Obesity is a chronic disease linked to heart disease, type 2 diabetes, and certain types of cancer, impacting the quality of life. Weight loss medications, including injectable options, may offer a boost for individuals with obesity who have had limited success with diet and exercise. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is one such medication approved by the FDA. However, for seniors, the decision to use weight loss injections requires careful consideration of the potential risks and benefits.
Understanding Semaglutide and Other GLP-1 Receptor Agonists
Semaglutide (Wegovy), liraglutide (Saxenda) and tirzepatide (Zepbound) are GLP-1 receptor agonists delivered via subcutaneous injection. These drugs were originally developed to treat type 2 diabetes. Semaglutide, specifically, mimics intestinal hormones, including GLP-1, slowing digestion and signaling fullness to the brain, leading to reduced food intake. These medications work on appetite centers in the brain, helping a person eat less food and still feel satisfied, also reducing feelings of hunger. Orforglipron, a nonpeptide oral GLP-1 receptor agonist, is also in development.
How Semaglutide Works
At the molecular level, semaglutide's mechanism of action involves the GLP-1 receptor (GLP-1R), a G-protein coupled receptor. Upon binding to GLP-1R, semaglutide leads to increased intracellular cyclic adenosine monophosphate (cAMP) levels, activating protein kinase A (PKA). PKA is involved in the synthesis and secretion of insulin but inhibits the release of glucagon. Increased levels of cAMP can also activate the Rap1 via EPAC (Exchange Protein directly Activated by cAMP), which is involved in regulation of insulin secretion. Semaglutide, mimicking GLP-1 signaling, can also activate the PI3K/Akt pathway involved in maintenance and viability of pancreatic β-cells. In pancreatic β-cells, this signaling cascade also enhances glucose-dependent insulin secretion and sensitivity of peripheral tissues to insulin.
Semaglutide, like GLP-1, also has an effect on receptors in the peripheral and central nervous systems. GLP-1 receptors are found diffusely in both the peripheral and central nervous systems. The central effects of semaglutide on energy homeostasis are mediated through its action on GLP-1 receptors in the hypothalamus and brainstem, leading to reduced appetite and food intake. The mechanism of reduced appetite involves neural circuits of the vagus nerve. Additionally, semaglutide has been shown to delay gastric emptying, further contributing to its weight loss effects.
Formulations and Administration
Semaglutide is available in oral and subcutaneous formulations.
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Oral Semaglutide: Therapy should start at 3 mg once daily for a month before doses are increased to 7 mg once daily. If necessary, after a month of maintenance, dosage can be increased to 14 mg once daily. This formulation should be taken on an empty stomach, with a 30-minute wait before eating or taking other medications to optimize absorption, as food and increased fluid intake can affect bioavailability. The absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) is used to improve its minimal bioavailability, which ranges from 0.4% to 1%. Peak concentration is reached approximately 1-hour post-dose, with steady-state achieved after 4-5 weeks. Recent clinical trials, like OASIS 1, have shown that overweight or obesity adults without T2DM should take oral semaglutide 50 mg once per day best weight loss results.
Subcutaneous Semaglutide: Therapy should start at 0.25 mg once weekly and after 4 weeks, dosage can be increased to 0.5 mg once weekly. If necessary, dosage can be increased to 1 mg once weekly after another 4 weeks. This route offers a high bioavailability of 89%, with peak concentrations reached within 1-3 days and steady-state occurring after 4-5 weeks. The subcutaneous administration is flexible regarding meal timing, with injection sites rotated weekly among the abdomen, thigh, and upper arm.
Both formulations share an elimination half-life of about one week, remaining in circulation for around five weeks post-last dose, with clearance rates of 0.05 L/h for subcutaneous and 0.04 L/h for oral in healthy individuals. Elimination occurs primarily through the urine and feces.
Potential Benefits for Seniors
For seniors struggling with obesity and related health issues, weight loss injections like semaglutide may offer several benefits:
- Improved Glycemic Control: Semaglutide has shown effectiveness in improving glycemic control in individuals with type 2 diabetes mellitus (T2DM).
- Weight Loss: Clinical trials have demonstrated significant weight reduction with semaglutide treatment. In SUSTAIN 1 and PIONEER 1 trials, subcutaneous semaglutide 1.0 mg led to a mean weight reduction of 4.5 kg, whereas oral semaglutide 14 mg achieved a 3.7 kg reduction in patients managing early-stage diabetes with diet and exercise alone.
- Cardiovascular Risk Reduction: Semaglutide has demonstrated superior cardioprotection for people with T2DM compared to other treatments. Clinical trials like SUSTAIN and PIONEER found that it reduced major adverse cardiovascular events (MACE) by approximately 26%, outperforming other diabetes drugs. Semaglutide therapy also reduced incidence of any stroke when compared to a placebo through significant reductions in risk of small-vessel occlusion in a post hoc analysis of the SUSTAIN 6 and PIONEER 6 trials.
- Reduced Risk of Dementia: GLP-1 medications have been tied to a decreased risk of dementia. Nørgaard et al. found that rates of dementia were lower in patients undergoing G1PR agonists compared to a placebo in both the randomized control trail patient data and nationwide cohort data.
- Improved Symptoms of Heart Failure: In patients with Heart Failure With Preserved Ejection Fraction (HFpEF) and obesity, semaglutide produced large improvements in HFpEF related symptoms.
- Potential Therapeutic Effects for Alzheimer’s Disease: Semaglutide therapy has been associated with decreased amyloid-beta plaque deposition and neuroinflammation.
- Kidney Protection: The FLOW clinical trial investigated whether semaglutide can slow the progression of CKD in people with T2DM. Among 3533 randomized participants, the semaglutide group had demonstrated benefits for kidney-specific outcomes, cardiovascular death, and other secondary outcomes, including a slower decline in kidney function.
- PCOS Improvement: GLP1-R agonist use was associated with a significant reduction in waist circumference, BMI, serum triglycerides, and total testosterone levels compared to placebo.
Risks and Considerations for Seniors
While weight loss injections can be beneficial, it's crucial to acknowledge the potential risks, especially for older adults:
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- Loss of Muscle and Bone: Weight loss, in general, can lead to the loss of muscle and bone mass. For every pound you lose, about 25 percent is muscle and bone - and older people typically have less of both to start with. Weight loss can cause additional bone deterioration, pushing people teetering on the brink of osteoporosis over the edge.
- Nutrient Deficiencies: Semaglutide and similar medications reduce appetite, making it easier to develop deficiencies in protein, vitamins and minerals.
- Gastrointestinal Issues: GLP-1RA drugs can negatively affect the pancreas and kidneys. While these adverse effects are uncommon, they can be very serious; physicians must be vigilant for signs of pancreatitis and monitor kidney function among people taking GLP-1RA medications.
- Potential Adverse Effects: Semaglutide therapy is also associated with concerning adverse effects like acute pancreatitis, anesthetic risks like pulmonary aspiration or residual gastric content, acute kidney injury, acute gallbladder injury, nonarteritic anterior ischemic optic neuropathy and diabetic retinopathy.
- Unintended Ongoing Weight Loss: It’s sometimes healthier to weigh a little more as you get into your 60s and beyond.
- Contraindications: Contraindications of semaglutide include history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and pregnancy.
- Drug Interactions: Drug interactions to consider with semaglutide therapy include those also used in diabetes treatment, like metformin, as well as anti-psychotics, due to anti-psychotics associated weight gain.
- Increased Risk of Gastrointestinal Problems: GLP-1RA drugs can negatively affect the pancreas and kidneys, including an increased risk of gastrointestinal problems such as nausea, vomiting, diarrhea, and in rare cases paralysis of the stomach.
- Kidney Health Monitoring: Kidney health needs to be closely monitored in seniors taking Ozempic or other GLP-1 drugs.
Important Questions to Ask
Before starting weight loss injections, seniors should consider these questions:
- Am I willing to stay on this for life? In one study, participants regained two-thirds of the weight they had lost on the medication after just one year.
- Is it worth the potential risks? Pancreatitis, kidney injury, even vision changes are potential side effects.
- Is my mental state solid? If you have a history of depression or suicidal thoughts, tell your doctor before taking the drugs.
- Do I have access to ongoing care? It’s important to start at a low dose and raise the dosage slowly to manage side effects including nausea.
- Am I willing to follow a strength-training routine? Everyone taking an anti-obesity drug needs to engage in strength training to protect bones and muscle - and that goes double for people over 50.
- Am I willing to eat plenty of protein? Older adults need about 1 gram for every 2.2 pounds of body weight.
- Am I prepared for the financial commitment? The newer injectable drugs have a high out-of-pocket cost. Novo Nordisk and Eli Lilly, makers of the GLP-1 agonist drugs Wegovy and Zepbound, recently cut prices for people without insurance. However, these medications still have high starting price tags of $499 and $349 per month, respectively.
The Importance of a Holistic Approach
Weight loss medications should not replace smart eating habits and exercise. Weight loss medications should not be taken solely for the sake of vanity. They’re meant for people who struggle with health problems due to being overweight or having obesity.
When combined with healthy lifestyle changes, these drugs could help you treat your condition, improve your health, and lose more weight in the long run. Shedding even 5% of your weight can help lower blood pressure and blood sugar, reduce triglyceride levels, ease joint pain, and improve sleep.
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