Diabetes and Weight Medicines

TL;DR. Two drug classes changed this field in the last decade. SGLT2 inhibitors make you excrete glucose in urine and turned out, unexpectedly, to protect the heart and kidneys regardless of whether you have diabetes. GLP-1 receptor agonists mimic a gut hormone, produce weight loss of 15 to 20 percent with the newer agents, and in a large randomised trial reduced cardiovascular events in people with obesity and no diabetes. Metformin remains first-line for type 2 diabetes after 70 years. The most important safety facts are the hypoglycaemia rules for insulin and sulfonylureas, and that GLP-1 drugs must be stopped before general anaesthesia.

1. What is being treated

Type 1 diabetes: autoimmune destruction of pancreatic beta cells. No insulin is made. Insulin is mandatory and lifelong; it is not a lifestyle disease and it cannot be managed with diet alone.

Type 2 diabetes: insulin resistance plus progressive beta cell failure (Chapter 11). Managed with lifestyle, oral drugs, injectables, and eventually insulin in many people.

Diagnosis: fasting glucose 7.0 mmol/L (126 mg/dL) or above, or HbA1c 48 mmol/mol (6.5 percent) or above, on two occasions.

Remission is possible in type 2. The DiRECT trial put a substantial proportion of participants into remission at one year using a structured low-calorie diet, with remission strongly related to weight loss achieved. This changed how type 2 diabetes is discussed: it is not necessarily a one-way progressive condition.

2. Metformin

First-line for type 2 diabetes in essentially every guideline, and derived from French lilac (Galega officinalis), a traditional remedy for excessive urination whose active guanidine compounds were identified in the 1920s.

Mechanism: not fully settled, which is remarkable for a drug used by hundreds of millions. It reduces hepatic glucose production (the dominant effect), improves peripheral insulin sensitivity, and acts partly through AMPK and partly through effects in the gut, including on the microbiome and on GLP-1 secretion.

Why it is first-line: effective, cheap, weight-neutral or slightly weight-reducing, does not cause hypoglycaemia on its own, and has 60-plus years of safety data.

Side effects:

• Gastrointestinal upset in 20 to 30 percent: nausea, diarrhoea, metallic taste, abdominal discomfort. Usually settles over weeks. Start low, go slow, take with food, and switch to the modified-release form if it persists, which resolves it for many people.
• Vitamin B12 deficiency with long-term use, through reduced ileal absorption. Levels should be checked periodically, and this is frequently overlooked (Chapter 15).
• Lactic acidosis: extremely rare (roughly 3 to 10 per 100,000 patient-years) and serious. Occurs when metformin accumulates in kidney failure. Hence the rules below.

The sick day rule, which matters and is under-communicated:

Stop metformin during any illness causing dehydration: vomiting, diarrhoea, high fever, or reduced oral intake. Also hold it around contrast imaging and surgery. Restart when eating and drinking normally. This applies to several other drugs too (ACE inhibitors, ARBs, diuretics, NSAIDs, SGLT2 inhibitors), collectively called "sick day rules," and being given a written list is worth asking for.

Contraindicated below an eGFR of 30, dose-reduced between 30 and 45.

3. SGLT2 inhibitors (-gliflozin)

Dapagliflozin, empagliflozin, canagliflozin

Mechanism: block the sodium-glucose cotransporter 2 in the kidney's proximal tubule, so glucose that would be reabsorbed is excreted in urine instead, roughly 50 to 80 g a day. It is a deliberately induced glycosuria.

The surprise: cardiovascular outcome trials mandated by regulators after the rosiglitazone episode found these drugs reduced cardiovascular death, heart failure hospitalisation, and kidney disease progression to a degree far beyond what their modest glucose lowering could explain. Subsequent trials (DAPA-HF, EMPEROR, DAPA-CKD, EMPA-KIDNEY) showed the benefits apply to people without diabetes.

They are now indicated for heart failure and chronic kidney disease in their own right, which is a genuinely unusual trajectory: a diabetes drug that turned out to be a cardiac and renal drug (Chapter 75). The mechanism is still debated, with theories involving haemodynamic effects, reduced cardiac workload, and a shift to ketone metabolism.

Side effects:

• Genital fungal infections (thrush, balanitis): common, from sugar in the urine. Usually manageable with hygiene and antifungals.
• Urinary tract infections.
• Volume depletion and hypotension, especially with diuretics.
• Euglycaemic diabetic ketoacidosis: rare and dangerous because the blood glucose can be normal or only mildly raised, so it is missed. Triggered by illness, surgery, fasting, very low carbohydrate diets, or alcohol. Stop SGLT2 inhibitors during acute illness and before surgery.
• Fournier's gangrene: a very rare but devastating necrotising infection of the perineum, carrying a regulatory warning.

4. GLP-1 receptor agonists (-glutide, -tide)

Semaglutide (Ozempic, Wegovy, Rybelsus), liraglutide (Victoza, Saxenda), dulaglutide, exenatide; tirzepatide (Mounjaro, Zepbound) is a dual GIP/GLP-1 agonist

Mechanism. GLP-1 is an incretin, a hormone released by the gut when food arrives (Chapter 10). These drugs are engineered analogues resistant to the enzyme that normally destroys GLP-1 within minutes, giving them half-lives of a day (liraglutide) to a week (semaglutide).

They:

• Stimulate insulin release in a glucose-dependent way, so they rarely cause hypoglycaemia alone
• Suppress glucagon
• Slow gastric emptying, so food stays in the stomach longer
• Act on hypothalamic appetite centres, reducing hunger and "food noise"

The effect sizes:

For comparison, previous weight-loss drugs achieved 3 to 8 percent. This is a step change, and it brings drug therapy into a range previously achievable only with bariatric surgery.

Beyond weight and glucose:

• SELECT trial (2023): semaglutide reduced major cardiovascular events by 20 percent in people with obesity and established cardiovascular disease and no diabetes. This established a cardiovascular indication independent of glycaemic control.
• FLOW trial: kidney benefit in diabetic kidney disease.
• Trials underway in heart failure, sleep apnoea, MASLD (fatty liver disease), and addiction, with early signals in several.

Side effects:

• Gastrointestinal, in most people: nausea, vomiting, diarrhoea, constipation, reflux. Usually worst on starting and after each dose increase, and improving over weeks. Dose escalation is slow specifically to manage this.
• Gallstones and gallbladder disease, related to rapid weight loss.
• Pancreatitis: uncommon; persistent severe abdominal pain radiating to the back needs urgent assessment.
• Muscle mass loss: a substantial share of weight lost is lean mass, as with any rapid weight loss. Resistance exercise and adequate protein (1.2 to 1.6 g/kg) matter considerably (Chapter 12).
• Thyroid C-cell tumours in rodents, prompting a contraindication in people with a personal or family history of medullary thyroid carcinoma or MEN2. Not demonstrated in humans.
• Weight regain on stopping is substantial: STEP 4 found participants regained around two thirds of lost weight within a year of stopping. These are treatments for a chronic condition, not a course.

Before any procedure with sedation or general anaesthesia, tell the team you take a GLP-1 drug. Delayed gastric emptying means the stomach may still contain food after standard fasting, with a risk of aspiration. Anaesthetic societies have issued specific guidance, generally advising holding weekly agents for a week beforehand.

Access, supply, and counterfeits. Demand has outstripped supply repeatedly. Counterfeit semaglutide pens have been found in several countries, some containing insulin instead, which has caused hospitalisations from severe hypoglycaemia. Buy only through regulated pharmacies with a genuine prescription; the online market is genuinely dangerous.

5. The other diabetes drugs

Rosiglitazone is the cautionary tale that reshaped the field: withdrawn or restricted from 2010 after meta-analyses suggested increased myocardial infarction. It is why regulators now require cardiovascular outcome trials for all new diabetes drugs, which is precisely how the SGLT2 and GLP-1 benefits were discovered.

6. Insulin

Mandatory in type 1, and used in type 2 when other treatments are insufficient.

Basal-bolus regimens mimic normal physiology: a long-acting background insulin plus rapid-acting doses with meals, adjusted by carbohydrate counting. Insulin pumps deliver continuous subcutaneous infusion. Closed-loop systems ("artificial pancreas") combine a pump with continuous glucose monitoring and an algorithm, and they are transformative for type 1 diabetes.

Practical points:

• Rotate injection sites. Repeatedly injecting the same spot causes lipohypertrophy, lumpy fatty tissue with erratic absorption, which is a common and preventable cause of unstable control.
• Absorption is fastest from the abdomen, slower from thigh and buttock.
• Heat, exercise, and massage speed absorption; cold slows it. A hot bath after injecting can precipitate hypoglycaemia.
• Store unopened insulin in the fridge; in-use pens at room temperature for up to a month. Never freeze insulin, which destroys it.
• Insulin prices in the US became a political issue after decades of increases, with caps eventually introduced. It is worth noting that Banting, Best, and Collip sold the insulin patent for one dollar each in 1923 explicitly so it would be affordable.

7. Hypoglycaemia: the emergency to know

Caused by insulin and sulfonylureas. Metformin, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 agonists do not cause it alone.

Symptoms, in two stages:

• Autonomic (early, 3.3 to 3.9 mmol/L): sweating, shaking, palpitations, hunger, anxiety, tingling lips.
• Neuroglycopenic (below ~3.0): confusion, slurred speech, odd behaviour, drowsiness, seizures, unconsciousness.

Hypoglycaemia unawareness develops with repeated episodes: the warning symptoms disappear, and the first sign becomes confusion or collapse. It is dangerous and is a reason for driving restrictions.

Treatment, the "15-15 rule":

1. 15 to 20 g of fast-acting carbohydrate: 4 to 5 glucose tablets, 150 to 200 mL of fruit juice or non-diet cola, or a tube of glucose gel. Not chocolate, whose fat slows absorption.
2. Wait 15 minutes and re-test.
3. Repeat if still below 4.0 mmol/L.
4. Then eat a longer-acting carbohydrate (sandwich, biscuits) to prevent recurrence, especially if the next meal is not imminent.

If unconscious or unable to swallow: do not put anything in their mouth. Place in the recovery position, give glucagon (injection or nasal spray) if available and you are trained, and call an ambulance.

Beta blockers mask the autonomic warning symptoms, which is a genuine safety consideration in people with diabetes (Chapter 75).

Alcohol causes delayed hypoglycaemia by suppressing hepatic glucose production, sometimes many hours later, overnight. Eat carbohydrate when drinking, and never assume symptoms are just drunkenness.

8. The bottom line

• Metformin remains first-line for type 2 diabetes: effective, cheap, no hypoglycaemia, and the GI side effects usually settle or resolve on the modified-release form. Check B12 periodically and stop it during dehydrating illness.
• SGLT2 inhibitors cause glucose loss in urine and unexpectedly reduce cardiovascular death, heart failure, and kidney disease progression, in people with and without diabetes. Watch for genital thrush and euglycaemic ketoacidosis.
• GLP-1 agonists produce 15 to 20 percent weight loss with the newer agents and, in SELECT, reduced cardiovascular events in obesity without diabetes. Weight returns when stopped; they are chronic treatments.
• Tell any anaesthetist you take a GLP-1 drug, because delayed gastric emptying creates aspiration risk. And buy them only from regulated pharmacies; counterfeits containing insulin have hospitalised people.
• Only insulin and sulfonylureas cause hypoglycaemia. Learn the 15-15 rule, know that beta blockers mask the warning signs, and know that alcohol causes it hours later.
• Type 2 diabetes remission is achievable with substantial weight loss.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium; US figures follow FDA labelling. Diagnostic thresholds follow WHO and ADA criteria. Metformin's mechanism, still incompletely resolved, follows Rena, Hardie, and Pearson's review, Diabetologia, 2017; its origin in Galega officinalis follows Bailey's history. Metformin-associated B12 deficiency follows Aroda et al.'s DPPOS analysis. Sick day rules follow NICE and Diabetes UK guidance. SGLT2 inhibitor cardiovascular and renal outcomes follow EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, DAPA-HF, EMPEROR-Reduced, DAPA-CKD, and EMPA-KIDNEY. Euglycaemic ketoacidosis and Fournier's gangrene follow FDA safety communications. GLP-1 pharmacology follows Drucker's reviews. Weight outcomes follow the STEP programme (Wilding et al., NEJM, 2021) and SURMOUNT-1 (Jastreboff et al., NEJM, 2022). Cardiovascular benefit in obesity without diabetes is SELECT, Lincoff et al., NEJM, 2023; renal benefit is FLOW. Weight regain on discontinuation follows STEP 4, Rubino et al., JAMA, 2021. Anaesthesia guidance on holding GLP-1 agonists follows the American Society of Anesthesiologists 2023 advisory. Counterfeit semaglutide pens containing insulin follow MHRA, EMA, and WHO alerts. Rosiglitazone withdrawal and the resulting FDA requirement for cardiovascular outcome trials follow Nissen and Wolski, NEJM, 2007, and the FDA's 2008 guidance. DiRECT is Lean et al., The Lancet, 2018. Hypoglycaemia management follows Diabetes UK and ADA guidance.

Open questions. Long-term safety and durability of GLP-1 therapy beyond a few years is not yet established, and neither is what happens to the large proportion of people who stop. Whether the SGLT2 cardiorenal benefit has a single mechanism remains debated.

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