SGLT2 Inhibitors in Type 2 Diabetes Mellitus

Agents: empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, bexagliflozin; also marketed as fixed-dose combinations with metformin and with DPP4 inhibitors.

Mechanism: inhibit the sodium–glucose co-transporter 2 in the proximal convoluted tubule, which normally reabsorbs about 90% of filtered glucose → glycosuria and a fall in plasma glucose.

The action is insulin-independent, so efficacy is preserved despite beta-cell failure and there is no intrinsic hypoglycaemia risk — a major advantage in the older patient.

HbA1c fall of about 0.5–1.0%; weight loss 2–3 kg; systolic blood pressure fall of roughly 3–5 mmHg.

Beyond glucose lowering: reduced circulating insulin, reduced hepatic steatosis, improved beta-cell function, mild uricosuria, and reduced hyperkalaemia risk.

In the cardiovascular outcome trials, empagliflozin and canagliflozin significantly reduced MACE (cardiovascular death, non-fatal MI, non-fatal stroke); empagliflozin also reduced cardiovascular death, hospitalisation for heart failure and worsening nephropathy. DPP4 inhibitors, by contrast, showed no cardiovascular benefit.

Heart failure across the whole ejection-fraction spectrum: HFrEF (DAPA-HF, EMPEROR-Reduced) and HFpEF (EMPEROR-Preserved, DELIVER). Benefit is independent of diabetes status and begins within days of initiation.

Renal protection — the three trials to name: CREDENCE (type 2 diabetes, eGFR >30, UACR >300 mg/g), DAPA-CKD (eGFR >25, with and without diabetes), and EMPA-KIDNEY (eGFR ≥20, including non-diabetic and non-albuminuric CKD) — EMPA-KIDNEY showed a 28% reduction in kidney disease progression or cardiovascular death.

Renal benefit is independent of glucose lowering. Mechanism: restoration of tubuloglomerular feedback with afferent arteriolar constriction → reduced intraglomerular hypertension, plus natriuresis and reduced tubular workload and hypoxia.

Initiation threshold: eGFR ≥20 mL/min/1.73 m². Once started, continue as eGFR falls — the glycaemic effect fades but cardiorenal protection persists — down to dialysis.

An acute “eGFR dip” of up to about 10% in the first 2–4 weeks is expected and haemodynamic; it does not predict worse outcome and is not a reason to stop the drug.

Assess volume status before starting; reduce or hold the loop diuretic in a euvolaemic older patient to avoid dehydration and postural hypotension.

Glycaemic efficacy is diminished in older people with renal impairment; monitor renal function more frequently in the elderly.

Genital mycotic infection (5–10% of women, 3–5% of men), volume depletion with symptomatic hypotension, and urinary tract infection — all more frequent above age 75.

Euglycaemic diabetic ketoacidosis — glucose may be near-normal, so it is easily missed. Precipitants: fasting, sepsis, surgery, very low-carbohydrate diet, insulin dose reduction, alcohol. Withhold 3 days before elective surgery (4 days for ertugliflozin).

Rare: Fournier's gangrene (necrotising fasciitis of the perineum). Canagliflozin carried a lower-limb amputation signal in CANVAS (boxed warning later downgraded to a standard warning).

Pathy's caution in frailty: consider avoiding an SGLT2 inhibitor in the frail because of weight loss, dehydration and toe amputation. This must now be balanced against the strong cardiorenal benefit — see Current Practice Update.

Avoid or contraindicated in: type 1 diabetes, prior DKA, recurrent genital infection, significant volume depletion, active foot ulceration, and where oral intake is unreliable.

Metformin remains first-line after lifestyle measures; an SGLT2 inhibitor is a standard second-step choice. However, in the presence of established atherosclerotic disease, heart failure or CKD, an SGLT2 inhibitor is now indicated irrespective of HbA1c — it is prescribed for organ protection, not for glucose.

Blood pressure and lipid targets must be addressed in parallel: systolic 130–139 mmHg in those over 65, diastolic <80 but not <70 mmHg, with LDL targets graded by cardiovascular risk.