SGLT2 inhibitors and GLP-1 receptor agonists in the older adult

SGLT2 inhibitors — mechanism. They block the sodium–glucose cotransporter 2 in the proximal tubule, producing glycosuria and natriuresis. The natriuresis restores tubuloglomerular feedback, causing afferent arteriolar constriction and a fall in intraglomerular pressure — this, not the glucose lowering, explains the renoprotection. Drugs: empagliflozin, dapagliflozin, canagliflozin.

GLP-1 receptor agonists — mechanism. They produce glucose-dependent insulin secretion, suppress glucagon, delay gastric emptying and act centrally to reduce appetite. Drugs: liraglutide, semaglutide, dulaglutide, exenatide; tirzepatide is a dual GIP/GLP-1 receptor agonist.

The key geriatric advantage — negligible intrinsic hypoglycaemia risk. Because the insulin effect of GLP-1 receptor agonists is glucose-dependent and SGLT2 inhibitors act independently of insulin, neither causes hypoglycaemia on its own. Risk appears only when they are combined with a sulphonylurea or insulin — so reduce the dose of those agents when adding either class. Both also cause weight loss.

Cardiovascular outcome trial data. Overall cardiovascular safety was demonstrated across all classes using the three-point MACE endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke). DPP-4 inhibitors showed no cardiovascular benefit, whereas empagliflozin and canagliflozin significantly reduced cardiovascular and renal events, with empagliflozin also reducing hospitalisation for heart failure and worsening nephropathy.

GLP-1 receptor agonists in older participants. Among the GLP-1 receptor agonist trials, exenatide showed cardiovascular benefit in participants aged 65 and over — but with a 43% treatment discontinuation rate, which is itself an important geriatric lesson about tolerability and adherence in this age group.

Indications now extend well beyond glycaemia. SGLT2 inhibitors are indicated in heart failure with both reduced and preserved ejection fraction and in chronic kidney disease, with or without diabetes. GLP-1 receptor agonists are indicated in established atherosclerotic cardiovascular disease and in obesity. Prescribe them for the organ, not only for the HbA1c.

Adverse effects of SGLT2 inhibitors. Genital mycotic infection and urinary tract infection, volume depletion with postural hypotension, euglycaemic diabetic ketoacidosis, an initial reversible "eGFR dip" of up to 30% which is haemodynamic and expected, rare Fournier's gangrene, and the amputation and fracture signal seen with canagliflozin.

Adverse effects of GLP-1 receptor agonists. Nausea, vomiting and diarrhoea (dose-limiting, and the reason for the high discontinuation rate), anorexia with unintended weight loss, gallstones and cholecystitis, pancreatitis, and injection-site reactions. Contraindicated with a personal or family history of medullary thyroid carcinoma or MEN2.

Geriatric prescribing cautions — the marks are here. Avoid or use SGLT2 inhibitors very cautiously in recurrent urinary tract infection, urinary incontinence, poor perineal hygiene, recurrent genital candidiasis, or in a patient on a loop diuretic with orthostatic hypotension and falls. Avoid GLP-1 receptor agonists in frailty with unintentional weight loss, sarcopenia, gastroparesis, poor oral intake or significant anorexia — the weight loss that is a benefit in the obese 55-year-old is a hazard in the sarcopenic 85-year-old. Screen for sarcopenia and monitor weight before and during therapy.

Practical use. Start an SGLT2 inhibitor down to an eGFR of 20 mL/min/1.73 m² and continue until dialysis. Apply sick-day rules — suspend during acute illness, dehydration, fasting or before surgery. Reduce sulphonylurea or insulin doses when adding either agent. In India, generic empagliflozin and dapagliflozin are widely available and inexpensive, whereas GLP-1 receptor agonists remain costly and are a major barrier to access — a point worth stating in an Indian examination.

FLOW trial (NEJM 2024) — GLP-1 receptor agonists become a kidney drug. In 3,533 adults with type 2 diabetes and CKD, mean age 66.6 years and median follow-up 3.4 years, semaglutide 1 mg weekly reduced major kidney disease events by 24% (HR 0.76), major cardiovascular events by 18% and all-cause death by 20%, and slowed the annual eGFR decline by 1.16 mL/min/1.73 m². The trial was stopped early for efficacy, and benefit held across every stratum of baseline eGFR and albuminuria, including advanced CKD. This established the four-pillar approach: RAS blocker + SGLT2 inhibitor + finerenone + GLP-1 receptor agonist.

ADA Standards of Care 2026. Glucose-lowering therapies are now recommended explicitly for heart, kidney and liver protection independent of HbA1c; there is new guidance on individualised dosing of obesity medications in people with diabetes; Section 12 highlights GLP-1-associated reduction in amputation risk in diabetic foot disease; and Section 13 adds guidance on protein intake and on assessing geriatric syndromes in older adults — relevant because both classes cause weight loss in a population already at risk of sarcopenia.