Browse the evidence

Weight stigma and discrimination act as independent social determinants of obesity that increase adiposity through biological stress pathways (glucocorticoid activity) and behavioral coping mechanisms, regardless of individual health behaviors.

Recognize that stress from discrimination can biologically and behaviorally contribute to weight gain, independent of your personal choices. Addressing this requires systemic changes and supportive environments, not just individual willpower. Healthcare providers should screen for discrimination exposure and address stigma to improve health outcomes equitably.

Caloric restriction (14% reduction for 2 years) reduces circulating C3a levels in humans, independent of BMI changes, thereby suppressing complement-mediated inflammation.

Adopting a moderate caloric restriction (around 14% less than maintenance) for an extended period (e.g., 2 years) can significantly lower specific inflammatory markers like C3a in the blood. This reduction happens regardless of how much weight you lose, suggesting that the act of eating less directly modulates your immune system to reduce age-related inflammation.

Integrase strand transfer inhibitors (INSTIs), particularly dolutegravir and bictegravir, cause significant weight gain and treatment-emergent obesity in people living with HIV, with effects most pronounced in women and Black individuals.

If you are living with HIV and starting or switching to an INSTI-based regimen (like dolutegravir or bictegravir), be aware that significant weight gain is a known side effect, especially if you are a woman or Black. Monitor your weight closely. If you experience excessive gain, discuss switching to a regimen with a lower weight gain profile (like one using TDF instead of TAF) with your provider.

Genetic variation in the GLP1R locus is associated with cardiometabolic traits (BMI, blood pressure, type 2 diabetes) across diverse ancestries, but these variants do not influence GLP1R gene expression in a way that explains mental ill-health (MIH) endophenotypes.

If you are taking or considering GLP-1 receptor agonists (like semaglutide or tirzepatide) for weight loss or diabetes, be aware that any mental health benefits you experience are likely not due to the drug acting directly on your GLP-1 receptors. Genetic evidence suggests these behavioral effects operate through different mechanisms, possibly involving other genes or secondary metabolic improvements.

Elevated plasma levels of GDF15 and its receptors (RET and GFRAL) mediate the causal relationship between smoking intensity and reduced adiposity (lower BMI and body fat percentage).

Smoking suppresses weight partly through the GDF15 protein pathway. When people quit, this pathway downregulates, potentially leading to weight gain. Future treatments might target GDF15 (e.g., using drugs like metformin to boost it) to help people quit without gaining weight, rather than relying solely on nicotine replacement.

Genetically proxied exposure to GLP-1 receptor agonists is associated with a significantly reduced risk of Obstructive Sleep Apnea (OSA).

If you have OSA and obesity, GLP-1 agonists (like semaglutide or liraglutide) may help reduce your OSA risk by addressing underlying metabolic factors. This is supported by genetic evidence, but clinical trials are still needed to confirm efficacy in diverse populations. Consult your doctor to see if this is a suitable adjunct to your current OSA treatment.

Leptin acts as a critical signal linking nutritional status to puberty onset and reproductive function in females, with sufficient levels required to activate hypothalamic pathways for ovulation.

For females, maintaining healthy body fat levels is crucial for the onset of puberty and regular ovulation. Leptin, a hormone from fat cells, signals the brain that energy reserves are sufficient for reproduction. Extreme leanness can delay puberty or cause infertility, which may be reversible with leptin treatment.

Initiation of GLP-1 receptor agonists is associated with a small but statistically significant increased risk of acute pancreatitis, particularly during the first 6 months of treatment.

Be aware that GLP-1 RAs carry a small increased risk of acute pancreatitis, especially in the first 6 months. If you have a history of pancreatitis, discuss this carefully with your doctor. Report severe, persistent abdominal pain to your provider immediately, as it could be a sign of pancreatitis.

SGLT2 inhibitors lower blood pressure primarily through early osmotic diuresis and volume contraction, with sustained effects driven by reduced arterial stiffness and improved endothelial function.

If you have heart failure or diabetes, SGLT2 inhibitors (like Jardiance or Farxiga) will likely lower your blood pressure slightly, but this is a bonus, not the main reason for taking them. The benefit comes from reducing fluid volume and improving artery health, not just sugar control.

GLP-1 receptor agonist treatment alone, despite causing significant weight loss, does not improve physical functional performance or cardiorespiratory fitness compared to placebo.

Taking GLP-1 medication will help you lose weight, but it will not make you more physically fit or improve your ability to perform daily tasks. If you rely solely on medication, you may lose weight but not gain the stamina or functional strength that exercise provides. To improve fitness, you must add structured exercise.

GLP-1 and dual GLP-1/GIP receptor agonists cause predictable, dose-dependent gastrointestinal adverse events (nausea, vomiting, diarrhea, constipation) that are generally mild to moderate and transient, though they significantly impact treatment adherence.

Expect digestive side effects like nausea or constipation when starting GLP-1 medications. These are common, usually mild, and tend to improve as your body adjusts. To minimize them, start with the lowest dose and increase slowly as directed by your doctor. Staying hydrated and eating smaller meals can help manage symptoms.

Epigenetic silencing of the GLP-1 receptor (GLP-1R) via DNMT3A-mediated hypermethylation impairs incretin signaling and insulin secretion in pancreatic beta-cells.

In Type 2 Diabetes, the body's ability to respond to GLP-1 (a hormone that stimulates insulin) is often turned off by epigenetic silencing of the GLP-1 receptor. This silencing is driven by enzymes like DNMT3A. Understanding this mechanism highlights why therapies that target these epigenetic modifiers or mimic GLP-1 (like GLP-1 agonists) are effective, as they bypass or reverse this specific block in insulin secretion.

Classical anti-obesity agents (orlistat, phentermine-topiramate, naltrexone-bupropion) typically achieve only modest weight loss (3-10%) and are limited by tolerability and safety concerns.

Orlistat is an older, oral weight loss medication that helps block fat absorption. It typically leads to modest weight loss (3-5%) and can cause gastrointestinal side effects like oily stools. It is generally reserved for patients who cannot access or tolerate newer, more effective injectable therapies.

Multi-agonist therapies (GLP-1/GIP, GLP-1/Glucagon, GLP-1/GIP/Glucagon) do not inherently offer better tolerability than GLP-1 monotherapy; in fact, glucagon receptor activation may increase nausea and vomiting rates.

Do not assume that newer, multi-agonist weight loss drugs are easier on your stomach than older GLP-1 drugs. Some of these newer drugs actually cause more nausea because they target additional receptors that can trigger vomiting. You still need to start with a low dose and go slow, regardless of how many receptors the drug targets.

Combination therapy with ARNIs and SGLT2 inhibitors produces synergistic cardiovascular, metabolic, and renal benefits in cardiometabolic syndrome (CMS) patients, though implementation is hindered by hypotension risks and cost.

If you have cardiometabolic syndrome, current guidelines suggest combining an ARNI (like sacubitril/valsartan) with an SGLT2 inhibitor (like empagliflozin or dapagliflozin) for the best heart, kidney, and metabolic protection. Start with low doses and increase slowly to avoid dizziness or low blood pressure. Monitor your kidney function and electrolytes regularly. Discuss insurance coverage with your provider, as these drugs can be expensive but are cost-effective long-term by preventing hospitalizations.

Novel mineralocorticoid receptor antagonists (MRAs) like finerenone reduce cardiovascular events and slow CKD progression in CMS patients with lower hyperkalemia risk compared to traditional MRAs.

If you have kidney disease and heart issues, ask your doctor about finerenone. It protects your kidneys and heart with a lower risk of dangerous potassium levels compared to older drugs. It is taken once daily.

Genetically proxied GIPR agonist reduces the risk of 14 cardiometabolic diseases, including obesity, hypertension, and coronary heart disease, with effects on angina and myocardial infarction partially mediated by the inflammatory biomarker Flt3L.

Genetic evidence supports that activating the GIP receptor reduces the risk of major cardiometabolic diseases, including obesity, hypertension, and heart conditions. This benefit is partly achieved by lowering levels of the inflammatory protein Flt3L, which is linked to angina and heart attacks. This suggests GIP-targeting therapies could offer broader heart health benefits beyond blood sugar control.

Both semaglutide and liraglutide cause gastrointestinal adverse effects (nausea, vomiting, diarrhea) which are the most common reason for drug discontinuation.

Expect gastrointestinal side effects like nausea when starting GLP-1 medications. These are common, usually mild, and tend to decrease over time. Slow titration can help manage them.

GLP-1 and GIP receptor agonists (semaglutide, tirzepatide) are teratogenic in animal models and lack human pregnancy safety data, necessitating discontinuation prior to conception.

Stop semaglutide or tirzepatide 1-2 months before you start trying to get pregnant. While no defects have been reported in humans yet, animal studies show potential risks, so it is safer to be off the medication before conception.

Endogenous GLP-1 and GIP hormones play a critical role in cardiovascular physiology, with GLP-1 promoting cardioprotection through anti-apoptotic signaling and improved glucose utilization, while GIP's role is complex and species-dependent.

Your body naturally produces hormones called GLP-1 and GIP that help protect your heart and blood vessels. GLP-1 improves blood flow, reduces inflammation, and helps your heart use energy efficiently during stress. GIP also plays a role in metabolism and heart health. Understanding these natural pathways helps explain why medications that mimic them are so effective for heart health.

GLP-1 receptor agonists (Semaglutide and Tirzepatide) are associated with gastrointestinal adverse effects and specific contraindications, including personal or family history of medullary thyroid cancer.

Be aware that these medications can cause gastrointestinal issues, which are best managed by starting at a low dose and increasing slowly. Do not use these medications if you have a personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia type 2.

Tirzepatide (0.144 mg/kg) significantly reduces voluntary alcohol consumption, prevents binge-like drinking, and suppresses relapse-like behaviors in rodents.

Tirzepatide, a dual GLP-1/GIP agonist, significantly reduces alcohol consumption and prevents relapse in rodent models by attenuating dopamine reward signaling. While preclinical, these findings suggest potential for treating Alcohol Use Disorder (AUD) and its metabolic complications.

Administration of BHB-Phe (50 mg/kg, IP) suppresses food intake and body weight in obese mice by activating distinct hypothalamic and brainstem neural populations, independent of melanocortin, GLP-1, or GDF15 pathways.

This research identifies a specific metabolite, BHB-Phe, which reduces food intake in obese mice. It works by activating specific brain regions, distinct from other known weight loss pathways. While the pathway is conserved in humans, direct efficacy in humans has not been established. Current BHB supplements do not necessarily provide this specific conjugate in bioavailable forms or doses shown to be effective in mice.

SGLT2 inhibitors reduce the risk of developing diabetes in high-risk patients with heart failure or chronic kidney disease.

If you have heart failure or kidney disease, even without diabetes, ask your doctor if an SGLT2 inhibitor is right for you. These drugs protect your heart and kidneys and may also prevent diabetes.