In patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease — prior myocardial infarction, stroke, or symptomatic peripheral arterial disease — the choice of antihyperglycemic agent is driven primarily by cardiovascular outcome trial evidence, not by glycated hemoglobin level. Current guidelines position a glucagon-like peptide-1 receptor agonist with proven cardiovascular benefit or a sodium-glucose cotransporter-2 inhibitor with proven cardiovascular benefit as preferred agents in this population, often regardless of baseline glycated hemoglobin or whether metformin has been tried first.

The cardiovascular outcome trial evidence is strongest for liraglutide (LEADER: 13 percent major adverse cardiovascular event reduction, 38 percent cardiovascular mortality reduction), semaglutide (SUSTAIN-6: 26 percent major adverse cardiovascular event reduction), and empagliflozin (EMPA-REG OUTCOME: 14 percent major adverse cardiovascular event reduction, 38 percent cardiovascular mortality reduction). The combination of a glucagon-like peptide-1 receptor agonist and a sodium-glucose cotransporter-2 inhibitor is increasingly used and provides complementary mechanisms — the glucagon-like peptide-1 receptor agonist adds weight loss and antiatherosclerotic effects, while the sodium-glucose cotransporter-2 inhibitor adds hemodynamic benefits and renal protection.

Heart failure is both a common comorbidity and a treatment target in type 2 diabetes mellitus. The pharmacological approach differs by ejection fraction and requires awareness of which antihyperglycemic agents worsen heart failure versus which provide proven benefit.

Sodium-glucose cotransporter-2 inhibitors are the preferred antihyperglycemic agents in type 2 diabetes mellitus with heart failure across the ejection fraction spectrum. In heart failure with reduced ejection fraction, DAPA-HF and EMPEROR-Reduced demonstrated approximately 25 percent reductions in cardiovascular death or worsening heart failure. In heart failure with preserved ejection fraction, EMPEROR-Preserved and DELIVER demonstrated benefit of empagliflozin and dapagliflozin respectively. These agents are now classified as heart failure medications in their own right, recommended by cardiology guidelines independently of their antihyperglycemic role.

Glucagon-like peptide-1 receptor agonists have a more complex relationship with heart failure. While liraglutide, semaglutide, and dulaglutide reduce heart failure hospitalization in the cardiovascular outcome trials, the FIGHT trial (liraglutide in advanced heart failure with reduced ejection fraction) showed no benefit and a trend toward harm in patients with severe heart failure. Current guidance is to use glucagon-like peptide-1 receptor agonists with caution in severe or decompensated heart failure but not to avoid them in stable mild-to-moderate heart failure with reduced ejection fraction.

Diabetes management in older adults requires individualization of glycemic targets based on functional status, cognitive function, life expectancy, and the balance between the harms of hypoglycemia and the benefits of tight glucose control. For many older adults, avoiding hypoglycemia is a higher priority than achieving the tightest possible glycated hemoglobin level.

The American Diabetes Association stratifies glycemic targets by health status in older adults. Healthy older adults with preserved function and long life expectancy: glycated hemoglobin target below 7.5 percent — similar to younger adults. Complex or intermediate health (multiple chronic conditions, mild cognitive impairment, functional limitations): glycated hemoglobin target below 8.0 percent. Very complex or poor health (end-stage organ disease, moderate-to-severe cognitive impairment, dependence in activities of daily living, limited life expectancy): glycated hemoglobin target below 8.5 percent — the focus shifts entirely to symptom management and avoidance of hypoglycemia, with consideration of deprescribing antihyperglycemic agents entirely if the patient cannot safely recognize or respond to hypoglycemia.

Drug selection in older adults prioritizes agents with low hypoglycemia risk. Metformin remains appropriate in healthy older adults with preserved renal function. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors are preferred add-on agents when cardiovascular or renal benefit is desired. Dipeptidyl peptidase-4 inhibitors are well tolerated and weight neutral. Sulfonylureas — particularly glyburide — are on the Beers Criteria as potentially inappropriate in older adults due to prolonged hypoglycemia risk. Insulin can be used when needed but requires careful patient selection given the cognitive and functional demands of insulin self-management.