Browse the evidence

The peptide triple agonist GEP44, targeting GLP-1, Y1, and Y2 receptors, promotes profound weight loss and glycemic control in diet-induced obese rats without triggering the nausea or malaise associated with standard GLP-1 receptor agonists.

This research highlights a promising new class of drugs (triple agonists like GEP44) that may offer superior weight loss and blood sugar control compared to current GLP-1 medications, without causing the nausea that often stops people from taking them. However, this is currently only proven in animals, not humans. For now, standard GLP-1s remain the primary option, but patients experiencing intolerable side effects might discuss clinical trials or future availability of these multi-agonists with their healthcare provider.

GLP-1RAs activate neurons in the paraventricular nucleus (PVH) and ventromedial hypothalamus (VMH) to suppress food intake and increase energy expenditure or thermogenesis.

GLP-1 medications also target other brain regions (PVH and VMH) to suppress food intake and increase energy expenditure. This helps explain why these medications can lead to weight loss even without significant changes in diet or exercise.

GIP receptor agonism contributes to insulin sensitivity independently of weight loss by promoting glucose capture in white adipose tissue and catabolism of branched-chain amino acids in brown adipose tissue.

The addition of GIP receptor activation in dual agonists may help improve insulin sensitivity through metabolic pathways in fat tissue, independent of just losing weight.

Adjunctive liraglutide 1.8 mg for 6 months following laparoscopic adjustable gastric banding (LAGB) provides no significant additional improvement in HbA1c or body weight compared to LAGB alone, and cessation of therapy leads to significant weight regain and worsening glycemic control relative to placebo.

If you have had a gastric band and are considering adding Liraglutide (Victoza) for 6 months, current evidence suggests it will not provide extra weight loss or blood sugar benefits during that time, and you may regain more weight after stopping it compared to not taking it. This does not rule out other GLP-1 drugs (like Semaglutide) or longer durations, but for this specific protocol, it is not recommended.

Social media platforms (Instagram, TikTok) misrepresent semaglutide by promoting off-label weight loss use while omitting common adverse effects like gastrointestinal disorders, leading to unreflected medication use and supply shortages for indicated patients.

If you are considering semaglutide for weight loss, understand that it is a prescription medication with significant side effects, primarily gastrointestinal issues. Social media often omits these risks. Consult a healthcare provider to ensure it is appropriate for you and to avoid contributing to shortages for diabetic patients.

Enhancing insulin signaling specifically in adipose tissue improves obesity-related metabolic disorders by promoting healthy fat expansion and preventing ectopic fat accumulation, whereas enhancing insulin signaling in the liver exacerbates metabolic dysfunction.

Treating obesity-related metabolic issues requires targeting the right tissue. Simply boosting insulin systemically can be harmful, particularly to the liver. Future therapies must distinguish between adipose tissue (where boosting insulin helps store fat safely) and the liver (where boosting insulin worsens fat accumulation). Current clinical focus remains on lifestyle changes and existing drugs that improve sensitivity, but the research highlights the need for tissue-specific drugs.

Tirzepatide treatment in high-fat diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) mice significantly reduces hepatic lipid accumulation and liver damage by downregulating fatty acid uptake proteins (Cd36, Fabp2/4) and upregulating cholesterol efflux regulators (Hnf4a, Abcg5, Abcg8).

For individuals with fatty liver disease, tirzepatide (a dual GIP/GLP-1 agonist) has been shown in preclinical models to reduce liver fat and inflammation. It works by decreasing fatty acid uptake and increasing cholesterol excretion. While promising, these results are from mice, and human clinical data is needed to confirm efficacy and safety for liver health specifically.

Laparoscopic sleeve gastrectomy reduces the leptin-to-adiponectin ratio (LAR) in adults with severe obesity, which serves as a marker for improved insulin sensitivity and reduced cardiovascular risk.

For individuals with severe obesity considering sleeve gastrectomy, expect a significant improvement in insulin sensitivity, measured by the leptin-to-adiponectin ratio, within a year. This hormonal shift is a key driver of metabolic health improvement, potentially reducing the need for diabetes medications. While weight loss is substantial, the hormonal changes, particularly increased adiponectin, are critical for long-term metabolic benefits.

Pharmacological activation of brown adipose tissue (BAT) and induction of 'browning' in white adipose tissue (WAT) via agents such as β3-adrenergic receptor agonists, thyroid receptor agonists, and GLP-1-based multi-agonists enhances energy expenditure and improves metabolic parameters, offering a potential therapeutic avenue for obesity management.

This research suggests that certain medications (like GLP-1 agonists or specific receptor agonists) may help manage obesity not just by suppressing appetite, but by actively turning on your body's internal heating system (brown fat). This process burns energy as heat, which can improve blood sugar and lipid levels. While this might not always lead to massive weight loss on its own, it addresses the metabolic slowdown that often hinders long-term weight management.

Obesity-associated low-grade inflammation and adipose tissue dysfunction can induce resistance to β3-adrenergic receptor agonists (like CL316243) by suppressing β3-AR expression via the EPAC/RAP2A signaling pathway, thereby blunting thermogenic efficacy.

If you have obesity-related inflammation, standard fat-burning medications that target specific receptors (like β3-agonists) might be less effective because your body's inflammatory state can block these receptors. This highlights why some people don't respond to certain treatments and why newer drugs with different mechanisms might be needed.

Tirzepatide demonstrates potential kidney-protective effects by slowing the decline in eGFR and reducing urinary albumin-to-creatinine ratio (UACR) compared to insulin glargine.

While not yet a primary indication, early data suggests tirzepatide may help protect kidney function in T2D patients, potentially slowing kidney disease progression compared to insulin. This benefit is observed even in patients already taking other kidney-protective medications.

SGLT2 inhibitors reduce epicardial fat volume independently of significant weight loss, suggesting a direct lipolytic effect on epicardial tissue.

SGLT2 inhibitors are a key pharmacological option for HFpEF patients. They reduce epicardial fat directly, which may improve heart mechanics and reduce hospitalizations. Discuss with your doctor if SGLT2 inhibitors are appropriate for your condition.

Patients with active psychiatric disorders, particularly depression, may exhibit lower response rates to semaglutide and are at risk of weight gain during treatment.

If you have active depression or other psychiatric conditions, monitor your weight closely when starting semaglutide, as some patients may not lose weight or may even gain weight.

BGM0504, a GLP-1R/GIPR dual agonist with optimized acylation, demonstrates superior glycemic control, weight loss, and liver health improvements compared to Tirzepatide in diabetic and NASH mouse models.

BGM0504 is an experimental dual-agonist peptide designed to treat diabetes and obesity more effectively than existing drugs like Tirzepatide. In animal studies, it lowered blood sugar and body weight with fewer side effects on liver health. It is not yet available for human use.

Bariatric surgery (Roux-en-Y gastric bypass) significantly reduces circulating microvesicles (MVs) of monocyte and endothelial origin, specifically those expressing the CD36 scavenger receptor, within three months post-surgery.

For patients undergoing Roux-en-Y gastric bypass, significant reductions in inflammatory vascular markers (specifically CD36-bearing microvesicles from monocytes and endothelial cells) occur within just three months. This suggests that the surgery rapidly alleviates endothelial stress and low-grade inflammation associated with obesity, potentially reducing long-term cardiovascular risk beyond just weight loss.

Soluble GPNMB (sGPNMB) promotes lipogenesis in white adipose tissue by activating SREBP1c via CD44 binding, thereby acting as a risk factor for obesity progression.

This research highlights that obesity involves complex signaling where soluble proteins released by fat cells can drive further fat storage. While not a direct lifestyle intervention, understanding this mechanism underscores why reducing adiposity (via caloric deficit and exercise) is crucial, as it reduces the source of these pro-lipogenic signals.

Membrane-bound GPNMB on anti-inflammatory macrophages reduces oxidative stress, lipid accumulation, and fibrosis in the liver by interacting with calnexin on Kupffer and stellate cells.

This finding suggests that maintaining healthy macrophage function in fat tissue may have downstream benefits for liver health, potentially reducing the risk of fatty liver disease associated with obesity.

Semaglutide use is associated with a significantly higher reporting odds ratio for vision impairment and retinopathy compared to other GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, metformin, phentermine, and orlistat.

If you are taking semaglutide, be aware that there is a statistical signal for increased vision impairment reports in post-market data compared to other diabetes or weight loss drugs. This does not mean everyone will experience this, but it warrants vigilance. Ensure you have regular ophthalmological check-ups, especially if you have pre-existing diabetic retinopathy or rapid glycemic changes, and report any visual disturbances to your provider immediately.

Ghrelin levels, specifically the ratio of unacylated to acylated ghrelin, are altered in NAFLD patients, with decreased plasma unacylated/acylated ghrelin ratio and increased hypothalamic acylated ghrelin expression correlating with insulin resistance and NAFLD severity.

Research indicates that ghrelin signaling is disrupted in NAFLD, with specific changes in ghrelin ratios correlating with insulin resistance. While ghrelin antagonists like pegvisomant are being studied, they are not yet established treatments. Current clinical focus remains on GLP-1 agonists for managing NAFLD.

Bariatric surgery (BS) improves NAFLD outcomes by altering bile acid bioavailability, which activates the Fxr-Glp-1 axis, improves glucose homeostasis, and reestablishes normal ghrelin responses.

For obese patients with NAFLD, bariatric surgery is a viable treatment option that not only reduces weight but also improves liver health through hormonal changes. It reestablishes normal ghrelin responses and activates pathways that improve glucose homeostasis. If you are considering surgery, discuss how it might specifically benefit your liver health beyond weight loss.

GLP-1 receptor agonists protect endothelial function by reducing oxidative stress, inhibiting inflammation, and promoting nitric oxide (NO) production.

This node explains the biological mechanism: GLP-1 drugs help keep blood vessel linings healthy by reducing inflammation and oxidative stress, which prevents the buildup of plaque. This is a key reason why these drugs protect the heart.

GLP-1 receptor agonists reduce foam cell formation and promote anti-inflammatory M2 macrophage polarization, thereby stabilizing atherosclerotic plaques.

GLP-1 drugs help stabilize existing plaque in arteries by changing how immune cells (macrophages) behave. They encourage these cells to become 'anti-inflammatory' (M2 phenotype) and help remove excess cholesterol, which reduces the risk of plaque rupture and heart attack.

DPP-4 inhibitors, specifically sitagliptin, are significantly associated with an increased risk of biliary disorders, including gallbladder-related diseases and biliary malignant tumors.

If you are taking a DPP-4 inhibitor (like sitagliptin), be aware of symptoms like right-sided abdominal pain, nausea, or fever, which could indicate gallbladder issues. Discuss these risks with your doctor, especially if you have been on the medication for a long time.

Specific GLP-1 receptor agonists, semaglutide and liraglutide, are significantly associated with an increased risk of biliary disorders, including gallbladder-related diseases and biliary malignant tumors.

If you are taking Semaglutide or Liraglutide, watch for signs of gallbladder problems, such as pain in the upper right abdomen, nausea, or fever. These drugs can slow down your gallbladder, so report any such symptoms to your doctor promptly.