Browse the evidence

Adding the long-acting PYY3-36 analogue PYY1875 (1.0 mg/week) to semaglutide (2.4 mg/week) yields only modest, non-clinically meaningful additional weight loss in people with obesity and is poorly tolerated due to gastrointestinal adverse events.

For individuals already on semaglutide, adding PYY1875 at 1.0 mg weekly provides only a small, likely unnoticeable additional weight loss benefit while significantly increasing the risk of gastrointestinal side effects like nausea. The 2.0 mg dose was not tolerated. Current evidence suggests this combination is not a viable strategy for improving weight loss outcomes due to poor tolerability and lack of clinical significance.

Concerns about side effects, long-term health risks, and potential for weight regain are significant barriers to patient interest in incretin-based anti-obesity medications, with higher endorsement of these barriers associated with lower interest in using the therapies.

If you are considering incretin-based weight loss medications, know that your concerns about side effects, long-term risks, and weight regain are common and valid. These concerns directly impact your interest in the treatment. To overcome these barriers, engage in open discussions with your healthcare provider about the relative risks of the medication versus the risks of untreated obesity, and inquire about support for lifestyle programs designed for medication users.

Endogenous peripheral GLP-1 enhances glucose-induced insulin release primarily through a vago-vagal reflex mediated by GLP-1 receptors on vagal sensory fibers, rather than through direct endocrine action on pancreatic beta-cells.

Your body's natural response to eating involves a complex gut-brain-heart axis. GLP-1 released from your gut doesn't just float to your pancreas; it signals your vagus nerve to help manage insulin. This highlights the importance of the neural connection between digestion and metabolic control, suggesting that factors affecting nerve health or gut signaling might influence metabolic efficiency.

Central GLP-1 produced by hindbrain PPG neurons and peripheral GLP-1 from intestinal L-cells regulate food intake through independent pathways, rather than acting synergistically or additively.

Your body uses two separate GLP-1 systems—one in your gut and one in your brainstem—to control hunger. They don't necessarily rely on each other. This means issues with gut hormone production might not directly impair your brain's satiety signals, and vice versa.

Using percent body weight loss as the sole target for obesity management is not ideal because it is often not feasible or sustainable for most participants and fails to capture holistic health outcomes.

Stop fixating on a specific percentage of weight loss as the only measure of success. For many people, achieving even a modest weight loss is not sustainable. Instead, focus on patient-centered outcomes like improved blood pressure, better glycemic control, and increased quality of life, which can be achieved through various lifestyle changes regardless of the final number on the scale.

Hepatic protein kinase Cbeta (PKCβ) deficiency mitigates late-onset obesity in mice by increasing energy expenditure through β3-adrenergic receptor signaling, independent of FGF21.

This research suggests that as we age, our liver may produce more PKCβ, which can suppress our body's ability to burn fat and heat (thermogenesis). While you cannot change your genetics, maintaining liver health through regular physical activity—which is shown to repress PKCβ expression—may help preserve your metabolic rate and resistance to age-related weight gain.

Physiological levels of GIP promote fat accumulation and insulin resistance in the context of high-fat diets and aging, acting as a 'thrifty hormone' that stores nutrients.

In the context of a high-fat diet, your body's natural GIP hormone helps store fat and may contribute to insulin resistance. This is why blocking GIP (antagonism) can help reduce obesity, while stimulating it pharmacologically (agonism) works through different mechanisms like appetite suppression in the brain.

Utilization of newer non-insulin glucose-lowering drugs (SGLT2 inhibitors and GLP-1RAs) has increased significantly in Australia, driven by cardiovascular and renal benefits, while older agents (sulphonylureas, glitazones) have declined.

If you have Type 2 Diabetes, talk to your doctor about newer medications like SGLT2 inhibitors or GLP-1RAs. These drugs not only lower blood sugar but also protect your heart and kidneys. While they are more expensive than older medications, they are increasingly recommended as first-line treatments due to these additional benefits.

Tirzepatide (5-15 mg weekly) does not increase the risk of adjudication-confirmed pancreatitis compared to placebo, insulin, or GLP-1 receptor agonists, despite causing greater elevations in serum pancreatic amylase and lipase.

If you are prescribed Tirzepatide for weight loss or diabetes, do not panic if your blood tests show higher pancreatic enzymes. The data shows this is a common side effect of the drug's mechanism but does not translate to actual pancreatitis. Routine monitoring is still advised, but the risk of clinical pancreatitis is no higher than with other standard treatments.

Switching antipsychotics to Aripiprazole results in significant weight reduction, but adding Aripiprazole to an existing regimen is not recommended due to increased risks of agitation and akathisia.

If you are gaining weight on your current antipsychotic, switching to Aripiprazole can lead to significant weight loss. However, do not simply add Aripiprazole to your current medication, as this can cause agitation and anxiety. Switching must be done carefully with your doctor, weighing the mental health stability against the metabolic benefits.

Increasing resistance training volume from moderate (3 sets/exercise) to high (5 sets/exercise) does not improve lean mass or muscle thickness preservation during a moderate caloric deficit in trained males.

If you are dieting to lose fat but want to keep your muscle, you do not need to drastically increase your training volume. A moderate volume (e.g., 3 sets per exercise) is just as effective as high volume (5 sets) for preserving muscle mass, provided you are eating enough protein (approx. 2.8g/kg FFM) and maintaining a moderate caloric deficit. Focus on keeping weights heavy (close to failure) rather than adding extra sets.

Initiating insulin glargine in patients with type 2 diabetes is associated with a higher risk of gastroparesis, intestinal obstruction, and all-cause mortality compared to initiating SGLT2 inhibitors.

If you are considering insulin glargine for type 2 diabetes, know that it is associated with a higher risk of gastroparesis, intestinal obstruction, and death compared to SGLT2 inhibitors. This does not mean insulin is bad, but it highlights the importance of choosing the right medication for your specific health profile. If you are at risk for GI issues, SGLT2 inhibitors might be a safer choice.

Knockout of the microprotein encoded by Adipocyte-smORF-1183 significantly impairs adipocyte differentiation and reduces lipid droplet formation.

This research identifies a specific, previously unknown protein (Adipocyte-smORF-1183) in mouse fat cells that is essential for storing fat. Knocking out this protein reduces fat storage by about half in these cells. While this is a fundamental biological discovery that could lead to future therapies for obesity, it is currently limited to cell culture models and does not yet translate to a direct human treatment or lifestyle intervention.

Higher circulating estrogen levels in women are predictive of increased rates of nausea and vomiting when taking GLP-1 receptor agonists, and estrous cycle phase modulates drug sensitivity in female mice.

Your risk of side effects from GLP-1 drugs may fluctuate with your menstrual cycle, peaking when estrogen is highest. While this paper used mice, human data suggests higher estrogen levels correlate with more nausea. Tracking your cycle might help you and your doctor anticipate and manage side effects.

Daily supplementation with 0.6 g/kg body weight of whey protein does not enhance body composition, core muscle endurance, or joint flexibility adaptations in trained women performing 10 weeks of Pilates training, despite increasing total daily protein intake to ~1.78 g/kg.

If you are a trained woman doing Pilates regularly, adding whey protein supplements on top of your normal diet will not make you lose more fat, gain more muscle, or improve your flexibility compared to just doing the training. Focus on consistent training and adequate whole-food protein intake rather than buying supplements.

Males in the US have consistently higher diabetes incidence and prevalence than females across all age groups, with a significant disparity that becomes more pronounced in older cohorts.

Men in the US are diagnosed with diabetes more often than women, and this gap widens with age. This may be partly due to biological factors and partly due to less frequent healthcare engagement. Men should prioritize regular screening and not delay care due to cultural norms.

The Behavioral Change Technique 'Instruction on how to perform behaviour' is associated with weight GAIN (mean weight change +2.53 kg) rather than loss, suggesting it may be counterproductive in brief, opportunistic primary care advice.

Avoid using 'Instruction on how to perform behaviour' (like handing out leaflets or directing to websites) as a primary strategy in brief weight loss advice. This study found it was associated with weight gain, likely because it is used as a 'simple way to intervene' with patients who are less ready to change. Instead, focus on motivational feedback and follow-up.

Low baseline ribosome-related gene expression and resistance training-induced declines in ribosome-related gene expression are associated with greater skeletal muscle hypertrophy in young men and women.

If you are struggling to build muscle despite consistent resistance training, your baseline cellular machinery (ribosomes) might be a limiting factor, but this is largely genetic or determined by prior activity levels. The key takeaway is that 'more' isn't always 'better' for muscle growth; your body may adapt by becoming more efficient with what it has rather than expanding its capacity. Focus on progressive overload and consistency, as the body's response is individual and not strictly dictated by having the highest possible baseline ribosome levels.

Usual intakes of animal and plant protein are not adversely associated with all-cause, cardiovascular disease, or cancer-related mortality risk in adults.

You do not need to restrict your protein intake, whether from animal or plant sources, to avoid increasing your risk of death from all causes, heart disease, or cancer. The data suggests that typical protein intakes within recommended ranges are safe and not linked to higher mortality.

GLP-1RA treatment induces distinct molecular changes in skeletal muscle proteome (upregulation of mitochondrial proteins) compared to calorie restriction, despite similar weight loss and muscle mass changes.

This finding is primarily mechanistic and suggests GLP-1s may improve muscle metabolic efficiency (mitochondrial function) beyond just weight loss, though this does not currently translate to a specific user action beyond standard treatment.

GLP-1 receptor agonists and MC4R modulators are emerging therapeutic strategies that target hypothalamic pathways to treat metabolic diseases.

Current treatments for obesity and diabetes, such as GLP-1 receptor agonists, work by targeting specific pathways in the hypothalamus. This highlights the importance of central nervous system mechanisms in these conditions and supports the use of these medications as effective treatments.

GLP-1 receptor agonists slow renal disease progression and reduce albuminuria in patients with diabetic kidney disease, although evidence is less robust than for SGLT2 inhibitors.

If you have diabetic kidney disease, GLP-1 receptor agonists may help slow kidney damage and reduce protein in your urine. While there is less data on their kidney benefits compared to SGLT2 inhibitors, they are still considered valuable. Discuss with your doctor if they are appropriate for you, especially if you have cardiovascular risks.

Orforglipron is associated with a dose-dependent increase in gastrointestinal adverse events (nausea, vomiting, diarrhea, constipation) and treatment discontinuation rates, particularly at doses of 12 mg and higher.

While effective, orforglipron often causes stomach problems like nausea, vomiting, and diarrhea, especially at higher doses (12 mg and above). These side effects are the main reason people stop taking the medication. Patients should be aware that higher doses provide more weight loss but also carry a higher risk of stopping treatment due to discomfort. Starting at a lower dose and titrating slowly may help manage these side effects.

Discontinuing or interrupting GLP-1 receptor agonist (GLP-1RA) treatment progressively erodes cardiovascular protection, with longer durations of non-use associated with a graded increase in the risk of major adverse cardiovascular events (MACE).

If you have Type 2 Diabetes and take a GLP-1RA (like Ozempic or Wegovy), your heart protection is tied to continuous use. Stopping the medication does not leave you in a 'safe' state; it actively increases your risk of heart attack or stroke, and the longer you stay off the drug, the higher that risk becomes. If you must stop due to side effects or cost, do not just stop abruptly; consult your provider for a strategy to manage the increased cardiovascular risk during the transition.