The Trial Exclusion Problem
Pharmaceutical companies design trials to maximize their chances of showing efficacy with acceptable safety. This often means excluding the oldest, frailest patients—the very population clinicians need guidance on.
| Trial | Age Range | Mean Age | 75+ Included? |
|---|---|---|---|
| SELECT (Wegovy CV) | 45-75 | 61.6 years | Excluded by design |
| STEP 1 (Wegovy obesity) | ≥18 | 46 years | Few enrolled |
| SURMOUNT-1 (Zepbound) | ≥18 | 45 years | Few enrolled |
| FLOW (Wegovy kidney) | ≥18 | 66.6 years | Some 75+ included |
| SUSTAIN-6 (Ozempic CV) | ≥50 | 64.6 years | Limited 75+ data |
The FLOW trial is the most relevant, with a mean age of 66.6 years and some patients over 75—but it studied diabetic kidney disease patients, not general obesity. We're working with imperfect data for the 75+ population.
Why Age 75 Matters Clinically
The distinction between 65+ and 75+ isn't arbitrary. Several physiological changes accelerate after 75:
- Accelerated sarcopenia: Muscle loss occurs faster—1-2% per year after 75 vs 0.5-1% in younger elderly
- Reduced physiological reserve: Less capacity to recover from stressors like dehydration or GI illness
- Cognitive changes: Higher prevalence of mild cognitive impairment affects medication adherence
- Polypharmacy peaks: Average of 7+ medications, increasing interaction risk
- Fall risk increases: Falls become the leading cause of injury-related death
- Nutritional vulnerability: Appetite and absorption decline, malnutrition risk rises
These factors don't preclude GLP-1 use, but they shift the risk-benefit calculation substantially.
Frailty Assessment: More Important Than Age
Geriatric medicine increasingly recognizes that biological age matters more than chronological age. A robust 82-year-old may be a better candidate for GLP-1 therapy than a frail 70-year-old.
The Clinical Frailty Scale (CFS), developed by Rockwood and colleagues, provides a practical assessment tool:
When GLP-1s May Still Make Sense After 75
Despite limited trial data, there are clinical scenarios where GLP-1 therapy is reasonable in the 75+ population:
1. Type 2 Diabetes Management
GLP-1 receptor agonists are established diabetes therapies with good glucose control and low hypoglycemia risk. For a robust 78-year-old with diabetes who isn't achieving glucose targets on metformin, adding Ozempic at low doses is reasonable and within label use.
2. Cardiovascular Risk Reduction (With Diabetes)
The SUSTAIN-6 and FLOW trials included some patients 70-75+ with diabetes and established cardiovascular or kidney disease. For these patients, GLP-1s offer mortality benefit beyond glucose or weight control.
3. Mobility-Limiting Obesity
When excess weight directly prevents mobility, rehabilitation, or independence—such as an 80-year-old who can't participate in physical therapy due to weight—targeted weight loss may improve quality of life. This requires careful weighing of muscle loss risks.
Why Weight Loss Goals Differ After 75
The obesity medicine paradigm—lose as much weight as possible—doesn't apply to older adults. Several factors argue for modest, slow weight loss if any:
For adults 75+ who do pursue GLP-1 therapy, reasonable goals might be:
- 5-10% weight loss maximum (not 15-20%)
- Improved glycemic control (A1c target 7.5-8% rather than <7%)
- Maintained physical function and independence
- Cardiovascular event prevention (if diabetic)
- No weight loss target—focusing on metabolic markers alone
Practical Prescribing Considerations
Extreme Dose Titration
Standard titration schedules are too aggressive for most adults 75+. Consider:
| Medication | Standard Titration | Modified for 75+ |
|---|---|---|
| Semaglutide | 0.25mg → 0.5mg → 1mg → 1.7mg → 2.4mg (each step 4 weeks) |
0.25mg × 8-12 weeks 0.5mg × 8-12 weeks May stop at 0.5-1mg |
| Tirzepatide | 2.5mg → 5mg → 7.5mg → 10mg → 12.5mg → 15mg (each step 4 weeks) |
2.5mg × 8-12 weeks 5mg × 8-12 weeks May stop at 5-7.5mg |
Aggressive Hydration Monitoring
GI side effects cause dehydration, which is more dangerous for older adults with reduced kidney reserve. Consider:
- Baseline kidney function (creatinine, eGFR) before starting
- Check kidney function 2-4 weeks after each dose increase
- Explicit hydration targets (e.g., 6-8 glasses water daily)
- Hold medication during acute illness with vomiting/diarrhea
- Lower threshold to pause therapy if GI symptoms occur
Mandatory Resistance Training
For adults 75+ who proceed with GLP-1s, resistance training isn't optional—it's essential. The muscle loss from GLP-1-induced weight loss compounds age-related sarcopenia.
- 2-3x weekly resistance training (can be chair-based or bands)
- Work with physical therapist if needed for safe programming
- Balance training to reduce fall risk
- Protein intake 1.0-1.2g/kg body weight daily
- Consider creatine supplementation (evidence supports safety and efficacy in older adults)
When to Say No
GLP-1 therapy for weight loss is likely not appropriate in adults 75+ when:
- Clinical Frailty Scale score ≥6
- Recent unintentional weight loss (>5% in 6 months)
- Significant sarcopenia or low muscle mass
- BMI already <27 (or even <30 in very elderly)
- Active malnutrition or protein deficiency
- Moderate-to-severe cognitive impairment affecting medication management
- Limited life expectancy (<5 years) where long-term CV benefits won't accrue
- Unable or unwilling to engage in resistance training
- History of severe GI disease (gastroparesis, bowel obstruction)
These aren't absolute contraindications for GLP-1 use in diabetes, but they argue strongly against pursuing weight loss as a goal.
The Shared Decision-Making Conversation
For adults 75+ considering GLP-1s, the conversation should include:
- Honest acknowledgment: "We don't have strong trial data for people your age. We're extrapolating."
- Goal clarification: "What are we trying to achieve? Weight loss? Blood sugar control? Mobility?"
- Risk discussion: "The main concern is muscle loss, which could affect your strength and increase fall risk."
- Commitment assessment: "Are you willing and able to do resistance training and eat adequate protein?"
- Trial approach: "We can try a low dose for 3 months and see how you respond. We can always stop."
- Family involvement: For patients with cognitive changes, involving caregivers in the decision and monitoring is appropriate.
What Research Is Needed
The 75+ population remains understudied. Needed research includes:
- Trials specifically enrolling robust adults 75-85
- Studies with functional outcomes (fall rates, ADL performance) as primary endpoints
- Body composition analysis (lean mass vs fat mass changes) in older cohorts
- Frailty-stratified outcomes to identify who benefits vs who is harmed
- Lower-dose regimens designed for metabolic benefit without aggressive weight loss
- Lincoff AM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389:2221-2232. (SELECT Trial - Age cap 75)
- Perkovic V, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024. (FLOW Trial - Mean age 66.6)
- Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021. (STEP 1 - Mean age 46)
- Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022. (SURMOUNT-1 - Mean age 45)
- Rockwood K, et al. A Global Clinical Measure of Fitness and Frailty in Elderly People. CMAJ. 2005. (Clinical Frailty Scale)
- Morley JE, et al. Frailty Consensus: A Call to Action. J Am Med Dir Assoc. 2013.
- Flicker L, et al. Body Mass Index and Survival in Men and Women Aged 70 to 75. J Am Geriatr Soc. 2010. (Obesity Paradox)
- Bauer JM, et al. Sarcopenia: A Time for Action. J Cachexia Sarcopenia Muscle. 2019.
- American Geriatrics Society. Guidelines on Diabetes in Older Adults. 2023.
- FDA. Wegovy (semaglutide) Prescribing Information. 2021, updated 2024.
- FDA. Zepbound (tirzepatide) Prescribing Information. 2023.
- Conte C, et al. Body Composition Changes With GLP-1 Receptor Agonists. Obesity Reviews. 2024.
- Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016. (SUSTAIN-6)
- American Diabetes Association. Standards of Care in Diabetes—2025. (Older Adult chapter)