madman
Super Moderator
Abstract
Purpose of Review
The history of multiple weight loss medications has been a concerning paradox based on an increased cardiovascular risk despite significant reductions in adipose tissue and weight. A new class of weight loss medications could change this past narrative based on early preliminary results of cardiovascular risk (not events—still need to be determined) and weight reduction in non-diabetics that acutely competes with results achieved with bariatric surgery. The purpose of this review is to provide a comprehensive summary of the advantages and disadvantages of these newer medications, and how they could impact urology.
Recent Findings
Weight loss of−15 to−20% compared to baseline has become plausible in the short-term and preliminary guidance to reduce acute and chronic adverse events are receiving attention. However, the cost, access, conflicts of interest, supply chain, life-long adherence issues, and the long-term diverse implications on mental and physical health when exposed to this class of medications (GLP-1 agonists) are unknown. The profound caloric reductions should also result in baseline or ongoing nutritional deficiency testing, and general and specific dietary recommendations, which could theoretically mimic some bariatric surgery pre- and post-surgical protocols but has yet to be studied. Regardless, the potential impact of these medicines within a variety of medical specialties needs clinical research.
Summary
Current and future lifestyle interventions, dietary patterns, and medicines in the weight loss category need to be held to a paradigm whereby cardiovascular health should improve with significant weight loss without a negative impact on mental health. In urology, the ability to impact cancer risk, ED, FSD, incontinence, infertility, nephrolithiasis, and multiple other endpoints are plausible (based on bariatric surgery data) but need preliminary clinical research. Other medicines with a similar or even larger potential impact are in clinical trials, and thus, a concise overview for clinicians and researchers was needed for objective guidance. Currently, comprehensive lifestyle changes utilized with and without these medications continue to garner positive mental, physical, and legacy effects, which suggest that they are as necessary as ever in the treatment of the numerous conditions impacted by unhealthy weight gain.
*Acute and Chronic Adverse Effects and Medication Discontinuation Before Some Procedures
*Appetite, Cravings, Energy Intake, Food Preferences, Satiation, Taste, and Addictions?
*Adipose Tissue (Fat Mass) vs Lean Muscle Mass Lost and Resistance Exercise?
*BMI Controversial Indication
*Cardiovascular Risk and Event Reduction? SELECT Trial
*Cost, Conflict of Interest, Compounding, Competition (Head‑to‑Head), and Priority Review Voucher Programs
*Dietary Deficiency/Insufficiency, Laboratory Testing, and Supplementation?
*Urologic Opportunities and Concerns (Bariatric Surgery Lessons and Comparisons)
Conclusion
Weight loss, at least in the first 2 years of semaglutide or tirzepatide utilization, is unprecedented in medicine with a non-surgical option. It is imperative that clinicians and researchers throughout medical specialties become accustomed to the evolving potential advantages and disadvantages of these products within their respective disciplines [29••, 31••], and even from case series [93]. What clinically occurs with long-term utilization of these agents from side effects to efficacy is unknown, but thus far the ability to reduce weight, and cardiovascular risk appears impressive enough to consider studying their impacts, even observationally, in urologic settings. What should also be appreciated is the pipeline of these and related medications. Results suggest that similar or even greater weight reduction to injectable semaglutide or tirzepatide is occurring at this moment [63•]. Oral orforglipron (−15% weight loss) [94] and onceweekly subcutaneous retatrutide are two of the many examples [95]. For example, retatrutide, a triple agonist (GLP-1, GIP, and glucagon receptor), recently demonstrated the most profound percentage weight loss from baseline of any trial to date with an impressive−24.2% after 48 weeks in the 12-mg dosage group. Drug delivery advances and options also recently occurred in a phase 3 trial of high-dose (50 mg) oral semaglutide, which appeared to provide weight loss identical to their injectable product [96]. Perhaps we need to visualize these novel medications indifferently if they indeed remain on the market for the long term. It was not long ago the idea of controlling blood pressure, cholesterol, or glucose and reducing morbidity and mortality with a potentially lifelong medication would have seemed innovative and today it has become an untenable evidence-based foundation of preventive medicine. So, why not weight loss medication? Could this be the moment they prevail or will compliance [97], or another physical or mental health issue alter the fate of these newer medications [98], somewhat akin to what was forementioned with some past notable medications?
Finally, what will be the fate of diet and exercise if the situation remains optimistic for these medications? Lifestyle or behavioral changes impact some of the same established cardiovascular parameters, and they can enhance conventional treatment outcomes, reduce the dosage of some medications, and improve mental health outcomes [7]. Could this be the case with the weight loss medications? It is the hope of this author, especially if safety and efficacy continue, and cost and access issues profoundly change. In the meantime, lifestyle changes from aerobic to resistance exercise in conjunction with proper dietary changes are also what appear to result in enhanced efficacy and reduced adverse effects from these novel medications. Thus, lifestyle changes and traditional proven medications will be as critical as ever, because they also have legacy effects on their own, even when reduced or discontinued that need to be embraced [99–103], just as much as these novel pharmacologic weight loss interventions, which as of this moment have not demonstrated similar such effects when medication cessation occurs.
Purpose of Review
The history of multiple weight loss medications has been a concerning paradox based on an increased cardiovascular risk despite significant reductions in adipose tissue and weight. A new class of weight loss medications could change this past narrative based on early preliminary results of cardiovascular risk (not events—still need to be determined) and weight reduction in non-diabetics that acutely competes with results achieved with bariatric surgery. The purpose of this review is to provide a comprehensive summary of the advantages and disadvantages of these newer medications, and how they could impact urology.
Recent Findings
Weight loss of−15 to−20% compared to baseline has become plausible in the short-term and preliminary guidance to reduce acute and chronic adverse events are receiving attention. However, the cost, access, conflicts of interest, supply chain, life-long adherence issues, and the long-term diverse implications on mental and physical health when exposed to this class of medications (GLP-1 agonists) are unknown. The profound caloric reductions should also result in baseline or ongoing nutritional deficiency testing, and general and specific dietary recommendations, which could theoretically mimic some bariatric surgery pre- and post-surgical protocols but has yet to be studied. Regardless, the potential impact of these medicines within a variety of medical specialties needs clinical research.
Summary
Current and future lifestyle interventions, dietary patterns, and medicines in the weight loss category need to be held to a paradigm whereby cardiovascular health should improve with significant weight loss without a negative impact on mental health. In urology, the ability to impact cancer risk, ED, FSD, incontinence, infertility, nephrolithiasis, and multiple other endpoints are plausible (based on bariatric surgery data) but need preliminary clinical research. Other medicines with a similar or even larger potential impact are in clinical trials, and thus, a concise overview for clinicians and researchers was needed for objective guidance. Currently, comprehensive lifestyle changes utilized with and without these medications continue to garner positive mental, physical, and legacy effects, which suggest that they are as necessary as ever in the treatment of the numerous conditions impacted by unhealthy weight gain.
*Acute and Chronic Adverse Effects and Medication Discontinuation Before Some Procedures
*Appetite, Cravings, Energy Intake, Food Preferences, Satiation, Taste, and Addictions?
*Adipose Tissue (Fat Mass) vs Lean Muscle Mass Lost and Resistance Exercise?
*BMI Controversial Indication
*Cardiovascular Risk and Event Reduction? SELECT Trial
*Cost, Conflict of Interest, Compounding, Competition (Head‑to‑Head), and Priority Review Voucher Programs
*Dietary Deficiency/Insufficiency, Laboratory Testing, and Supplementation?
*Urologic Opportunities and Concerns (Bariatric Surgery Lessons and Comparisons)
Conclusion
Weight loss, at least in the first 2 years of semaglutide or tirzepatide utilization, is unprecedented in medicine with a non-surgical option. It is imperative that clinicians and researchers throughout medical specialties become accustomed to the evolving potential advantages and disadvantages of these products within their respective disciplines [29••, 31••], and even from case series [93]. What clinically occurs with long-term utilization of these agents from side effects to efficacy is unknown, but thus far the ability to reduce weight, and cardiovascular risk appears impressive enough to consider studying their impacts, even observationally, in urologic settings. What should also be appreciated is the pipeline of these and related medications. Results suggest that similar or even greater weight reduction to injectable semaglutide or tirzepatide is occurring at this moment [63•]. Oral orforglipron (−15% weight loss) [94] and onceweekly subcutaneous retatrutide are two of the many examples [95]. For example, retatrutide, a triple agonist (GLP-1, GIP, and glucagon receptor), recently demonstrated the most profound percentage weight loss from baseline of any trial to date with an impressive−24.2% after 48 weeks in the 12-mg dosage group. Drug delivery advances and options also recently occurred in a phase 3 trial of high-dose (50 mg) oral semaglutide, which appeared to provide weight loss identical to their injectable product [96]. Perhaps we need to visualize these novel medications indifferently if they indeed remain on the market for the long term. It was not long ago the idea of controlling blood pressure, cholesterol, or glucose and reducing morbidity and mortality with a potentially lifelong medication would have seemed innovative and today it has become an untenable evidence-based foundation of preventive medicine. So, why not weight loss medication? Could this be the moment they prevail or will compliance [97], or another physical or mental health issue alter the fate of these newer medications [98], somewhat akin to what was forementioned with some past notable medications?
Finally, what will be the fate of diet and exercise if the situation remains optimistic for these medications? Lifestyle or behavioral changes impact some of the same established cardiovascular parameters, and they can enhance conventional treatment outcomes, reduce the dosage of some medications, and improve mental health outcomes [7]. Could this be the case with the weight loss medications? It is the hope of this author, especially if safety and efficacy continue, and cost and access issues profoundly change. In the meantime, lifestyle changes from aerobic to resistance exercise in conjunction with proper dietary changes are also what appear to result in enhanced efficacy and reduced adverse effects from these novel medications. Thus, lifestyle changes and traditional proven medications will be as critical as ever, because they also have legacy effects on their own, even when reduced or discontinued that need to be embraced [99–103], just as much as these novel pharmacologic weight loss interventions, which as of this moment have not demonstrated similar such effects when medication cessation occurs.
