Cushing's syndrome is the most frequently missed endocrine cause of weight gain in primary care — the characteristic fat distribution (truncal/central obesity with thin extremities, 'buffalo hump' of upper back, 'moon face' from supraclavicular and temporal fat pads), combined with proximal myopathy (difficulty rising from a chair without using arms), violaceous striae (wide, >1 cm, purple-red — unlike the white striae of simple obesity), easy bruising, and hypertension forms the classic Cushingoid phenotype. Exogenous corticosteroid use is by far the most common cause of Cushing's syndrome in the UK — any patient taking prednisolone, inhaled high-dose corticosteroids (particularly in combination), or topical potent steroids over large areas can develop iatrogenic Cushing's. The GP's first step: a thorough steroid exposure history (all routes — oral, inhaled, intranasal, topical, intra-articular injections). Endogenous Cushing's (ACTH-dependent — pituitary adenoma Cushing's disease, or ectopic ACTH from small cell lung cancer; ACTH-independent — adrenal adenoma or carcinoma) requires biochemical confirmation before referral — a single elevated cortisol is insufficient.

Drug-induced weight gain is one of the most important and most frequently overlooked causes of weight gain in primary care — the GP who prescribes olanzapine 10 mg without monitoring metabolic parameters or without advising the patient about weight gain risk is setting up a preventable adverse outcome. Olanzapine and clozapine are the most potent weight-gain-inducing antipsychotics (average 4-6 kg in 10 weeks of olanzapine in the CATIE trial, with some patients gaining 10-15 kg over a year). The mechanism: H1 receptor antagonism (appetite increase and sedation), muscarinic antagonism (dry mouth → increased caloric beverages), and direct effects on hypothalamic appetite regulation. NICE Medicines and Prescribing guidance recommends that BMI, waist circumference, blood pressure, fasting glucose, and fasting lipids are monitored: at baseline before starting any antipsychotic, at 1 month, 3 months, and then annually. GPs with patients on antipsychotics who have not had annual metabolic monitoring should initiate this at the next review.

The waist circumference measurement is a more important cardiovascular risk indicator than BMI alone and is systematically underused in UK primary care — BMI does not distinguish fat from muscle mass or central from peripheral fat distribution. A patient with BMI 28 (overweight) who has a waist circumference of 105 cm has metabolic syndrome and significantly elevated cardiovascular risk. Conversely, a muscular patient with BMI 28 and waist circumference 88 cm has much lower metabolic risk. The action thresholds: waist circumference above 94 cm in men (above 90 cm in South Asian men — lower threshold because South Asian populations have greater metabolic risk at equivalent waist circumference) or above 80 cm in women increases the risk of metabolic syndrome. Above 102 cm in men and above 88 cm in women substantially increases the risk. NICE NG187 and QOF indicators include waist circumference measurement in obesity assessment. GPs who measure BMI but not waist circumference at cardiovascular risk assessments are missing clinically important information.

NAFLD/MASLD assessment using the FIB-4 score is a NICE-recommended, guideline-endorsed approach for stratifying liver fibrosis risk in patients with obesity and elevated liver enzymes in primary care — the FIB-4 formula (age × AST / (platelet count × √ALT)) uses readily available blood test results and predicts the likelihood of significant hepatic fibrosis (F2+ fibrosis) with an AUROC of approximately 0.80. The cut-offs: FIB-4 below 1.3 = low risk (negative predictive value approximately 90% for advanced fibrosis — no further investigation needed, monitor annually); FIB-4 1.3-2.67 = indeterminate (ELF test or FibroScan); FIB-4 above 2.67 = high risk (hepatology referral). NICE NG49 (Non-Alcoholic Fatty Liver Disease) recommends FIB-4 as the primary non-invasive fibrosis assessment tool in primary care. GPs should calculate FIB-4 at the annual review of all patients with NAFLD/MASLD risk factors (obesity, T2DM, metabolic syndrome). This is a 30-second calculation from existing blood tests and can prevent unnecessary hepatology referrals for low-risk patients while identifying high-risk patients who need specialist input.

The bariatric surgery referral pathway in the UK has been expanded by NICE NG189 — notably, the accelerated pathway allows direct referral for bariatric surgery consideration in patients with BMI ≥35 and recently diagnosed T2DM (diagnosed within 10 years), bypassing the requirement to first complete Tier 2-3 weight management programmes. This is because the SOS trial, STAMPEDE trial, and multiple other RCTs demonstrate that bariatric surgery achieves T2DM remission in approximately 30-70% of patients (depending on procedure and duration of diabetes), which is substantially better than any medical treatment. The DiRECT trial also shows that intensive dietary intervention (800 kcal/day VLCD for 12 weeks) achieves T2DM remission in approximately 46% at 12 months — this can be offered through NHS Tier 2 programmes before surgical referral for motivated patients. GPs should be aware that bariatric surgery in eligible patients reduces: T2DM burden, cardiovascular events, sleep apnoea, and all-cause mortality — it is not a cosmetic intervention.

Semaglutide 2.4 mg (Wegovy) represents the most significant advance in pharmacological obesity treatment in decades — the STEP 1 trial demonstrated 14.9% mean weight loss versus 2.4% for placebo over 68 weeks in adults with BMI ≥30 (or ≥27 with comorbidity), without diabetes. The SELECT trial (2023, NEJM) showed that semaglutide 2.4 mg reduces major adverse cardiovascular events (MACE — myocardial infarction, stroke, cardiovascular death) by 20% in patients with overweight/obesity and established cardiovascular disease, independently of weight loss. This cardiovascular outcome data has transformed the framing of obesity pharmacotherapy from 'cosmetic' to 'life-saving' — semaglutide is now indicated both for weight reduction and for cardiovascular risk reduction in appropriate patients. NICE TA875 approved semaglutide 2.4 mg for weight management in England for patients with BMI ≥35 (or ≥30 with at least one weight-related comorbidity) as part of a Tier 3 specialist weight management programme. GPs cannot currently initiate Wegovy — referral to Tier 3 services is required — but this pathway is evolving rapidly.

Metformin for antipsychotic-induced weight gain is an evidence-based intervention that is underused in UK primary care — a meta-analysis (Zheng 2015) showed that metformin 500-1000 mg BD in patients on antipsychotics reduced body weight by approximately 3 kg and improved insulin sensitivity compared to placebo, without significant adverse effects. The mechanism: metformin reduces hepatic glucose output and improves insulin sensitivity, partially counteracting the insulin-resistance-promoting effects of olanzapine and clozapine. NICE guideline CG178 (psychosis and schizophrenia in adults) acknowledges that metformin can be considered for patients with antipsychotic-induced weight gain who have not responded to lifestyle interventions alone. GPs reviewing patients with antipsychotic-induced metabolic syndrome should consider metformin as part of the management — prescribing it alongside the antipsychotic for its insulin-sensitising and weight-modulating effects, not just waiting for frank T2DM to develop before starting it.

The VLCD (very low calorie diet, 800 kcal/day) approach for T2DM remission, tested in the DiRECT trial (Lean et al., NEJM/Lancet 2018), represents one of the most important recent paradigm shifts in obesity and diabetes management — the trial showed that intensive dietary intervention (Counterweight-Plus total diet replacement programme, 825-853 kcal/day for 12 weeks, then food reintroduction and structured support) achieved T2DM remission (HbA1c <48 mmol/mol off all antidiabetic medications) in 46% of participants at 12 months and 36% at 24 months, compared to 4% in the standard care group. Weight loss of 10-15 kg was the critical driver of remission. This is substantially better than any pharmacological treatment for T2DM remission (metformin and SGLT2 inhibitors do not cause remission — they control glucose). NHS England has commissioned the NHS Low Calorie Diet Programme, which delivers VLCD intervention to patients with T2DM diagnosed within 6 years and BMI ≥27 (≥25 in South Asian populations). GPs should refer eligible patients to this programme — it is the single most effective intervention for T2DM remission in primary care.

The QRISK3 recalculation at annual weight management review is a tangible motivator for patients that GPs often overlook — showing a patient their QRISK3 cardiovascular risk score before and after a 5-10% weight loss demonstrates the direct health benefit of their effort in quantitative terms. A 5% weight loss in a 55-year-old man with metabolic syndrome might reduce QRISK3 from 18% to 12% 10-year cardiovascular risk — a meaningful reduction that translates into reduced likelihood of needing statins or antihypertensives, and a tangible reward for the patient's effort. Similarly, showing HbA1c reduction from 58 to 46 mmol/mol (T2DM remission) is a powerful motivator. GPs should incorporate before/after metabolic data comparisons into every annual weight management review — framing weight loss not as an aesthetic goal but as a directly measurable health improvement with quantified outcomes.