation.

Cardiovascular Disease Prevention

The SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) trial represents a paradigm shift in how we think about obesity medications. This trial enrolled 17,604 adults aged 45 or older with established cardiovascular disease (prior myocardial infarction, stroke, or peripheral artery disease) and overweight or obesity (BMI ≥27), but without diabetes. Participants were randomized to semaglutide 2.4 mg weekly or placebo and followed for up to 4 years.

Major Adverse Cardiovascular Events

Semaglutide reduced the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 20% (HR 0.80, 95% CI 0.72-0.90, p<0.001). The absolute risk reduction was 1.5 percentage points (8.0% vs 9.5%), meaning 67 people would need to be treated for approximately 3 years to prevent one major cardiovascular event. This benefit emerged early, with separation of the survival curves evident by 6 months and continuing to diverge throughout the trial.

The cardiovascular benefit appeared consistent across subgroups defined by age, sex, race, baseline BMI, and type of prior cardiovascular event. Importantly, the benefit was evident even in participants who lost minimal weight, suggesting mechanisms beyond weight loss contribute to cardiovascular protection. These might include anti-inflammatory effects, improvements in endothelial function, blood pressure reduction, and direct effects on atherosclerotic plaque stability.

Heart Failure Outcomes

SELECT also examined heart failure outcomes, finding that semaglutide reduced heart failure events (hospitalization or urgent medical visits for heart failure) by 18%. This benefit was particularly pronounced in participants with reduced ejection fraction heart failure. The mechanism may involve reductions in cardiac workload due to weight loss, improvements in myocardial metabolism, reductions in inflammation and fibrosis, and favorable effects on neurohormonal activation.

These findings have sparked interest in semaglutide as a treatment for heart failure itself, not just prevention of cardiovascular events. The STEP-HFpEF trial is currently examining whether semaglutide improves symptoms and functional capacity in patients with heart failure with preserved ejection fraction (HFpEF), a condition strongly associated with obesity for which few effective treatments exist.

Implications for Cardiovascular Prevention

The SELECT results have profound implications for cardiovascular disease prevention. They suggest that semaglutide should be considered not just as an obesity medication but as a cardiovascular protective agent for people with established cardiovascular disease and overweight or obesity. This represents a new paradigm—using a medication approved for weight management as a strategy to prevent recurrent cardiovascular events.

Questions remain about whether semaglutide provides cardiovascular benefits in people without established cardiovascular disease (primary prevention) and whether the benefits extend to people with normal weight. Ongoing trials are examining these questions. Additionally, cost-effectiveness analyses will be crucial in determining how widely semaglutide should be used for cardiovascular prevention, given its high cost.

Investigational and Off-Label Uses

Beyond its approved indications, semaglutide is being studied for several other conditions. While these uses are not FDA-approved, they represent areas of active research interest.

Non-Alcoholic Fatty Liver Disease (NAFLD/NASH)

Non-alcoholic fatty liver disease affects approximately 25% of adults globally and can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver failure. Weight loss is the primary treatment, but achieving sufficient weight loss through lifestyle modification alone is challenging. Several studies have examined whether semaglutide can improve liver outcomes.

A phase 2 trial in 320 participants with biopsy-confirmed NASH found that semaglutide 0.4 mg daily (a higher dose than used for diabetes but lower than for weight management) led to NASH resolution without worsening fibrosis in 59% of participants compared to 17% with placebo. Liver fat content decreased by approximately 50%, and markers of liver inflammation and injury improved significantly. Importantly, improvements in liver histology correlated with the amount of weight lost, suggesting weight loss is the primary mechanism.

Phase 3 trials are now underway to determine whether semaglutide can prevent progression to cirrhosis or reduce liver-related complications in patients with NASH. If successful, semaglutide could become the first FDA-approved pharmacotherapy for NASH, a condition for which no approved treatments currently exist. The challenge will be demonstrating that improvements in liver histology translate into reduced clinical outcomes (cirrhosis, liver failure, hepatocellular carcinoma) over the long term.

Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome affects 5-10% of women of reproductive age and is characterized by irregular menstrual cycles, hyperandrogenism, and often insulin resistance and obesity. Weight loss improves both metabolic and reproductive outcomes in PCOS, but achieving sufficient weight loss is challenging. Small studies suggest semaglutide may be beneficial.

A pilot study in 27 women with PCOS and obesity found that semaglutide 1 mg weekly for 24 weeks led to average weight loss of 7.3 kg, restoration of regular menstrual cycles in 67% of women with oligomenorrhea, and improvements in androgen levels and insulin sensitivity. Larger randomized trials are needed to confirm these findings and determine optimal dosing and treatment duration.

An important consideration is that semaglutide is contraindicated during pregnancy due to potential teratogenic effects observed in animal studies. Women of reproductive age using semaglutide for PCOS must use effective contraception. Additionally, because semaglutide can restore ovulation in women with PCOS, there is a risk of unintended pregnancy if contraception is not used consistently.

Obstructive Sleep Apnea

Obesity is the primary risk factor for obstructive sleep apnea (OSA), and weight loss is an effective treatment. The STEP trials included assessments of sleep apnea symptoms and found that semaglutide significantly improved sleep quality and reduced daytime sleepiness. A dedicated trial (STEP-OSA) is examining whether semaglutide can reduce the apnea-hypopnea index (the primary measure of OSA severity) and potentially allow some patients to discontinue CPAP therapy.

Preliminary results suggest semaglutide reduces the apnea-hypopnea index by approximately 50% in patients with moderate to severe OSA, with many participants achieving resolution of OSA (AHI <5 events per hour). These improvements correlate with weight loss and reductions in neck circumference. If confirmed in larger trials, semaglutide could become an important treatment option for OSA, potentially reducing the need for CPAP therapy in some patients.

Chronic Kidney Disease

The FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial is examining whether semaglutide can slow progression of chronic kidney disease in patients with type 2 diabetes and kidney disease. The trial was stopped early due to overwhelming efficacy, with semaglutide reducing the risk of kidney disease progression by 24%. This benefit appeared to result from multiple mechanisms including improved glycemic control, blood pressure reduction, weight loss, and direct anti-inflammatory and anti-fibrotic effects on the kidney.

These findings suggest semaglutide may join SGLT2 inhibitors and ACE inhibitors/ARBs as cornerstone therapies for diabetic kidney disease. Whether semaglutide provides kidney protection in people without diabetes remains to be determined, though the mechanisms suggest it might. Ongoing trials are examining this question.

Alzheimer's Disease and Cognitive Decline

Emerging evidence suggests GLP-1 receptors in the brain may play roles in neuroprotection, neuroinflammation, and cognitive function. Observational studies have found that people with diabetes treated with GLP-1 agonists have lower rates of dementia compared to those treated with other diabetes medications. This has sparked interest in whether semaglutide might prevent or slow cognitive decline.

The EVOKE trials are examining whether semaglutide can prevent cognitive decline in people at high risk for Alzheimer's disease. These trials will take several years to complete, but if successful, they could open an entirely new therapeutic avenue for neurodegenerative diseases. The mechanism might involve improved cerebral glucose metabolism, reduced neuroinflammation, enhanced clearance of amyloid-beta, and improved vascular health.

Addiction and Substance Use Disorders

Anecdotal reports from patients taking semaglutide for weight loss or diabetes have described reduced cravings for alcohol, tobacco, and other substances. This has led to research interest in whether GLP-1 agonists might be useful for treating addiction. The mechanism may involve GLP-1 receptors in brain reward pathways, particularly the nucleus accumbens and ventral tegmental area.

Preclinical studies in rodents show that GLP-1 agonists reduce alcohol consumption, nicotine self-administration, and cocaine-seeking behavior. Small human studies have found that exenatide (an earlier GLP-1 agonist) reduces alcohol consumption in people with alcohol use disorder. Clinical trials of semaglutide for alcohol use disorder are now underway. If successful, this could represent a novel approach to addiction treatment, though much more research is needed.

Who Benefits Most from Semaglutide?

While semaglutide is effective across diverse populations, certain groups appear to derive particular benefit:

People with Type 2 Diabetes and Obesity

Individuals with both diabetes and obesity represent an ideal population for semaglutide, as it addresses both conditions simultaneously. The combination of glucose lowering, weight loss, and cardiovascular protection makes semaglutide particularly valuable for this group. Many patients can achieve both glycemic targets and meaningful weight loss, potentially allowing reduction or discontinuation of other diabetes medications.

People with Cardiovascular Disease and Obesity

The SELECT trial demonstrated clear cardiovascular benefits in people with established cardiovascular disease and overweight or obesity, even without diabetes. For this population, semaglutide should be considered as part of comprehensive cardiovascular risk reduction, alongside statins, antihypertensives, and antiplatelet agents. The 20% reduction in major cardiovascular events is comparable to the benefit seen with statins in secondary prevention.

People with Obesity and Multiple Comorbidities

Individuals with obesity and multiple weight-related comorbidities (hypertension, dyslipidemia, sleep apnea, NAFLD, osteoarthritis) often see improvements across multiple conditions with semaglutide-induced weight loss. This can lead to reduced medication burden, improved quality of life, and potentially reduced healthcare costs. The challenge is ensuring these individuals have access to semaglutide given its high cost.

People Who Have Failed Lifestyle Modification

Many people with obesity have made repeated attempts at weight loss through diet and exercise but have been unable to achieve or maintain meaningful weight loss. For these individuals, semaglutide can provide the additional support needed to achieve their weight loss goals. The medication doesn't replace lifestyle modification but rather facilitates adherence to reduced-calorie diets by suppressing appetite and enhancing satiety.

Limitations and Considerations

While semaglutide is highly effective, it's important to understand its limitations:

Not Effective for Everyone

Approximately 10-15% of people do not achieve meaningful weight loss (defined as ≥5% of body weight) with semaglutide, even at the maximum dose. The reasons for non-response are not fully understood but may include genetic factors affecting GLP-1 receptor function, differences in gut microbiome composition, or behavioral factors. There are currently no reliable predictors of who will respond well to semaglutide.

Weight Regain After Discontinuation

Most people regain a substantial portion of lost weight when semaglutide is discontinued. The STEP-4 trial showed that participants regained about two-thirds of lost weight within one year of stopping semaglutide. This raises questions about treatment duration—should semaglutide be viewed as a long-term therapy for obesity, similar to how we treat hypertension or diabetes? Or should it be used as a tool to achieve weight loss, after which intensive lifestyle modification maintains the loss?

Cost and Access

The high cost of semaglutide (over $1,000 per month in the United States) limits access for many people who could benefit. Insurance coverage varies widely, with many plans covering Ozempic for diabetes but not Wegovy for weight management. This has led to widespread off-label prescribing of Ozempic for weight loss and a booming market for compounded semaglutide. Addressing cost and access barriers will be crucial for realizing semaglutide's public health potential.

Long-Term Safety Unknown

While semaglutide has been studied for up to 4 years in clinical trials, longer-term safety data are limited. Questions remain about potential risks with decades of use, particularly regarding thyroid cancer (a theoretical concern based on animal studies), pancreatitis, and gallbladder disease. Post-marketing surveillance will be important for detecting rare adverse events that may not have been apparent in clinical trials.