Table 3.

Pros and cons of antihyperglycaemic therapies for the treatment of type 2 diabetes in older adults

Antihyperglycaemic therapy	Pro	Con
Metformin Alters mitochondrial cell energetics to inhibit gluconeogenesis, oppose the action of glucagon and increase insulin sensitivity [79]	• Inexpensive • Well-established, generally well-tolerated standard therapy • Potential CV benefit demonstrated in UKPDS study [80] • Low hypoglycaemia risk • Can be combined with all other diabetes therapies	• Reduced appetite and gastrointestinal disturbance • Possible association with vitamin B12 deficiency [81] • Moderate weight loss seen in some people may be undesirable with frailty • Contraindicated in severe renal failure • Should be used with caution in those with impaired hepatic function or cardiac failure, due to increased risk of lactic acidosis
Sulphonylureas and glinides Stimulate pancreatic insulin secretion regardless of blood glucose concentration [82]	• Inexpensive • Can be combined with other therapies • Increased potency in older adults may sometimes be beneficial	• Require functioning beta-cells • Hypoglycaemia risk [45] • Increased potency following weight loss (with improved insulin sensitivity) may further increase hypoglycaemia risk
DPP-4 inhibitors Inhibit breakdown of endogenous GLP-1, which glucose-dependently stimulates insulin secretion and inhibits glucagon secretion [82]	• Well tolerated • Formally tested in older adults [53] • May delay disease progression if used early with metformin • Low risk of hypoglycaemia [52] • Safe in all stages of renal failure, at an appropriate dose • No effect on weight	• Moderate glucose-lowering efficacy • Neutral effect (apart from saxagliptin) on CV death, MI, stroke and hospitalisation for heart failure [54], in contrast to SGLT-2is and GLP-1 RAs • Possible issues with increased hospitalisation for heart failure with saxagliptin (± alogliptin) [83] • Relatively expensive
SGLT-2 inhibitors Inhibit reabsorption of glucose (from renal tubules), leading to increased urinary glucose output and osmotic diuresis [84]	• CVOTs have shown reduction in MACE [57] • Benefits demonstrated for people with diabetes and heart failure [54] • Potential benefit in reducing progression of renal impairment [59] • Low hypoglycaemia risk	• Weight loss could result in sarcopenia • Risk of candidiasis • Potential increased urinary incontinence • Lack of glucose-lowering efficacy in established renal impairment [61] • Risk of euglycaemic diabetic ketoacidosis • Fluid volume depletion
GLP-1 RAs Stimulate insulin secretion, inhibit glucagon secretion and also reduce appetite. GLP-1 RAs work in a glucose-dependent manner [82]	• CVOTs have shown CV benefits with some, particularly in patients with ASCVD, and those at high risk of CV events [57, 58] • Renoprotective effects [59] • Low hypoglycaemia risk despite good glucose-lowering efficacy • Once-weekly administration possible with some [55] • A once-daily oral formulation of semaglutide is now available [56]	• Weight loss could result in sarcopenia • Nausea is common, and reduced appetite could be problematic • Most are given by sc injection • Relatively expensive
TZDs Increase cellular expression of glucose transporters, thereby increasing insulin sensitivity and peripheral glucose uptake [85]	• Generally well tolerated • Low hypoglycaemia risk • Potential CV benefit with pioglitazone [47]	• Fluid retention may exacerbate heart failure [19] • Risk of osteoporosis and fractures [49–51] • Ongoing debate regarding risk of bladder cancer [48]
Exogenous basal insulin Binds to insulin receptors in liver to inhibit glycogenolysis and gluconeogenesis, and binds to peripheral insulin receptors (muscle, adipose) to stimulate glucose uptake
NPH insulin [63]	• Established efficacy • Inexpensive	• Requires resuspension • May need twice-daily injections • Weight gain (limited harm) • Hypoglycaemia risk • Variable glucose-lowering effect from injection to injection
First-generation basal insulin analogues [54]   Insulin glargine   Insulin detemir	• Established efficacy • Lower hypoglycaemia risk than NPH insulin • Cost lower than ultra-long acting insulins • Once-daily injection possible • Insulin detemir associated with relatively little weight gain	• Requirement for injection at same time each day may be problematic • Hypoglycaemia risk
Ultra-long-acting insulin analogues [76]   Insulin degludec   Insulin glargine U300	• Established efficacy • Increased dosing flexibility • Lower hypoglycaemia risk than other basal insulins • Stable glucose-lowering action	• More expensive than other basal insulins (possibly offset by reduced need for nurse visits ± reduced doses and longer-lasting pens)

ASCVD Atherosclerotic cardiovascular disease, CV cardiovascular, CVOT cardiovascular outcome trial, DPP-4 dipeptidyl peptidase-4, GLP-1 glucagon-like peptide-1, GLP-1 RA glucagon-like peptide-1 receptor agonist, insulin glargine U300, MACE major adverse cardiovascular events, MI myocardial infarction, NPH neutral protamine Hagedorn, SGLT-2 sodium-glucose cotransporter-2, sc subcutaneous, TZD thiazolidinedione