Key Takeaways

  • 3+ year data from STEP and SUSTAIN extensions shows a stable safety profile — no new safety signals have emerged with prolonged use
  • Muscle mass loss is the most significant long-term concern — preventable with resistance training and adequate protein
  • Gallbladder issues affect ~2% of long-term users — related to rapid weight loss rather than the drug itself
  • Thyroid cancer risk in humans remains unproven — rodent data has not translated to human incidence after 9+ years of use
  • Weight regain after stopping is the rule, not the exception — STEP 4 showed ~67% regain within 1 year of discontinuation

Medical disclaimer: This article reviews published clinical research. It is not a substitute for medical advice. Discuss long-term medication decisions with your doctor.

The Long-Term Data We Have

Semaglutide has been available since 2017 (Ozempic for diabetes) and 2021 (Wegovy for obesity). The key long-term datasets include:

  • SUSTAIN extensions (diabetes): Up to 5 years of follow-up data
  • STEP extension studies (obesity): 2–3 year continuation data from the original STEP trials
  • SELECT trial: 4+ years of cardiovascular outcomes data in overweight/obese patients
  • Real-world pharmacovigilance: Post-marketing safety data from millions of prescriptions globally since 2017

The reassuring headline: no new, unexpected safety signals have emerged with longer use. The side effects seen at year 3 are the same ones seen at month 3 — they don't appear to worsen or accumulate over time. But several concerns deserve careful examination.

Muscle Mass Loss: The Most Important Long-Term Concern

This is the side effect that should concern long-term users the most, because it's subtle, progressive, and has lasting metabolic consequences.

What the Data Shows

  • In STEP 1, participants lost an average of 14.9% body weight — but ~39% of this was lean mass (muscle + water + bone mineral)
  • Extension data shows lean mass loss continues proportionally with ongoing weight loss
  • Once lean mass is lost, it's significantly harder to rebuild — especially in older adults

Why It Matters

  • Reduced basal metabolic rate: Less muscle = fewer calories burned at rest = easier weight regain if you stop medication
  • Functional decline: Muscle weakness affects mobility, balance, and daily activities — particularly concerning for patients over 50
  • Sarcopenic obesity: Losing muscle while retaining (or regaining) fat creates a metabolically harmful body composition
  • "Skinny fat" outcomes: Some patients reach a lower weight but with a higher body fat percentage than before treatment

Mitigation Strategies

  • Resistance training 2–3x/week: This is the single most effective intervention. Studies show resistance-trained patients on GLP-1s preserve significantly more muscle than those who don't exercise
  • High protein intake: 1.2–1.6g per kg body weight daily. For a 75kg person: 90–120g protein/day. Malaysian sources: chicken, fish, eggs, tempeh, tofu, whey protein
  • Don't excessively restrict calories: Let the medication reduce your appetite naturally. Adding aggressive caloric restriction on top accelerates muscle loss
  • Creatine supplementation: 3–5g daily — well-evidenced for supporting muscle maintenance and strength, safe, and cheap (RM30–50/month)
  • Monitor body composition: Regular DEXA scans or bioimpedance measurements track muscle vs fat changes. Weight alone tells you nothing about composition

For detailed nutritional strategies, see our GLP-1 diet plan for Malaysians.

Bone Density

Weight loss from any cause reduces mechanical loading on bones, which can decrease bone mineral density (BMD). Additionally, if nutritional intake is inadequate, calcium and vitamin D deficiency can accelerate bone loss.

What the Data Shows

  • STEP extension data shows modest reductions in BMD consistent with the degree of weight loss — similar to what's seen after bariatric surgery or diet-induced weight loss
  • No significant increase in fracture risk has been observed in semaglutide trials to date
  • The SELECT trial (4+ years) did not identify fractures as a safety concern

Who Should Be Concerned

  • Post-menopausal women (already at elevated osteoporosis risk)
  • Patients over 65
  • Anyone with pre-existing osteopenia or osteoporosis
  • Patients with very low vitamin D levels (common in Malaysia despite the sunshine — many Malaysians are deficient due to indoor lifestyles and limited dairy intake)

Mitigation

  • Weight-bearing and resistance exercise (protects both muscle AND bone)
  • Adequate calcium intake (1,000–1,200mg/day)
  • Vitamin D supplementation if deficient (1,000–2,000 IU daily is common)
  • Baseline and periodic DEXA scans for at-risk patients

Gallbladder Issues

Gallbladder-related problems are a genuine long-term concern with semaglutide, though they're primarily driven by rapid weight loss rather than the drug's direct effects.

The Mechanism

Rapid fat mobilisation during weight loss increases cholesterol concentration in bile. This promotes gallstone formation. Semaglutide may also slow gallbladder motility, allowing stones to form more easily.

Long-Term Incidence

  • STEP trials: Cholelithiasis (gallstones) in 1.6% of semaglutide patients vs 0.7% placebo
  • SELECT trial (4 years): Gallbladder-related events remained elevated but manageable
  • Cholecystectomy (gallbladder removal): Required in a small subset of patients

Risk Factors

  • Female sex (gallstones are more common in women)
  • Rapid weight loss (>1.5kg/week sustained)
  • Pre-existing gallstones or biliary sludge
  • Family history of gallbladder disease

What to Watch For

  • Sudden, intense upper right abdominal pain — especially after fatty meals
  • Pain radiating to the back or right shoulder
  • Nausea and vomiting with abdominal pain (different from the usual GLP-1 nausea)
  • Jaundice (yellow skin/eyes)

Action: If you experience these symptoms, seek emergency medical care. Don't assume it's normal GLP-1 GI effects.

Pancreatitis

What the Long-Term Data Shows

  • Acute pancreatitis remains a rare event: <0.5% across all semaglutide trials
  • No evidence of increased chronic pancreatitis with prolonged use
  • The rate hasn't increased with longer treatment duration — if anything, most cases occur in the first year
  • Real-world pharmacovigilance data from 9+ years of semaglutide use has not elevated the concern beyond clinical trial levels

Practical Advice

  • Baseline lipase/amylase levels are useful for comparison if symptoms develop
  • Avoid excessive alcohol consumption (an independent pancreatitis risk factor)
  • Severe, persistent abdominal pain radiating to the back = emergency department, always
  • If pancreatitis is confirmed, semaglutide should be permanently discontinued

Thyroid Cancer: Separating Rodent Data from Human Reality

The thyroid C-cell tumour warning is one of the most anxiety-inducing aspects of GLP-1 therapy. Let's look at this objectively:

The Rodent Data

  • In rats and mice, semaglutide (and other GLP-1 agonists) caused thyroid C-cell hyperplasia and tumours (medullary thyroid carcinoma)
  • These occurred at doses many times higher than human therapeutic levels
  • Rodents have significantly more GLP-1 receptors on thyroid C-cells than humans do

The Human Data

  • No increase in medullary thyroid carcinoma has been detected in human clinical trials or post-marketing surveillance
  • The SELECT trial (4+ years, 17,000+ patients) did not identify thyroid cancer as a safety signal
  • Population-level studies of GLP-1 users have not found elevated thyroid cancer rates
  • The mechanism (calcitonin elevation) seen in rodents has not been consistently observed in humans on GLP-1 therapy

The Bottom Line on Thyroid Risk

The boxed warning exists because regulators cannot definitively rule out a risk based on the rodent data. It's a precautionary measure, not evidence of a demonstrated human risk. However:

  • Semaglutide remains contraindicated in patients with personal/family history of medullary thyroid carcinoma or MEN 2 syndrome — this is non-negotiable
  • Routine thyroid monitoring (TSH, clinical examination) during long-term use is reasonable
  • Report new neck lumps, hoarseness, or difficulty swallowing to your doctor

What Happens When You Stop: The Weight Regain Problem

This is the most practically important long-term consideration for most patients.

The STEP 4 Evidence

  • Patients who stopped semaglutide after 20 weeks of treatment regained approximately 67% of lost weight within one year
  • Cardiometabolic improvements (blood pressure, lipids, blood sugar) also partially reversed
  • Weight regain was not due to lack of willpower — it reflects the body's biological drive to return to its previous weight "set point"

STEP 5 Extension (2 Years Continuous)

  • Patients who continued semaglutide for 2 full years maintained their weight loss
  • This confirms semaglutide works as chronic therapy, not a "course" of treatment

Implications for Malaysian Patients

The financial reality of long-term therapy needs honest discussion:

  • Ozempic at maintenance: ~RM1,200–1,500/month × 12 = RM14,400–18,000/year indefinitely
  • Potential cost-saving strategies:
    • Maintain on a lower dose (some patients sustain weight loss at 0.5mg rather than 1mg)
    • Switch to oral semaglutide (Rybelsus) for maintenance (RM600–900/month)
    • Intermittent dosing (e.g., every 10 days instead of weekly) — limited evidence but some clinicians explore this
  • The lifestyle investment matters: Patients who build strong exercise and dietary habits while on medication have better outcomes if they eventually stop or reduce dosing

Emerging Long-Term Concerns Being Studied

Gastroparesis (Stomach Paralysis)

  • Reports of persistent delayed gastric emptying even after stopping GLP-1s
  • Most cases are mild and resolve, but severe gastroparesis has been reported in rare cases
  • Long-term studies are ongoing to determine if prolonged GLP-1 use can cause permanent gastroparesis

Mental Health Effects

  • Some patients report changes in mood, anxiety, or depression on GLP-1s
  • The EMA (European Medicines Agency) investigated suicidal ideation reports in 2023 and found no causal link
  • However, any significant mood change while on semaglutide should be reported to your doctor

Intestinal Obstruction

  • Rare reports of ileus (bowel obstruction) — primarily in post-surgical patients or those with pre-existing GI conditions
  • Slowed motility from GLP-1s may contribute in susceptible individuals

Long-Term Monitoring Recommendations

If you're on semaglutide for the long haul, here's what your monitoring should include:

Test/Assessment Frequency Purpose
Weight + body composition Monthly → Quarterly Track fat vs muscle changes
Blood glucose / HbA1c Every 6 months Metabolic health monitoring
Lipid panel Every 6–12 months Cardiovascular risk assessment
Liver function (ALT, AST) Every 6–12 months Hepatic health (NAFLD improvement tracking)
Kidney function (creatinine, eGFR) Every 6–12 months Renal safety
Thyroid (TSH) Annually Thyroid monitoring
Vitamin D, B12, iron Annually Nutritional deficiency screening
DEXA scan (if at risk) Every 1–2 years Bone density + body composition

The Research Horizon

Several ongoing studies will provide crucial long-term data in the coming years:

  • STEP extension studies: 4–5 year follow-up data expected by 2026–2027
  • SELECT long-term follow-up: Continued cardiovascular outcomes monitoring
  • FLOW trial: Kidney outcomes with semaglutide — already showing renoprotective effects
  • Real-world registries: Nordic countries (Denmark, Sweden) with comprehensive health registries are tracking GLP-1 outcomes at population scale

Frequently Asked Questions

Is it safe to take semaglutide for 5+ years?

Based on available data (SUSTAIN extensions, SELECT trial, post-marketing surveillance), the safety profile appears stable through 4–5 years. No evidence suggests risk increases with duration. However, true long-term data (10+ years) doesn't exist yet for semaglutide specifically.

Does semaglutide cause cancer?

There is no evidence that semaglutide causes cancer in humans. The thyroid concern is based on rodent data at supraphysiological doses and has not been replicated in humans. Large-scale studies have not identified increased cancer risk.

Can I take semaglutide forever?

Potentially yes, similar to how patients take blood pressure or cholesterol medication indefinitely. The decision should be reviewed periodically with your doctor based on ongoing risk-benefit assessment.

What's the longest someone has been on semaglutide?

The earliest clinical trial participants have been on semaglutide since 2013–2014 (Phase 2/3 trials), giving us approximately 10–12 years of data in select individuals. Broader population use dates to 2017 (Ozempic launch).

The Bottom Line

The long-term safety data for semaglutide is reassuring — and getting more reassuring with each passing year of accumulated evidence. No new, unexpected dangers have emerged. The major concerns (muscle loss, bone density, gallbladder events) are predictable, related to the weight loss process itself, and largely mitigable with proper lifestyle measures.

The biggest practical long-term issue isn't safety — it's sustainability. Semaglutide works while you take it. Stopping it means weight regain for most people. This makes it a chronic therapy commitment with significant ongoing costs.

For Malaysian patients on long-term semaglutide: prioritise resistance training, maintain high protein intake, stay hydrated, get regular blood work, and have an honest ongoing conversation with your doctor about your treatment plan. The medication handles the appetite; you handle the lifestyle.