Oral hypoglycaemic agents (oral antihyperglycaemic drugs)

Classes at a glance

Textbook points

• Sulfonylureas. Tolbutamide, glipizide, glyburide and related drugs "lower blood glucose by increasing the secretion of insulin. They only work in patients with some remaining B cells and are ineffective after pancreatectomy or in type 1 diabetes." They bind the ATP-inhibited K+ channels, depolarise the B cell and increase Ca2+ influx, independent of plasma glucose. - Ganong's Review of Medical Physiology, 26th Ed, Oral Hypoglycemic Agents
• Metformin. It "acts primarily by reducing gluconeogenesis and therefore decreasing hepatic glucose output". It can be combined with a sulfonylurea. Lactic acidosis is possible but uncommon. - Ganong's Review of Medical Physiology, 26th Ed
• Thiazolidinediones. They "increase insulin-mediated peripheral glucose disposal" by activating nuclear PPARγ. - Ganong's Review of Medical Physiology, 26th Ed
• Metformin as first line. It is the preferred initial drug for T2D because of its low cost, high efficacy and low hypoglycaemia risk. It also lowers weight and lipids, and has beneficial effects on cardiovascular and all-cause mortality. In kidney impairment, reduce the dose to 500 mg twice daily at eGFR below 45 and stop at eGFR below 30. - Comprehensive Clinical Nephrology, 7th Ed, Metformin
• SGLT2 inhibitors. They cause osmotic diuresis and natriuresis. They lower systolic BP by about 4 to 6 mmHg and cut albuminuria by 30 to 40%. Their kidney protection is roughly 2.5 times that of an RAS inhibitor added to a maximal RAS inhibitor dose. The initial eGFR dip is reversible. - Comprehensive Clinical Nephrology, 7th Ed, SGLT2 Inhibitors

Choosing a drug

• First line: metformin, unless it is contraindicated or not tolerated.
• Established ASCVD, heart failure or CKD: add an SGLT2 inhibitor or a GLP-1 receptor agonist, independent of HbA1c. This is the current guideline direction, and the KDIGO 2022 algorithm in the nephrology text follows it.
• Cost-limited settings: sulfonylurea or pioglitazone. Prefer gliclazide or glimepiride over glibenclamide in the elderly or in renal impairment.
• Weight gain or hypoglycaemia to avoid: DPP-4 inhibitor or SGLT2 inhibitor.

Other points

• Hypoglycaemia: it is mainly a problem with sulfonylureas and meglitinides. Metformin, TZDs, DPP-4 inhibitors and SGLT2 inhibitors rarely cause it when used alone.
• Metformin contraindications: severe renal impairment, decompensated liver disease, hypoxic states, sepsis and alcohol excess. Stop it before iodinated contrast in at-risk patients.
• Sulfonylurea interactions: drugs that potentiate hypoglycaemia include salicylates, sulfonamides, warfarin, alcohol and beta-blockers (which mask symptoms). Cimetidine and fluconazole also interact. Sulfonylureas are also used in some monogenic diabetes (MODY, neonatal diabetes).
• Pregnancy: insulin is the standard. Metformin and glibenclamide are sometimes used. The maternal-fetal medicine and gynaecology texts in the library have dedicated sections.

Recent evidence check (PubMed, last 2 years)

• A 2024 BMJ network meta-analysis of GLP-1 receptor agonists for glycaemia, weight and lipids: PMID 38286487.
• A 2024 meta-analysis of first-line SGLT2 inhibitors and GLP-1 receptor agonists in people at low cardiovascular risk: PMID 38348420.
• A 2024 meta-analysis of dorzagliatin, a glucokinase activator, a new oral class: PMID 38394489.

Latest guidelines for T2DM drug selection (as of October 2026)

1. ADA Standards of Care 2026 (Section 9, Diabetes Care 2026;49 Suppl 1)

• Timing. Start drug therapy at diagnosis, without delay, unless contraindicated. The plan should be strong enough to reach and hold individualised goals for glucose, cardiovascular and kidney risk, and weight.
• ASCVD, high ASCVD risk, heart failure or CKD. Use an SGLT2 inhibitor and/or GLP-1 RA with proven cardiovascular benefit, independent of HbA1c and with or without metformin. If a patient is already on dual or multiple therapies without one of these agents, consider switching to one.
• Heart failure with preserved EF (new in 2026). For symptomatic HFpEF with obesity, use a dual GIP/GLP-1 RA (tirzepatide) or a GLP-1 RA with proven benefit on HF symptoms or events (Recs 9.9a and 9.9b).
• CKD.
  • Preferred agents are GLP-1 RAs and SGLT2 inhibitors.
  • SGLT2 inhibitors can be started at eGFR above 20 and slow CKD progression.
  • Semaglutide has shown kidney and CV benefit in CKD.
  • Rec 9.11 was updated on starting and continuing GLP-1-based therapy in advanced CKD.
• MASLD or MASH (new in 2026). Use a GLP-1 RA or dual GIP/GLP-1 RA for MASLD. For biopsy-proven MASH or high fibrosis risk, use pioglitazone or a dual GIP/GLP-1 RA.
• Other 2026 changes.
  • CGM should be considered in T2D on basal insulin.
  • GLP-1-based therapy is now suggested in type 1 diabetes with obesity.
  • Cost tables were updated to July 2025.

2. ADA/EASD consensus report 2026 (Diabetologia)

• Metformin is still valued for its efficacy, low cost, safety and minimal hypoglycaemia. It is no longer the automatic first step for everyone.
• SGLT2 inhibitors and GLP-1-based therapy (GLP-1 RAs and tirzepatide) give organ-protective benefit independent of metformin. They should be first-line considerations in people with established or high-risk CVD, heart failure or CKD.
• Established CVD: use a GLP-1-based therapy with proven benefit to reduce MACE and mortality, or an SGLT2 inhibitor to reduce MACE, heart failure and mortality.
• High CV risk, established CVD or kidney disease: combining an SGLT2 inhibitor with GLP-1-based therapy can be considered irrespective of HbA1c, because the benefits may be additive.
• PAD: semaglutide can be used to improve symptoms.
• CKD:
  • Start an SGLT2 inhibitor and continue it until kidney replacement therapy, regardless of UACR.
  • Start GLP-1-based therapy as well. Semaglutide is indicated to reduce CKD progression.
  • Add a non-steroidal MRA if UACR is above 30 mg/g.
• Intolerance or contraindication to these agents: use metformin, DPP-4 inhibitors, TZDs or sulfonylureas. Choose by balancing efficacy against side effects. Evidence for these older drugs has not changed.
• Long-term insulin users: add a GLP-1-based therapy and/or an SGLT2 inhibitor to limit insulin dose and weight. Reduce the insulin dose and monitor more closely, especially if HbA1c is under about 8%.

3. Other recent guidelines (found on PubMed, not read in full)

• AACE 2026 algorithm update: Endocr Pract 2026, PMID 41842862
• BMJ living guideline (2025) on the cardiovascular, kidney and weight effects of T2DM drugs: PMID 40813129
• ACP 2024 guideline on newer pharmacologic treatments: PMID 38639546. From memory (not rechecked), it keeps metformin first and adds an SGLT2 inhibitor or GLP-1 RA for CV, kidney or HF indications.
• ABCD-UKKA joint guideline on CKD in T2D (2025): PMID 39415639
• Chinese expert consensus 2025 on triple oral therapy (metformin, DPP-4 inhibitor, SGLT2 inhibitor): PMID 41084961
• Italian CGM guidelines in T2D (2026): PMID 42207272

4. Practical selection summary