Semaglutide: Beyond Glycemic Control and Weight Loss – Exploring Pleiotropic Effects and Future Therapeutic Potential

Many thanks to our sponsor Esdebe who helped us prepare this research report.

Abstract

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has revolutionized the treatment of type 2 diabetes (T2D) and obesity. While its efficacy in glycemic control and weight management is well-established, emerging evidence suggests a broader spectrum of potential therapeutic benefits, extending beyond its primary indications. This report explores the pleiotropic effects of semaglutide, delving into its impact on cardiovascular health, renal function, neuroprotection, and other areas of ongoing research. We critically analyze the current literature, highlighting both promising findings and areas requiring further investigation. Furthermore, we discuss the potential future applications of semaglutide and related GLP-1 RAs in various disease states, considering the challenges and opportunities associated with their widespread use. This review aims to provide an expert-level overview of semaglutide’s expanded therapeutic horizons and stimulate future research in this rapidly evolving field.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have become a cornerstone in the treatment of type 2 diabetes (T2D) and obesity. These agents mimic the effects of the endogenous GLP-1 hormone, stimulating insulin secretion, suppressing glucagon release, and slowing gastric emptying. Semaglutide, a long-acting GLP-1 RA, has demonstrated remarkable efficacy in both glycemic control and weight loss, surpassing many other antidiabetic medications. Its approval for the treatment of obesity, under the brand name Wegovy, has further solidified its role in managing metabolic disorders. However, accumulating evidence suggests that semaglutide’s therapeutic potential extends far beyond its established indications. This report aims to delve into the pleiotropic effects of semaglutide, examining its impact on various organ systems and exploring its potential applications in other disease states. Understanding these broader effects is crucial for optimizing patient care and unlocking the full therapeutic potential of this drug.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Cardiovascular Effects: More Than Just Risk Reduction

Semaglutide’s cardiovascular (CV) benefits have been a major focus of clinical trials. The SUSTAIN-6 trial demonstrated a significant reduction in major adverse cardiovascular events (MACE) in patients with T2D at high CV risk. This finding was a landmark achievement, establishing semaglutide as a cardioprotective agent. However, the mechanisms underlying these CV benefits are complex and likely involve more than just improvements in glycemic control and weight loss.

Several potential mechanisms have been proposed, including:

• Improved lipid profile: Semaglutide has been shown to reduce triglyceride levels and improve other lipid parameters, which can contribute to a lower risk of atherosclerosis.
• Reduced blood pressure: Studies have shown a modest but consistent reduction in systolic blood pressure with semaglutide treatment, potentially mitigating hypertension-related CV risks.
• Anti-inflammatory effects: GLP-1 RAs, including semaglutide, have demonstrated anti-inflammatory properties, which may reduce inflammation within the vasculature and contribute to plaque stability. The effects may be mediated through GLP-1 receptors on immune cells such as macrophages.
• Improved endothelial function: Semaglutide may enhance endothelial function, promoting vasodilation and reducing the risk of thrombosis.
• Direct effects on cardiomyocytes: In vitro and animal studies suggest that GLP-1 RAs may have direct protective effects on cardiomyocytes, improving cardiac function and reducing myocardial damage in response to ischemia.

While the SUSTAIN-6 trial provided strong evidence for CV risk reduction, it’s important to acknowledge that the trial population included individuals with a history of CV disease, and the observed benefits may not be directly generalizable to lower-risk populations. Ongoing studies are investigating the CV effects of semaglutide in broader populations, including those without pre-existing CV disease.

Furthermore, research is exploring the potential of semaglutide in treating specific CV conditions, such as heart failure with preserved ejection fraction (HFpEF). The beneficial effects of semaglutide on body weight and glycemic control could indirectly improve HFpEF. Future clinical trials are crucial to understand whether semaglutide directly improves cardiac function or reduces disease progression in HFpEF patients.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Renal Protection: Emerging Evidence and Future Directions

Diabetic kidney disease (DKD) is a major complication of T2D and a leading cause of end-stage renal disease (ESRD). Semaglutide has shown promising results in protecting renal function in patients with T2D. The SUSTAIN-6 trial also reported a reduction in the incidence of new or worsening nephropathy in the semaglutide group compared to placebo. More recently, the FLOW trial investigated the impact of semaglutide on renal outcomes and also found renal protective benefits. These findings suggest that semaglutide may have direct renoprotective effects beyond its glycemic control and blood pressure lowering effects.

The potential mechanisms underlying these renoprotective effects include:

• Reduction in albuminuria: Semaglutide has been shown to reduce albuminuria, a marker of kidney damage, in patients with T2D. This effect may be mediated by improving glomerular filtration barrier function.
• Improved renal hemodynamics: GLP-1 RAs may improve renal hemodynamics by reducing glomerular hypertension and hyperfiltration, which are key drivers of DKD progression.
• Anti-inflammatory effects in the kidney: Semaglutide may reduce inflammation in the kidney, protecting against tubular damage and fibrosis.
• Direct effects on renal cells: In vitro studies suggest that GLP-1 RAs may have direct protective effects on renal cells, such as podocytes and tubular epithelial cells, preventing apoptosis and promoting cell survival.

While the available evidence is encouraging, further research is needed to fully elucidate the mechanisms underlying semaglutide’s renoprotective effects and to determine its efficacy in preventing or slowing the progression of DKD in different patient populations. Specifically, studies are needed to assess the long-term effects of semaglutide on renal outcomes and to identify subgroups of patients who are most likely to benefit from its renoprotective effects. Additionally, research is exploring the potential of combining semaglutide with other renoprotective agents, such as ACE inhibitors or ARBs, to maximize the benefit for patients with DKD.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Neuroprotective Potential: A New Frontier

Emerging evidence suggests that GLP-1 RAs may have neuroprotective effects, potentially slowing the progression of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). These effects are likely mediated by multiple mechanisms, including:

• Improved insulin sensitivity in the brain: Insulin resistance in the brain has been implicated in the pathogenesis of AD. GLP-1 RAs may improve insulin sensitivity in the brain, enhancing neuronal function and reducing the accumulation of amyloid plaques.
• Reduced inflammation in the brain: Neuroinflammation plays a crucial role in the progression of neurodegenerative diseases. Semaglutide may reduce neuroinflammation, protecting against neuronal damage and cognitive decline.
• Enhanced neurotrophic factor signaling: GLP-1 RAs may enhance the production and signaling of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which are essential for neuronal survival and function.
• Protection against oxidative stress: Oxidative stress contributes to neuronal damage in neurodegenerative diseases. Semaglutide may protect against oxidative stress by scavenging free radicals and enhancing antioxidant defenses.

Preclinical studies have shown that GLP-1 RAs can improve cognitive function, reduce amyloid plaque deposition, and protect against neuronal loss in animal models of AD and PD. Several clinical trials are currently underway to evaluate the efficacy of semaglutide in treating neurodegenerative diseases. Early results from some of these trials are promising, but more definitive evidence is needed to confirm the neuroprotective potential of semaglutide in humans.

One of the major challenges in developing GLP-1 RAs for neurodegenerative diseases is their limited ability to cross the blood-brain barrier (BBB). Researchers are exploring strategies to enhance the brain penetration of GLP-1 RAs, such as developing novel formulations or using drug delivery systems that can effectively transport these agents across the BBB. Furthermore, it is crucial to identify biomarkers that can predict the response to GLP-1 RA therapy in patients with neurodegenerative diseases. If successful, it may open up a new way to use semaglutide to treat neurodegenerative conditions.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Other Potential Therapeutic Applications

Beyond its established indications and the emerging areas discussed above, semaglutide is being investigated for a variety of other potential therapeutic applications. These include:

• Nonalcoholic steatohepatitis (NASH): NASH is a common liver disease characterized by inflammation and fat accumulation in the liver. Semaglutide has shown promising results in reducing liver fat content and improving liver enzymes in patients with NASH. Clinical trials are ongoing to evaluate its efficacy in preventing disease progression and improving long-term outcomes.
• Polycystic ovary syndrome (PCOS): PCOS is a common endocrine disorder affecting women of reproductive age. Semaglutide may improve insulin sensitivity, reduce androgen levels, and promote weight loss in women with PCOS, potentially improving fertility and reducing the risk of metabolic complications.
• Sleep apnea: Obesity is a major risk factor for obstructive sleep apnea (OSA). Semaglutide’s weight loss effects may improve OSA severity and reduce the need for continuous positive airway pressure (CPAP) therapy. However, more research is needed to confirm these effects and to determine the optimal dose and duration of treatment.
• Addiction: Some preclinical studies suggest that GLP-1 RAs may reduce reward-seeking behavior and cravings in animal models of addiction. Clinical trials are needed to evaluate the efficacy of semaglutide in treating addiction in humans.
• Cancer: Early data suggest that semaglutide may have anti-cancer effects. GLP-1 RAs may inhibit tumor growth and angiogenesis, potentially reducing the risk of certain types of cancer. Further research is needed to confirm these effects and to determine the optimal use of semaglutide in cancer prevention and treatment. However, other studies have indicated GLP-1 RA receptor activation in vitro promotes cell survival and proliferation in certain types of thyroid cancer, this underscores the need for additional studies.

The diverse range of potential therapeutic applications highlights the pleiotropic nature of semaglutide and its potential to impact a wide range of disease states. However, it is important to emphasize that many of these applications are still in the early stages of research, and further clinical trials are needed to confirm the efficacy and safety of semaglutide in these settings.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Safety and Tolerability Considerations

While semaglutide has demonstrated remarkable efficacy in various clinical settings, it is important to carefully consider its safety and tolerability profile. The most common side effects of semaglutide are gastrointestinal (GI) symptoms, such as nausea, vomiting, diarrhea, and constipation. These symptoms are typically mild to moderate in severity and tend to resolve over time. However, in some cases, they can be severe enough to warrant discontinuation of treatment. Strategies to minimize GI side effects include starting with a low dose of semaglutide and gradually increasing the dose over time, as well as advising patients to avoid large meals and fatty foods.

Rare but potentially serious adverse events associated with semaglutide include pancreatitis, gallbladder disease, and thyroid C-cell tumors. While the risk of these events is low, it is important to monitor patients for any signs or symptoms and to discontinue treatment if they occur. Furthermore, semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN 2). Due to animal studies showing increased incidence of C-cell tumors of the thyroid with GLP-1 RAs, clinicians need to carefully weigh the benefits and risks when prescribing semaglutide to individuals with pre-existing thyroid conditions.

There is ongoing debate regarding the risk of diabetic retinopathy associated with GLP-1 RAs. Some studies have suggested an increased risk of retinopathy complications, particularly in patients with pre-existing diabetic retinopathy. However, other studies have not confirmed these findings. It is important to carefully monitor patients with diabetic retinopathy for any signs of worsening vision and to consider ophthalmological consultation if necessary.

Finally, it is important to note that semaglutide can interact with other medications, such as insulin and sulfonylureas, increasing the risk of hypoglycemia. Careful monitoring of blood glucose levels is necessary when using semaglutide in combination with these agents, and dose adjustments may be required to minimize the risk of hypoglycemia. Special caution is needed for patients prone to hypos.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Comparison to Tirzepatide and Other Emerging Therapies

Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, represents a new class of antidiabetic medication that has shown even greater efficacy in glycemic control and weight loss compared to semaglutide. Clinical trials have demonstrated that tirzepatide can achieve greater reductions in HbA1c and body weight than semaglutide. This enhanced efficacy may be due to the synergistic effects of GLP-1 and GIP receptor activation.

Several other emerging therapies are also being developed for the treatment of T2D and obesity, including:

• Oral GLP-1 RAs: Oral semaglutide is already available, offering a more convenient alternative to injectable GLP-1 RAs. Other oral GLP-1 RAs are also in development, with the potential to further expand treatment options.
• Triple agonists: Triple agonists targeting GLP-1, GIP, and glucagon receptors are being developed, with the potential to provide even greater metabolic benefits.
• Amylin analogs: Amylin is a hormone co-secreted with insulin from pancreatic beta cells. Amylin analogs can complement the effects of GLP-1 RAs by further suppressing glucagon secretion and slowing gastric emptying.
• SGLT2 inhibitors: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are another class of antidiabetic medications that have shown cardiovascular and renal benefits. Combining SGLT2 inhibitors with GLP-1 RAs may provide synergistic benefits in patients with T2D and high CV or renal risk.

The rapidly evolving landscape of antidiabetic and obesity therapies presents both challenges and opportunities for clinicians. Careful consideration of the individual patient’s needs, preferences, and risk factors is essential when selecting the optimal treatment regimen.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Future Directions and Conclusion

Semaglutide has emerged as a powerful therapeutic agent with a broad range of potential applications beyond glycemic control and weight loss. Its cardiovascular and renal benefits have been well-established, and emerging evidence suggests a neuroprotective role. However, further research is needed to fully elucidate the mechanisms underlying these pleiotropic effects and to determine the optimal use of semaglutide in various disease states.

Future research should focus on the following areas:

• Long-term clinical trials: Long-term clinical trials are needed to evaluate the long-term efficacy and safety of semaglutide in various patient populations.
• Mechanism of action studies: Further studies are needed to fully elucidate the mechanisms underlying semaglutide’s pleiotropic effects.
• Biomarker identification: Identifying biomarkers that can predict the response to semaglutide therapy will help to personalize treatment and optimize outcomes.
• Combination therapies: Exploring the potential of combining semaglutide with other therapeutic agents may lead to synergistic benefits.
• Novel formulations and delivery systems: Developing novel formulations and delivery systems may enhance the bioavailability and brain penetration of semaglutide, expanding its therapeutic potential.

In conclusion, semaglutide represents a significant advancement in the treatment of T2D and obesity, and its potential therapeutic applications are continuing to expand. As research progresses, semaglutide and related GLP-1 RAs may play an increasingly important role in the prevention and treatment of a wide range of diseases.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844.
2. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21(5):895-908.
3. Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2.4 mg once weekly in adults with overweight or obesity and type 2 diabetes (STEP 4): a randomised, double-blind, parallel-group, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021;9(3):143-155.
4. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002.
5. Lean MEJ, McCombie L, Batterham RL, et al. Counterweight-Plus: sequential very low calorie diet (VLCD) and management of obesity long term: a randomised controlled trial. Lancet. 2019;393(10178):1478-1489.
6. Cosentino F, Dilorenzo A, Mahaffey KW, et al. Efficacy of semaglutide on cardiovascular outcomes in patients with type 2 diabetes with or without established cardiovascular disease: post hoc analysis of SUSTAIN 6. Eur Heart J. 2020;41(33):3117-3126.
7. Aroda VR, Bain SC, Cariou B, et al. Effects of Semaglutide versus Placebo on Cardiovascular, Renal, and Retinal Outcomes in Patients with Type 2 Diabetes: Integrated Analysis of Four SUSTAIN Trials. Cardiovasc Diabetol. 2020;19(1):95.
8. Preiss D, Sattar N, Curhan GC, et al. Effects of semaglutide on kidney outcomes in people with type 2 diabetes with and without kidney disease: a post-hoc analysis of the SUSTAIN 6 trial. Lancet Diabetes Endocrinol. 2022;10(10):707-717.
9. Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor stimulation induces insulin gene expression and increases beta-cell mass in pancreatic duct-ligated rats. Am J Physiol Endocrinol Metab. 2000;278(5):E858-E866.
10. Hölscher C. Potential Role of GLP-1R Agonists for the Treatment of Neurodegenerative Diseases. J Alzheimers Dis. 2018;62(3):1391-1411.
11. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in type 2 diabetes: state-of-the-art. Mol Metab. 2021;46:101102.
12. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216.
13. Dahl D, Onishi Y, Norwood P, Huh R, Ikegami H, Kaufman KD, Hansen TK, Zacho J, Classi CM, DeLozier AM, et al: Effect of subcutaneous semaglutide on glycaemic control in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7:360–369.
14. Perdomo-Pantoja A, Yang Y. The Role of GLP-1 Receptor Agonists in Cancer Therapy: An Updated Review. Int J Mol Sci. 2022 Nov 25;23(23):14894. doi: 10.3390/ijms232314894. PMID: 36499301; PMCID: PMC9690771.
15. Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse Effects of GLP-1 Receptor Agonists. Diabetes Metab Syndr Obes. 2014;7:95-103.
16. Mannucci E, Dicembrini I, Janowska J, Löffler M, Mosenzon O, Pratley RE, Zoungas S, Marx N, Standl E; DECLARE-TIMI 58. Retinopathy and Treatment With GLP-1 Receptor Agonists in the DEVOTE and SUSTAIN 6 Trials. Diabetes Care. 2018 Dec;41(12):2657-2660. doi: 10.2337/dc18-1297. Epub 2018 Oct 11. PMID: 30305373.
17. The FLOW Trial Investigators. Cardiovascular and Kidney Outcomes with Semaglutide in Patients with Type 2 Diabetes and Chronic Kidney Disease. NEJM. 2024.