Pros & Cons of GLP-1 Weight Loss Drugs

[madman]

In this video, Mark Scholz and Mark Moyad discuss the pros and cons of weight loss drugs, particularly those that have shown significant weight loss results in patients. They emphasize that these drugs are not for cosmetic purposes, but for individuals with severe weight-related health issues. While the drugs have shown positive outcomes, there are also concerns and potential risks associated with their use, such as the need to stop the drugs before elective surgery. The physicians are optimistic about the potential benefits of these medications, but also acknowledge the need for more research to fully understand their impact on cardiovascular health. Additionally, they highlight the importance of maintaining healthy behaviors such as diet and exercise in conjunction with using these weight loss drugs.

Key Takeaways:

*Weight loss drugs can result in an average of 15% weight loss in individuals with unhealthy weight.

*A phase 2 trial of a triple Agonist drug showed a 24% drop in weight.

*There are still ongoing concerns and potential risks associated with the use of these drugs, such as needing to stop them before elective surgery.

*The drugs are seen as a new option for individuals who need immediate weight loss for life-threatening conditions.

*The cost, potential conflict of interest, and the need for lifelong treatment are cons associated with weight loss drugs.

*The select trial aims to determine if these drugs can reduce the risk of cardiovascular events, which could be a gamechanger.

*While not everyone experiences a 15% weight loss, the drugs have still shown positive responses in patients.

*The drugs are seen as a way for people to fight back against the challenges of processed and unhealthy food.

*The best results are seen when patients maintain healthy behaviors like diet and exercise in tandem with the medications.

*The physicians emphasize that these drugs are meant for individuals in critical need of weight loss, not for cosmetic purposes.

 

[Guided_by_Voices]

These people should know better than to use the term "weight loss" when in fact fat loss, particularly visceral fat, is the goal. Muscle loss and the problems that come with it (e.g. frailty, reduced glucose uptake) could negate much of the fat loss benefit, so until a meaningful population has shown that they can come off of the drugs, rebuild muscle, and retain a healthy body composition and overall health, then these can't be considered a success.

 

[Nelson Vergel]

Thread 'Tirzepatide vs Semaglutide: Pros and Cons'

Jul 18, 2024

Tirzepatide and semaglutide are both injectable medications used for weight loss and type 2 diabetes management, but they differ in their mechanisms of action and effectiveness. Here's a comparison of the two drugs:

Mechanism of Action​

Tirzepatide:

• Dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist
• Activates both GIP and GLP-1 receptors

Semaglutide:

• Selective GLP-1 receptor agonist
• Activates only GLP-1 receptors

Effectiveness for Weight Loss​

Tirzepatide:

• ...

• Nelson Vergel
• gip/glp-1; tirzepatide; obesity; weight loss obesity; surgery; glp-1; gut hormones semaglutide tirzepatide vs semaglutide
• Replies: 17
• Forum: Weight Loss Options

• 

 

[Nelson Vergel]

Beyond slimming down the waistline, GLP-1 receptor agonists (and the newer dual GIP/GLP-1 agents such as tirzepatide) now sit at the center of a broad “metabolo-cardio-renal-neuro” paradigm shift. Robust randomized trials and meta-analyses show that these drugs lower A1C, cut cardiovascular events and kidney failure, shrink liver fat, ease heart-failure symptoms, improve some reproductive‐hormonal profiles, and even hint at protection against dementia, addiction, and certain cancers. Benefits appear to stem from multisystem GLP-1 receptors that modulate insulin : glucagon balance, natriuresis, endothelial nitric-oxide, inflammation, and central-nervous reward circuitry. Below is a detailed evidence map (with the most recent data available through 4 July 2025); caveats and knowledge gaps follow.

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1 | Why effects extend beyond fat loss​

• GLP-1 receptors populate pancreas, brain, heart, vasculature, kidney, and immune cells, explaining pleiotropic actions such as insulinotropic signaling, glucagon suppression, slowed gastric emptying, natriuresis, endothelial NO release, and anti-inflammatory cytokine shifts frontiersin.org.
• These pathways act irrespective of weight change, so metabolic, vascular, and neuro-hormonal benefits can accrue even when weight loss plateaus acc.org.

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2 | Glycemic control & β-cell preservation​

• The 2025 ADA Standards list GLP-1 RAs as first-line injectables after metformin, typically lowering HbA1c by ≈1 – 1.5 percentage points with a minimal hypoglycemia risk and evidence of β-cell stress reduction diabetesjournals.org.
• Time-in-range and glycemic variability improve independently of weight loss, supporting durable cardiometabolic disease modification dom-pubs.onlinelibrary.wiley.com.

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3 | Cardiovascular event reduction​

Key CVOTs	Population	Relative MACE reduction
LEADER (liraglutide)	T2DM + ASCVD	13%
SUSTAIN-6 (semaglutide)	T2DM + high risk	26%
REWIND (dulaglutide)	T2DM broad	12%
SELECT (semaglutide 2.4 mg)	Obesity without diabetes	20 %

• SELECT’s 17,604-patient trial demonstrated a 20 % drop in CV death, MI, or stroke over 33 months, the first proof of benefit in non-diabetic obesity nejm.orgwired.com.
• ACC expert guidance now endorses GLP-1 RAs for weight-neutral CV-risk lowering even in patients who cannot reach large weight losses acc.org.

Heart failure​

• In HFpEF, weekly semaglutide 2.4 mg improved Kansas City Cardiomyopathy Questionnaire score by +16 points and cut the composite of worsening HF or CV death nejm.orgthelancet.com.
• Exploratory analyses of SELECT suggest similar benefit in HFrEF subgroups, though some meta-analyses signal a neutral or slightly adverse signal warranting dedicated trials link.springer.com.

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4 | Renal protection​

• The kidney-specific FLOW trial showed a 24 % relative risk reduction in kidney failure, sustained eGFR decline, or renal death with semaglutide in T2DM + CKD diabetes.org.
• A 2024 Lancet meta-analysis of 11 RCTs ( > 85 000 participants) reported a 19 % fall in kidney failure and 22 % slower eGFR loss, extending to some non-diabetic cohorts thelancet.comtheguardian.com.

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5 | Liver disease (NAFLD / NASH / MASH)​

• Phase 2 semaglutide (2.4 mg) achieved NASH resolution without worsening fibrosis in 59 % vs 17 % of placebo, with parallel drops in ALT and liver fat on MRI-PDFF thelancet.com.
• A 2025 NEJM-reported MASH trial (800 participants) found 63 % histologic improvement and 37 % fibrosis regression at 72 weeks, positioning GLP-1 RAs ahead of most investigational agents nypost.com.
• Meta-analyses confirm class-wide reductions in hepatic steatosis and inflammatory markers sciencedirect.com.

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6 | Endocrine-reproductive benefits in PCOS​

• Liraglutide 3 mg improved follicle maturation, insulin resistance, and androgen profile in randomized PCOS trials rbej.biomedcentral.com.
• A 2025 systematic review found GLP-1 RAs plus metformin superior to metformin alone for ovulation rates and metabolic endpoints bmcwomenshealth.biomedcentral.com.
• Early phase data hint that dual GIP/GLP-1 analogue tirzepatide may further enhance weight, HbA1c, and ovulatory frequency in PCOS cohorts sciencepg.com.

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7 | Brain & cognition​

• In the 2024 AAIC Phase 2b trial, liraglutide slowed hippocampal and cortical atrophy by ~50 % versus placebo, translating to slower cognitive decline in prodromal Alzheimer’s disease aaic.alz.org.
• Ongoing large RCTs (e.g., EVOKE, REMODEL) will clarify disease-modifying potential in Alzheimer’s and Parkinson’s populations.

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8 | Addiction & reward dysregulation​

• NIAAA-sponsored pilot work shows semaglutide dampens alcohol reward and lowers weekly consumption in heavy-drinking adults niaaa.nih.gov.
• An eClinicalMedicine RCT found dulaglutide doubled 6-month smoking-abstinence rates, partly by attenuating post-cessation weight gain thelancet.com.

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9 | Inflammation, endothelial function & microvasculature​

• GLP-1 signaling reduces NF-κB activation, CRP, IL-6, and pro-atherogenic macrophage phenotypes, earning the moniker “metabolic anti-inflammatory” frontiersin.org.
• Pre-clinical and small human studies demonstrate enhanced endothelial NO synthase phosphorylation and improved skeletal-muscle microvascular perfusion within hours of infusion sciencedirect.comdiabetesjournals.org.

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10 | Cancer-risk modulation (signals, not proof)​

• Population data suggest lower incidence of obesity-related malignancies among GLP-1 RA users, possibly via weight-independent anti-proliferative effects on tumor metabolism oaepublish.com.
• Long-term registry follow-up does not show an increased pancreatic-cancer signal over nine years of exposure jamanetwork.com, although vigilance continues for rare neuro-endocrine tumors netrf.org.

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11 | Safety, controversies & knowledge gaps​

Domain	Key points
GI & gallbladder	Nausea/vomiting (~20 %), gallstone risk; titrate slowly.
Muscle loss	Rapid weight loss may reduce lean mass; emphasize protein/resistance exercise.
Reproductive	Male-fertility impact uncertain; rodent data prompt caution in those seeking conception frontiersin.org.
Heart failure HFrEF	Conflicting meta-analyses; dedicated outcome trials under way.
Cost & access	High prices and insurance hurdles remain major barriers.

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12 | Pipeline & future directions​

• FLOW-HF, SURMOUNT-HF, and SELECT-CKD will refine renal/heart-failure indications.
• Oral high-dose semaglutide 50 mg and emerging triple-agonists (GLP-1/GIP/glucagon) aim to extend benefits to wider populations.

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Bottom line​

When viewed through a 2025 lens, GLP-1–based therapies are evolving from “weight-loss shots” to disease-modifying agents with organ-protective effects spanning heart, kidney, liver, brain, and reproductive systems—though long-term safety, cost-effectiveness, and equitable access remain pressing concerns. As always, individual therapy choices should be guided by comorbidity profiles, patient preferences, and specialist input rather than weight alone. This summary is educational and not a substitute for personalized medical advice.