Diabetes Medications: Metformin, GLP-1 Agonists, SGLT2 Inhibitors and More

Diabetes pharmacotherapy has changed more in the last decade than in the four decades before it. What was once a stepwise sequence — metformin, sulfonylurea, insulin — has become a personalised choice, with classes (GLP-1 receptor agonists, SGLT2 inhibitors, dual GIP/GLP-1 agonists) chosen as much for cardiovascular and renal protection as for blood-glucose control.

This guide explains the major classes of diabetes medication, what current NICE and ADA guidelines recommend, and what to expect from each — including side effects, monitoring, and the situations where one class is preferred over another.

This page is educational. It does not replace personalised advice from your GP, diabetes specialist nurse, or endocrinologist. Never start, stop, or change a diabetes medication without speaking to your prescriber.

Metformin — still first-line for most adults

How it works: Metformin reduces the amount of glucose released by the liver, modestly improves insulin sensitivity in muscle and fat, and slows intestinal glucose absorption. It does not stimulate insulin secretion, so it carries minimal hypoglycaemia risk on its own.

When it’s used: NICE NG28 recommends metformin as the initial drug for most adults with newly diagnosed type 2 diabetes. Modified-release (“MR”) preparations are an option when standard metformin causes gastrointestinal side effects.

Common side effects: Nausea, diarrhoea, abdominal discomfort — usually settle within a few weeks if dose is built up gradually. Long-term use can lower vitamin B12 levels, so periodic B12 testing is reasonable.

Cautions: Dose should be adjusted in chronic kidney disease (eGFR 30–59) and avoided when eGFR is below 30. It should be temporarily stopped during acute illness with dehydration, before iodinated-contrast imaging in some scenarios, and around major surgery — your team will tell you when.

SGLT2 inhibitors — heart and kidney protection

The class: Empagliflozin, dapagliflozin, canagliflozin, ertugliflozin. Taken as a once-daily tablet.

How they work: They block glucose reabsorption in the kidney’s proximal tubule, so excess glucose is excreted in the urine. The mechanism also lowers blood pressure and produces modest weight loss.

Why they matter: Large randomised cardiovascular and renal outcome trials (EMPA-REG OUTCOME, DAPA-HF, DAPA-CKD, EMPEROR-Reduced/Preserved, CREDENCE, EMPA-KIDNEY) consistently showed reductions in heart-failure hospitalisation, progression of chronic kidney disease, and cardiovascular death. As a result, SGLT2 inhibitors are now recommended as first add-on (or even first-line, alongside metformin) when someone has established cardiovascular disease, heart failure, or chronic kidney disease — even if their HbA1c is at target.

Common side effects: Genital thrush (Candida) — particularly in women and uncircumcised men — and an increase in urinary tract infections. Mild-to-moderate volume depletion in older people or those on diuretics.

Important risk: Diabetic ketoacidosis (DKA) at lower-than-usual blood glucose levels (so-called “euglycaemic DKA”). The risk is higher around surgery, prolonged fasting, very low-carbohydrate diets, or acute illness. Patients should know the symptoms (nausea, vomiting, abdominal pain, fast breathing) and be told when to pause the medication.

GLP-1 receptor agonists

The class: Semaglutide (Ozempic — weekly injection; Rybelsus — daily oral; Wegovy — weight-loss licence), dulaglutide (Trulicity), liraglutide (Victoza, Saxenda), exenatide. Most are weekly injections.

How they work: They mimic the gut hormone GLP-1, which stimulates insulin release in response to food, suppresses glucagon, slows gastric emptying, and reduces appetite. The result is lower post-meal glucose and substantial weight loss in many people.

Why they matter: Cardiovascular outcome trials (LEADER, SUSTAIN-6, REWIND, SELECT) have shown reductions in major adverse cardiovascular events. GLP-1 agonists are increasingly used early in type 2 diabetes management, particularly when weight loss is a treatment goal or when cardiovascular risk is high.

Common side effects: Nausea, vomiting, constipation or diarrhoea — usually worst when starting and after each dose increase, and usually improves with time. Injection-site reactions are mild.

Important considerations: The substantial weight loss is partly fat and partly lean mass, so resistance training and adequate protein intake are important to preserve muscle. There is a class warning relating to medullary thyroid cancer in animal studies; the human signal is uncertain but the drugs are avoided in people with personal or family history of medullary thyroid carcinoma or MEN2. Acute pancreatitis is uncommon but recognised.

Dual GIP/GLP-1 agonists — tirzepatide

What it is: Tirzepatide (Mounjaro) acts on both GLP-1 and GIP receptors. The SURPASS programme in type 2 diabetes and SURMOUNT programme in obesity showed greater HbA1c and weight reductions than semaglutide head-to-head. SURMOUNT-1 demonstrated average weight loss of approximately 21% at the highest dose.

Side-effect profile is similar to GLP-1 agonists. Long-term cardiovascular outcome data are still maturing.

DPP-4 inhibitors

The class: Sitagliptin, linagliptin, alogliptin, saxagliptin, vildagliptin. Daily tablets.

They prolong the action of native GLP-1 by blocking the enzyme that breaks it down. They are weight-neutral and well-tolerated, with minimal hypoglycaemia risk. Glycaemic effect is modest. They are not associated with cardiovascular protection beyond glucose lowering, so they are typically chosen when GLP-1 agonists or SGLT2 inhibitors are unsuitable.

Sulfonylureas

The class: Gliclazide is the most commonly used in the UK; glimepiride and glipizide elsewhere.

Sulfonylureas stimulate insulin release from the pancreas. They are inexpensive and effective at lowering glucose, but they cause weight gain and carry meaningful hypoglycaemia risk — particularly in older adults, people with chronic kidney disease, or those who skip meals. They are no longer used as a first add-on in most NICE pathways but still have a role when cost or specific tolerability concerns make newer drugs unsuitable.

Pioglitazone

A thiazolidinedione that improves insulin sensitivity. Effective at lowering HbA1c and may help non-alcoholic fatty liver disease, but causes weight gain, fluid retention (avoid in heart failure), and an increased fracture risk. Bladder cancer signal has been reported in some studies and remains a topic of debate. Less commonly used today, but still helpful in selected patients with insulin resistance and fatty liver.

Insulin

When it’s used: Always in type 1 diabetes. In type 2 diabetes, insulin is added when oral and non-insulin injectable therapies are no longer enough. In gestational diabetes, insulin (often with metformin) is the standard when diet alone doesn’t keep glucose in target range.

Major regimens:

Basal-only: One long-acting injection (e.g. glargine, degludec, detemir) — often added first in type 2 diabetes.
Basal-bolus: Long-acting plus a rapid-acting insulin with each meal — the gold standard for type 1 diabetes.
Pre-mixed: A fixed-ratio mixture taken twice daily — convenient but less flexible.
Insulin pumps and automated insulin delivery (AID): Continuous subcutaneous infusion via pump, increasingly paired with continuous glucose monitoring as a hybrid closed-loop system. NICE and the NHS have expanded access to AID systems for type 1 diabetes.

How treatment is chosen — the modern algorithm

Current NICE NG28 (and the ADA Standards of Care) personalise the second drug to the person, not just the HbA1c:

Established cardiovascular disease, heart failure, or chronic kidney disease → SGLT2 inhibitor first add-on (or first-line alongside metformin). Add a GLP-1 agonist if further glycaemic or weight reduction is needed.
Obesity is a primary concern → GLP-1 receptor agonist or dual agonist as preferred add-on.
Cost is the dominant constraint → Sulfonylurea remains a reasonable second drug.
HbA1c well above target despite oral therapy → Insulin or GLP-1 agonist depending on patient preference, weight, and risk profile.

Frequently asked questions

Are GLP-1 agonists safe long term?

The longest cardiovascular outcome trials follow patients for around 5–6 years and show consistent cardiovascular benefit and acceptable tolerability. The most common long-term issue is muscle and bone-density loss with rapid weight loss, which is why resistance training and adequate protein are emphasised. Real-world experience now exceeds a decade for some agents (liraglutide, exenatide).

Will I have to take medication for life?

Not necessarily. People who achieve substantial weight loss (typically 10–15 kg) within the first 6 years of a type 2 diabetes diagnosis can sometimes come off all medication and meet remission criteria — HbA1c below 48 mmol/mol (6.5%) sustained for 3+ months without glucose-lowering drugs. This is most likely with structured low-calorie programmes, bariatric surgery, or sustained intensive lifestyle change.

Can SGLT2 inhibitors and GLP-1 agonists be combined?

Yes, and combination is increasingly standard for people with high cardiovascular or renal risk. The two classes work through completely different mechanisms and their effects on heart failure, kidney function, and HbA1c are largely additive.

What if I get side effects?

Tell your prescriber. Most diabetes medication side effects are dose-related and reversible. Often the first move is to slow the dose-escalation rather than stop the drug entirely. Stopping abruptly without a replacement can let glucose rise quickly — co-ordinate any change with your team.

Are there generic versions?

Metformin, gliclazide, pioglitazone, and most insulins (in biosimilar form) are widely available as generics. Most SGLT2 inhibitors and GLP-1 agonists are still under patent, but biosimilars and generics are starting to appear in some markets — your pharmacist can advise on the cheapest equivalent option for your prescription.

Reviewed against NICE NG28, the ADA Standards of Care 2026, and the BNF. Last reviewed: May 2026.

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