Antihyperglycaemic drugs and insulin

• Antihyperglycaemic treatment now aims at glucose, weight and organ protection at the same time; the right drug depends on the person's comorbidities, not only on the HbA1c.
• Metformin is the usual starting drug for type 2 diabetes when kidney function allows, but drugs that protect the heart, kidneys and weight (GLP-1 receptor agonists and SGLT2 inhibitors) are added or used first when those risks are present, whatever the HbA1c.
• Insulin is essential for type 1 diabetes and is still needed in type 2 diabetes when glucose is very high, when symptoms are present, or when other drugs are not enough.
• Every class differs in how much it lowers HbA1c, whether it causes weight gain or loss, and whether it can cause hypoglycaemia; SGLT2 inhibitors and GLP-1 receptor agonists add cardio-renal benefits beyond glucose lowering. ^[1]
• In low-resource settings the WHO keeps metformin and a sulfonylurea as the cheap first and second steps, with human insulin (NPH or regular) the usual insulin. ^[3]

By the end of this page you should be able to:

1. Name the ten main antihyperglycaemic classes, state how each lowers glucose, and compare their effects on HbA1c, weight and hypoglycaemia.
2. Choose and justify glucose-lowering therapy for a person with atherosclerotic cardiovascular disease, heart failure, chronic kidney disease or obesity, using current guideline logic.
3. Plan insulin therapy: which type to use, basal-bolus versus premixed versus pump, and how to start and titrate it.
4. Combine and sequence drugs safely, including the combinations that should not be used together.
5. Outline lifestyle measures that improve glucose and weight, and the support needed to use them.
6. Adapt prescribing when resources are limited, and know which safety issues (lactic acidosis, euglycaemic ketoacidosis, hypoglycaemia) demand action.

This page covers the medical management of high blood glucose: the drug classes used for type 2 diabetes, the insulin families used for type 1 and type 2 diabetes, and the way choices are made in 2026. Type 1 diabetes is an absolute insulin deficiency, so insulin replacement is not optional. Type 2 diabetes is a combination of insulin resistance and relative insulin shortage, with multiple organ targets; that is why there are many drug classes and why combinations are common. A good plan matches the patient, not just the number.

The table lists the ten classes in current wide use. Drug names are examples, not an exhaustive list, and local availability varies.

Notes on the numbers: the HbA1c figures for the alpha-glucosidase inhibitors come from a review of acarbose that reported a mean reduction of 0.8% with acarbose, while the other classes use the efficacy labels and experience reported in the ADA 2026 Standards of Care. Pramlintide's figures come from the ADA 2026 text for adults with type 1 diabetes. ^[1][4]

Each class hits a different part of glucose control, which is why combining them works.

• Metformin mainly reduces the liver's release of glucose and makes muscle and fat respond better to insulin. It does not push the pancreas to release insulin, which is why it rarely causes hypoglycaemia on its own.
• Sulfonylureas and meglitinides force the beta cell to release insulin by closing the K-ATP channel and depolarising the cell. This happens whether or not glucose is high, so hypoglycaemia is a real risk and weight tends to rise.
• Thiazolidinediones activate the nuclear receptor PPAR-gamma. They redistribute fat into safer depots and improve insulin sensitivity; the effect on HbA1c is slow to develop but durable.
• DPP-4 inhibitors stop the breakdown of the natural incretins (GLP-1 and GIP) released after food, so insulin secretion rises and glucagon falls in a glucose-dependent way. The glucose drop is modest.
• GLP-1 receptor agonists and the dual agonist mimic those hormones: they increase insulin release and suppress glucagon when glucose is high, slow gastric emptying and reduce appetite. The dual agonist also activates the GIP receptor, giving the largest weight and HbA1c effects in this family so far.
• SGLT2 inhibitors leave glucose in the urine. The result is lower glucose, modest weight loss and a drop in blood pressure from the accompanying water loss. Their heart and kidney benefits appear to be partly separate from glucose lowering.
• Alpha-glucosidase inhibitors compete with enzymes on the intestinal brush border, so complex carbohydrates are broken down and absorbed later. They only dampen post-meal rises.
• Pramlintide is a synthetic amylin that slows gastric emptying, suppresses the post-meal glucagon surge and promotes satiety. It is used with insulin because it copies a hormone that beta cells normally secrete with insulin.

Most differences here drive dosing and cautions rather than efficacy.

• Metformin is not metabolised. It is cleared by the kidneys and leaves the body unchanged; that is why kidney function gates its use. Extended-release preparations can be taken once daily with food.
• Sulfonylureas are metabolised and renally excreted; glibenclamide in particular can cause long-lasting hypoglycaemia in older people or in kidney impairment. "Short-acting secretagogues" (meglitinides) act for just a few hours.
• Pioglitazone is metabolised by the liver and does not need renal dose adjustment, but fluid retention is the limiting problem.
• DPP-4 inhibitors differ in renal clearance: sitagliptin, saxagliptin and alogliptin need dose reduction as kidney function falls, while linagliptin does not.
• GLP-1 receptor agonists are cleared partly by the kidneys and partly by other routes, but the major ones (liraglutide, semaglutide, dulaglutide) need no dose change in chronic kidney disease, although kidney function should be checked during severe vomiting or diarrhoea.
• SGLT2 inhibitors need adequate kidney function for their glucose effect, so their HbA1c benefit is smaller once filtration falls. Canagliflozin, dapagliflozin and empagliflozin are continued at low kidney function for heart and kidney protection, down to an eGFR above 20 mL per minute per 1.73 square metres. ^[1]
• Alpha-glucosidase inhibitors act locally in the gut and are not absorbed; acarbose is contraindicated in severe kidney or liver disease.
• Pramlintide is injected before meals and works within minutes; doses are reduced to avoid severe nausea.

The immediate indication for any of these drugs is glycaemic control in type 2 diabetes, usually alongside lifestyle change, with an individualised HbA1c target. In practice a sensible default is around 7% (53 mmol per mol) or less for most non-pregnant adults who can achieve it without hypoglycaemia or other harms, with looser targets for frailty or limited life expectancy and tighter ones when drugs carry no hypoglycaemia risk. ^[2] Many patients will need two drugs from the start when HbA1c is far above target, and insulin is indicated promptly if symptoms of hyperglycaemia are present or if HbA1c is above 10% (86 mmol per mol) or blood glucose is at least 300 mg per dL (16.7 mmol per L). ^[1]

Beyond glucose, specific classes are now used for organ protection irrespective of the HbA1c when their benefit has been proven in the relevant condition. That is the part of modern practice that has changed the most.

The ADA 2026 recommendations and the 2022 ADA/EASD consensus agree on the broad logic, although the thresholds are worded differently and guidelines differ on details.

• Atherosclerotic cardiovascular disease or high cardiovascular risk. Add a GLP-1 receptor agonist (liraglutide, dulaglutide, or subcutaneous semaglutide) and/or an SGLT2 inhibitor for glycaemic and comprehensive cardiovascular risk reduction, whether or not the person takes metformin, and irrespective of the HbA1c. ^[1][2]
• Heart failure with reduced or preserved ejection fraction. Add an SGLT2 inhibitor for glycaemic control and fewer heart failure hospitalisations. In symptomatic heart failure with preserved ejection fraction plus obesity, add a GLP-1-based drug (the dual agonist first, then a GLP-1 receptor agonist). ^[1]
• Chronic kidney disease. When eGFR is 20 to 60 mL per minute per 1.73 square metres and/or albuminuria is present, add an SGLT2 inhibitor or a GLP-1 receptor agonist, because each can slow kidney progression and cut cardiovascular events. The glucose-lowering effect of SGLT2 inhibitors is small once eGFR falls below 45. When eGFR is below 30, a GLP-1 receptor agonist is preferred. People on dialysis can still receive a GLP-1-based drug that is not cleared by the kidney. ^[1][2]
• MASLD or MASH with overweight or obesity. Consider a GLP-1 receptor agonist (or the dual agonist) for glucose and weight; if biopsy-proven MASH or high fibrosis risk is present, prefer a GLP-1 receptor agonist, with pioglitazone or the dual agonist as alternatives, and pioglitazone plus a GLP-1 receptor agonist in selected cases. Pioglitazone should still be avoided if heart failure is present. ^{[1] [2]}
• Obesity and weight goals. Weight management is a treatment goal in its own right; drug classes that cause weight loss (GLP-1, dual agonist, SGLT2) are preferred when weight reduction is needed, and GLP-1 therapy is preferred to insulin in people without severe hyperglycaemia or ketoacidosis. ^[1]
• No cardiovascular, kidney or liver complications. Metformin is a common first drug because it is effective, safe, inexpensive and weight-neutral, and it does not cause hypoglycaemia, but combination therapy from the start is reasonable when a large fall in HbA1c is needed. ^[1][2]
• Younger adults with diabetes (under 40) benefit from early combination therapy, and de-intensification should be considered in frail older people on hypoglycaemia-causing drugs. ^[2]

All people with type 1 diabetes need insulin. Many people with type 2 diabetes reach insulin after other drugs no longer achieve the goal, or start it early when glucose is very high.

• Rapid-acting analogues (lispro, aspart, glulisine) and the newer ultra-rapid analogues start within minutes and are given with or just before meals.
• Short-acting regular human insulin must be given about 30 minutes before a meal and lasts longer than the analogues. ^[1]
• Intermediate-acting NPH (isophane) lasts about half a day and is used as basal insulin, but it has a peak that can cause nocturnal hypoglycaemia.
• Long-acting analogues (glargine U100 and U300, detemir, degludec) have flatter profiles and a lower hypoglycaemia risk than NPH; degludec is the longest and allows flexible timing.
• Concentrated insulins (U200, U300, U500) give the same dose in a smaller volume, which helps when doses are large.
• Premixed insulins combine a basal component with a mealtime one in the same pen.
• Inhaled human insulin is a prandial option used in some countries.
• Human insulin (regular and NPH) remains the most affordable and effective option in most of the world and is strongly preferred over analogues when cost is a barrier, except when frequent severe hypoglycaemia occurs on human insulin. ^[3]

Bolus insulin that is short-acting (regular) should ideally be given about 30 minutes before eating; rapid analogues act in time to allow dosing just before or with the first bites. ^[1] When insulin is used in type 2 diabetes, a GLP-1 receptor agonist (including the dual agonist) should be combined with it for better glucose results, less weight gain and less hypoglycaemia, and the insulin dose should be reviewed when the GLP-1 drug is added or increased. ^[1]

Daily requirements for most stable adults are roughly 0.4 to 1 unit per kg per day, with lower needs in new-onset type 1 diabetes (about 0.2 to 0.6 units per kg per day) because some insulin is still produced. ^[1] Insulin is essential in diabetic ketoacidosis and hyperglycaemic hyperosmolar states, and sick-day rules should be written down in advance.

The natural history of type 2 diabetes is progressive, so most people need more than one drug over time. Combination therapy has several advantages: a larger and more durable glucose effect, simultaneous targeting of the underlying defects, better adherence and complementary benefits such as weight loss or organ protection.

• Before insulin: step up by adding drugs with different mechanisms rather than pushing a single drug to its maximum.
• Early combination can be used at diagnosis when glucose is very high or when cardiovascular, kidney or liver benefits are needed.
• Do not combine a DPP-4 inhibitor with a GLP-1 receptor agonist or the dual agonist: no additional glucose lowering occurs beyond the GLP-1-based therapy alone. ^[1]
• Insulin with GLP-1: fixed-ratio combinations of basal insulin plus liraglutide or lixisenatide exist and can improve control with fewer hypoglycaemic episodes than intensified insulin alone, plus better acceptance of the injectable GLP-1 drug. ^[2]
• When a new drug is started, reassess drugs that cause hypoglycaemia (sulfonylureas, meglitinides and insulin) and reduce or stop them to prevent lows. ^[1]
• In the GRADE trial, basal insulin and a GLP-1 receptor agonist were slightly more durable than a sulfonylurea or a DPP-4 inhibitor over five years in people already optimised on metformin, which supports choosing modern agents for long-term control. ^[2]
• Insulins and non-insulin drugs are generally continued together, because the non-insulin agents keep their weight, kidney and cardiovascular benefits even after insulin is started. ^[1]

Hypoglycaemia is the main side effect that limits therapy. It is most likely with sulfonylureas, meglitinides and insulin, and can be reduced by choosing modern non-hypoglycaemic drugs, de-intensifying, and using long-acting basal analogues rather than NPH when affordable. Sulfonylureas interact with alcohol and with other drugs that displace them from protein binding, and meglitinides must not be taken if the meal is skipped. Any hypoglycaemia from an alpha-glucosidase inhibitor combination should be treated with glucose (dextrose) rather than tablets or food, because absorption of complex carbohydrate has been delayed. ^[1][2][4]

Lactic acidosis is rare and happens mainly with severe overdose or when kidney function is badly impaired. Metformin is contraindicated once eGFR falls below 30 mL per minute per 1.73 square metres, and the dose should be reduced or reviewed when eGFR is between 30 and 45, because further drops in kidney function are more likely in that range. Moderate or intermittent use is considered safe at eGFR of 30 or above. Metformin also lowers vitamin B12, so periodic testing and repletion are advisable, especially with anaemia or neuropathy. ^[1][2]

Pioglitazone should not be used when heart failure is present because of fluid retention, and it raises the risk of bone fracture. Caution is needed with active or previous bladder cancer. Combining pioglitazone with drugs that promote weight loss and sodium loss (such as SGLT2 inhibitors and GLP-1 receptor agonists) can reduce fluid retention and weight gain. ^[2][1]

Acute pancreatitis has been reported with GLP-1 receptor agonists and DPP-4 inhibitors, but a causal link has not been established; a GLP-1 drug should not be started in someone at high risk of pancreatitis and should be stopped if pancreatitis is suspected. ^[1][2] Thyroid C-cell tumours were seen in rodents given GLP-1 receptor agonists, so these drugs are contraindicated in anyone with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2. ^[1] GLP-1-based drugs also increase the risk of gallbladder disease. The dual agonist carries the same cautions; its long-term cardiovascular profile was still pending when this page was written. ^[1]

Genital fungal infections are common but usually mild and can be reduced by hygiene advice. Urinary infections, including pyelonephritis, need prompt treatment. Euglycaemic diabetic ketoacidosis, where glucose may be only modestly raised, can occur, especially during fasting, surgery, acute illness or with very low carbohydrate intake; the drug should be stopped before scheduled surgery (about three to four days beforehand), during critical illness or prolonged fasting, and promptly whenever ketoacidosis is suspected. Volume depletion and a fall in blood pressure can occur, particularly with other diuretics. Dialysis and kidney transplantation considerations are covered in the treatment of kidney disease. ^[1][2]

• Antibiotic or pain combinations are not usually a problem with older oral agents, but ketoconazole, some antiepileptics and corticosteroids raise glucose and may need dose changes.
• Routine drug review: check kidney function when starting or escalating metformin, SGLT2 inhibitors and incretin-based drugs, especially after severe gastro-intestinal illness. ^[1]
• GLP-1 drugs slow gastric emptying, so the absorption of oral drugs (including the contraceptive pill) may be delayed during dose titration.
• Injection sites should be rotated to avoid lipohypertrophy, which makes insulin absorption unpredictable.
• Retinopathy: rapid glucose falls with GLP-1 therapy can worsen diabetic retinopathy, so closer monitoring is needed in long-standing type 2 diabetes. ^[1]
• Overdose: excess insulin or sulfonylurea causes prolonged hypoglycaemia, treated by feeding, intravenous glucose and, for repeated episodes, intravenous octreotide; metformin overdose risks lactic acidosis; give concentrated glucose orally or intravenously for acute hypoglycaemia and train people in the use of glucagon kits. No specific antidote exists for metformin, GLP-1 drugs or SGLT2 inhibitors.

Drugs work better on a foundation of behaviour change and education. Diabetes self-management education and support is as important as the prescription. ^[2]

• Medical nutrition therapy should identify healthy eating patterns that can be sustained rather than one perfect diet. Mediterranean and lower-carbohydrate patterns both improve glucose, and the Mediterranean diet also has cardiovascular benefits. ^[2]
• Energy balance matters for weight. A steady energy deficit, regular physical activity and, when appropriate, weight-loss medicines or surgery, all improve glycaemia and complications. ^[2]
• Physical activity improves control directly: at least 150 minutes a week of moderate to vigorous aerobic activity plus two or three sessions of resistance, flexibility or balance work. Breaking up sitting time, even with light movement, helps, and being active after meals is particularly useful. ^[2]
• Sleep affects glucose: fewer than 6 or more than 8 hours of sleep is associated with worse outcomes, and obstructive sleep apnoea is common in type 2 diabetes. Extending the sleep of short sleepers can improve insulin sensitivity. ^[2]
• Weight targets: 5 to 10% weight loss brings metabolic benefit and 10 to 15% or more can have disease-modifying effects and remission. Some very-low-calorie programmes have produced remission in a large minority of participants: in the DIRECT programme, 64% of those who maintained a loss of at least 10 kg achieved remission. ^[2]
• Metabolic (bariatric) surgery should be considered when appropriate for people with a body mass index of 40 or more, or 35 to 39.9 if weight loss and comorbidities do not improve with non-surgical methods; thresholds are lower by about 2.5 units in people of Asian ancestry. Surgery works best in diabetes of shorter duration (under five to eight years). ^[2]
• Hypoglycaemia precautions during fasting or large dietary changes: people on insulin or sulfonylureas need individualised advice and dose changes to avoid lows. ^[2]
• MASLD/MASH is common in type 2 diabetes; lifestyle weight loss remains the foundation, with drug choices as described above. ^[2]

The WHO 2018 guidance on second- and third-line medicines was written for adults with diabetes in primary care in low-resource settings, including disadvantaged groups in high-income countries.

• First line: metformin, with lifestyle advice. Consider a sulfonylurea when metformin is not tolerated or contraindicated. ^[3]
• Second line: if glucose is still not controlled, introduce human insulin (regular and NPH), which has a strong recommendation because evidence that analogues work better is lacking and human insulin has a far better resource-use profile. Newer oral agents (DPP-4, SGLT2, thiazolidinediones) are reserved for cases where insulin is unsuitable, such as someone who lives alone and cannot safely inject. ^[3]
• Which sulfonylurea: avoid glibenclamide (glyburide) in patients aged 60 or over, and use gliclazide or another agent with a better hypoglycaemia record in people at risk of falls, with impaired hypoglycaemia awareness, or who live alone, drive or operate machinery. ^[3]
• Insulin choice: prefer human insulin; consider long-acting analogues only if frequent severe hypoglycaemia occurs on human insulin, because they are much more expensive and evidence for long-term outcomes is limited. ^[3]
• Administration and delivery are the same for human and analogue insulin (vials, pens, cold chain, glucose monitoring); the main difference is price, which matters for budgets and for people paying out of pocket. ^[3]
• Practical points: human insulin still needs needles, monitoring and trained staff; the fasting blood glucose target commonly used in low-resource protocols is below 7 mmol per L (126 mg per dL), with individualisation. ^[3]
• Safety where monitoring is limited: prefer drugs that do not cause hypoglycaemia where possible; keep metformin or sulfonylurea back if kidney function cannot be tested; and use simplified sick-day and "stop SGLT2 before surgery or during illness" rules whenever the drug is available.

Pregnancy management of diabetes requires specialist care; insulin remains the usual mainstay, and the choice of any oral or injectable agent in pregnancy should follow product labelling and local obstetric guidance. Most oral agents are not licensed in pregnancy. Breastfeeding also needs individual advice. Children and adolescents with type 2 diabetes are managed in paediatric services, with metformin and insulin as the usual early agents; monogenic and secondary causes should be excluded first. Older adults are at high hypoglycaemia risk, and treatment should be relaxed rather than intensified when benefit is unlikely. ^[3]

• Type 1 diabetes needs insulin; type 2 diabetes needs a plan that covers glucose, weight and organ protection together.
• Metformin is the usual first drug in type 2 diabetes when eGFR is 30 or higher; reduce it at 30 to 45 and stop it below 30, because lactic acidosis is largely a problem of severe kidney impairment. ^[1]
• ASCVD or high cardiovascular risk: add a GLP-1 receptor agonist and/or an SGLT2 inhibitor, irrespective of HbA1c.
• Heart failure: add an SGLT2 inhibitor; for symptomatic HFpEF with obesity, add a GLP-1-based drug.
• CKD: add an SGLT2 inhibitor or GLP-1 receptor agonist (eGFR 20 to 60 or albuminuria); use a GLP-1 drug when eGFR is below 30; SGLT2 glycaemic benefit is small below 45.
• Obesity, MASLD and MASH: prefer GLP-1-based therapy, with pioglitazone for proven MASH.
• Sulfonylureas and meglitinides lower HbA1c strongly but cause hypoglycaemia and modest weight gain.
• TZDs give durable control and help MASH but cause fluid retention, heart failure, weight gain and fractures.
• GLP-1 and dual agonists lower HbA1c and weight strongly but cause nausea; check pancreatitis and thyroid C-cell contraindications.
• SGLT2 inhibitors give intermediate HbA1c lowering with weight loss and cardio-renal benefit, but beware genital infection, urinary infection, volume depletion and euglycaemic ketoacidosis; stop before surgery.
• DPP-4 inhibitors are well tolerated with modest effect and should not be combined with GLP-1 therapy. ^[1]
• Alpha-glucosidase inhibitors blunt post-meal rises by about 0.5 to 1.0% and cause wind and diarrhoea; AGI-related hypoglycaemia needs glucose, not complex carbohydrate. ^[4]
• Pramlintide is an amylin analogue adjunct for insulin users, with modest HbA1c and weight effects.
• Insulin regimen choice trades flexibility, cost and hypoglycaemia risk; basal analogues beat NPH on nocturnal hypoglycaemia; combine insulin with a GLP-1 drug when possible.
• Combine drugs with different mechanisms, reduce hypoglycaemia-causing ones when adding new agents, and reassess every three to six months.
• Lifestyle, education, activity (150 minutes per week plus resistance work), sleep and weight targets are as important as the drugs.
• In low-resource settings, WHO keeps metformin and sulfonylureas first, with human insulin next and newer oral drugs only when insulin is unsuitable. ^[3]

• Diabetes self-management education and support
• Diabetic ketoacidosis and hyperglycaemic hyperosmolar state
• Chronic kidney disease (diabetes and kidney disease)
• Cardiovascular risk management in diabetes
• Obesity management and metabolic surgery

A clear medical disclaimer applies: this page is educational and is not a substitute for clinical judgement or local guidelines.