Browse the evidence

NNC9204-1177, a glucagon/GLP-1 receptor co-agonist, produces dose-dependent, clinically relevant weight loss (up to 12.6%) in adults with overweight or obesity, but its clinical development was halted due to unexpected safety signals including increased heart rate, impaired glucose tolerance, and elevated inflammatory markers.

NNC9204-1177 is not available for clinical use because it caused unacceptable side effects like rapid heart rate and inflammation, despite causing significant weight loss. Do not seek this specific compound. However, the mechanism (glucagon/GLP-1 co-agonism) suggests that combining these pathways can be more effective for weight loss than GLP-1 alone, provided safety is managed. Current approved GLP-1 agonists (like semaglutide) do not have this glucagon component and thus avoid this specific safety profile.

GLP-1 receptor agonists (GLP-1RAs) significantly reduce liver fat content and improve histological markers of NASH (resolution without fibrosis worsening) in patients with NAFLD, with efficacy demonstrated across liraglutide, semaglutide, and tirzepatide.

If you have fatty liver disease (NAFLD) or NASH, GLP-1 medications like liraglutide, semaglutide, or tirzepatide are proven to reduce liver fat and improve liver health, often more effectively than placebo. These drugs work through hormonal mechanisms that reduce liver fat independently of weight loss in some cases. While gastrointestinal side effects like nausea are common, they are often manageable. Consult a doctor to see if you are a candidate, especially if you also have Type 2 Diabetes or obesity.

Non-beverage energy density and hyper-palatability (high sodium/fat or sodium/carb combinations) in ultra-processed foods positively predict meal energy intake and drive excess consumption.

Be aware that ultra-processed foods are engineered to be hyper-palatable and have high energy density (excluding beverages). This combination drives you to eat more without you necessarily feeling fuller. Choose foods with lower energy density and less engineered hyper-palatability.

Orlistat reduces body weight by inhibiting gastric and pancreatic lipases, thereby reducing the absorption of dietary fats, with efficacy demonstrated in obese patients.

Orlistat helps you lose weight by blocking the absorption of about 30% of the fat you eat. You take it with meals, but you must keep your fat intake low (less than 30% of calories) to avoid unpleasant gastrointestinal side effects. It is effective for weight loss, especially when combined with a hypocaloric diet, but may be less effective than newer GLP-1 drugs.

The combination of bupropion and naltrexone reduces body weight by stimulating POMC neurons to decrease energy intake and increase expenditure, with naltrexone blocking negative feedback to enhance this effect.

Bupropion/naltrexone is a combination pill that helps reduce appetite and increase energy expenditure by acting on brain pathways. It is effective for weight loss in people with obesity and comorbidities like hypertension or diabetes. However, it is not suitable for everyone, particularly those with a history of seizures or eating disorders. Consult your doctor to determine if it is safe for you.

Acute ingestion of plant proteins generally stimulates Muscle Protein Synthesis (MPS) to a lesser extent than animal proteins when matched for protein mass, due to lower leucine content and digestibility.

If you eat a small amount of plant protein, it won't spike muscle building as much as whey. However, this doesn't mean it doesn't work; it just means you need to eat more of it to get the same 'signal' to build muscle.

Dual SGLT1/SGLT2 inhibition with licogliflozin produces statistically significant but modest body weight loss (mean -3.73% to -3.83%) in adults with overweight or obesity, with responder rates (≥5% loss) reaching 45.3% at high doses, though accompanied by dose-dependent gastrointestinal adverse events.

Licogliflozin, a dual SGLT1/SGLT2 inhibitor, leads to modest but statistically significant weight loss (around 3-4% on average) in adults with overweight or obesity over 24 weeks. While about 45% of patients taking the highest doses lose at least 5% of their body weight, the average effect is smaller than other anti-obesity medications. Treatment is associated with gastrointestinal side effects like diarrhea, which are dose-dependent and often improve over time or with dose reduction. Patients should expect a gradual, modest weight loss rather than a dramatic reduction, and must adhere to lifestyle interventions (caloric restriction and exercise) as part of the protocol.

Bariatric surgery, particularly malabsorptive procedures, significantly increases the risk of nephrolithiasis (kidney stones) due to enteric hyperoxaluria, low urinary volume, and hypocitraturia.

If you have had bariatric surgery, especially a bypass, you are at a significantly higher risk for kidney stones. This is not just about weight; it is about how your body processes nutrients now. You must be vigilant about hydration and dietary oxalate to protect your kidneys.

Abdominal obesity, measured by waist circumference or waist-to-hip ratio, significantly increases the risk of coronary heart disease (CHD), whereas general obesity (BMI ≥30) shows a weaker, non-significant association when analyzed using G-estimation to account for time-varying confounding.

If you are concerned about heart disease risk, waist circumference or waist-to-hip ratio are more accurate predictors than BMI alone. Even if your BMI is in the 'normal' or 'overweight' range, a larger waist circumference (≥102 cm for men, ≥88 cm for women) or higher waist-to-hip ratio indicates a significantly higher risk of coronary heart disease. This risk persists even when accounting for other health factors like blood pressure and cholesterol, suggesting that visceral fat itself is a critical driver of heart disease.

Higher BMI is positively correlated with Diabetic Kidney Disease (DKD) and carotid atherosclerotic plaque, with the highest risk observed in the highest BMI quintile.

For Type 2 Diabetes patients, keeping BMI in a moderate range (23.5–25.2) is crucial for protecting kidney health. While being too thin increases nerve damage risk, being overweight (highest BMI quintile) significantly increases the risk of kidney disease and carotid plaque. Weight management should aim for this moderate zone to protect the kidneys.

The co-ingestion of protein and calcium produces a synergistic, potent stimulation of endogenous GLP-1 secretion that exceeds the effects of either nutrient alone.

To maximize your body's natural appetite-suppressing hormone (GLP-1), combine protein and calcium in your meals. Research shows this combination triggers a much stronger hormonal response than eating protein or calcium alone. This is a natural, side-effect-free way to support satiety and metabolic health.

Long-term adherence to a ketogenic diet carries risks of nutritional deficiencies, electrolyte disturbances, and potential renal stones (nephrolithiasis), requiring strict monitoring.

If you follow a ketogenic diet long-term, monitor your electrolytes (sodium, potassium, magnesium) and ensure you are getting essential vitamins through supplementation or carefully chosen food sources to prevent deficiencies and kidney stones.

High consumption of ultra-processed foods (UPF) is associated with increased risk of chronic diseases, including obesity, cardiometabolic outcomes, mortality, cancer, and depressive symptoms, independent of overall nutritional quality.

Prioritize whole, minimally processed foods. While checking nutritional labels (like Nutri-Score) is a good start, it is not enough. Actively limit ultra-processed foods (UPF) because they are linked to chronic disease risk through mechanisms beyond just calories and macros, such as additives and processing byproducts. Aim to replace UPF with raw or minimally processed alternatives.

Female sex is significantly associated with a hyper-response (>15% total body weight loss) to subcutaneous GLP-1 analogue therapy compared to non-response, whereas male sex is not.

If you are a woman taking a GLP-1 medication like semaglutide or liraglutide for obesity, you are statistically more likely to achieve significant weight loss (hyper-response) than a man taking the same medication. This is likely due to physiological differences in how your body processes the drug and regulates appetite hormones. Men may need higher doses to achieve similar results. If you are not losing weight, discuss dose adjustment or alternative treatments with your doctor rather than stopping abruptly.

Tirzepatide treatment in adults with obesity but without pre-existing type 2 diabetes significantly reduces the incidence of new-onset type 2 diabetes compared to semaglutide.

If you have obesity and are at risk for type 2 diabetes, tirzepatide may be a more effective option than semaglutide for preventing the onset of the disease. This is based on real-world data showing a 27% lower risk of developing type 2 diabetes with tirzepatide compared to semaglutide over a one-year follow-up period. Consult your doctor to see if this treatment is appropriate for you.

Tirzepatide treatment in adults with pre-existing type 2 diabetes significantly reduces the risk of major adverse cardiovascular events (MACE), including all-cause mortality and cerebral infarction, compared to semaglutide.

If you have type 2 diabetes, tirzepatide may offer greater cardiovascular protection than semaglutide, including a lower risk of heart attack, stroke, and death. This is based on real-world data showing a 46% lower risk of major adverse cardiovascular events with tirzepatide compared to semaglutide over a one-year follow-up period. Consult your doctor to see if this treatment is appropriate for you.

Modifying the sequence of macronutrient ingestion (specifically consuming protein before carbohydrates) improves post-prandial glycemic control by enhancing GLP-1 secretion and delaying gastric emptying, independent of total caloric intake.

To manage blood sugar spikes, start your meal with protein (meat/fish) or vegetables before eating carbohydrates (rice/pasta). This simple sequencing triggers beneficial hormones (GLP-1) that slow down digestion and stabilize glucose levels, even if the total food amount remains the same.

GLP-1 receptor agonists (GLP-1RAs) reduce the incidence of major adverse renal events (specifically new-onset macroalbuminuria and eGFR decline) in patients with type 2 diabetes, independent of glycemic control.

If you have Type 2 Diabetes and are at risk for kidney disease (especially if you already have high albumin in your urine or reduced kidney function), GLP-1 receptor agonists (like Semaglutide or Liraglutide) are a strong treatment option. They protect your kidneys through multiple mechanisms beyond just lowering blood sugar, including reducing inflammation and sodium retention. Clinical trials show they significantly lower the risk of serious kidney events. Discuss once-weekly options with your doctor to minimize injection burden.

High carbohydrate intake (defined as the highest category in prospective cohorts) is associated with a significantly increased risk of cardiovascular disease (CVD), with a pooled hazard ratio of 1.15 compared to the lowest intake.

If you consume a high-carbohydrate diet, particularly if carbohydrates make up more than 60% of your total daily calories, consider reducing this proportion. This meta-analysis suggests that lowering high carbohydrate intake is associated with a lower risk of cardiovascular disease. Focus on balancing macronutrients rather than eliminating carbs entirely.

The association between high carbohydrate intake and increased CVD risk is significantly stronger in Asian populations (1.52-fold increase) compared to non-Asian populations (no significant association), with risk escalating dramatically when carbohydrate intake exceeds 60% of total energy.

If you are of Asian descent, be particularly mindful of your carbohydrate intake. The risk of heart disease increases significantly if carbohydrates make up more than 60% of your calories. Consider reducing your intake of refined carbohydrates and rice to lower this risk.

Orlistat provides modest weight loss and cardiovascular risk reduction, but its efficacy is heavily dependent on dietary fat restriction.

Orlistat is an older weight loss medication that works by blocking fat absorption. It is less effective than newer drugs and requires you to eat a low-fat diet to avoid unpleasant gastrointestinal side effects like oily diarrhea. It may offer some cardiovascular benefits for people with metabolic syndrome.

Phentermine/topiramate combination therapy results in significant weight loss but is associated with increased heart rate and potential psychiatric side effects.

Phentermine/topiramate is a combination pill that can lead to significant weight loss. However, it can increase your heart rate and cause psychiatric side effects like anxiety or depression. It requires careful monitoring by a doctor, and if you don't lose enough weight after a few months, the treatment may be stopped.

Bariatric surgery, particularly Roux-en-Y gastric bypass and biliopancreatic diversion, induces Type 2 Diabetes remission in a majority of patients through mechanisms exceeding simple caloric restriction, including hormonal changes (GLP-1, PYY) and altered gut microbiome.

For eligible patients with obesity and T2DM, bariatric surgery is the most potent intervention for achieving remission, often outperforming medication. It works by altering gut hormones that improve insulin sensitivity, not just by making the stomach smaller. Consultation with a bariatric specialist is required to assess eligibility based on BMI and diabetes duration.

Dual-agonists (GLP-1R/GIPR) and tri-agonists (GLP-1R/GIPR/GCGR) provide superior weight loss and cardiometabolic risk factor improvement (blood pressure, lipids) compared to GLP-1RAs alone, though their direct impact on hard cardiovascular outcomes (MACE) is still under investigation.

Newer medications like Tirzepatide (a dual agonist) may offer greater weight loss and improvements in blood pressure and cholesterol than older GLP-1 drugs. However, long-term data on whether this translates to fewer heart attacks or strokes is still being collected. If standard GLP-1s are not achieving your metabolic goals, discuss these newer options with your doctor.