Patients with type 2 diabetes mellitus (T2DM) can have multiple comorbidities and premature mortality due to atherosclerotic cardiovascular disease, hospitalization with heart failure and/or chronic kidney disease. Traditional drugs that lower glucose, such as metformin, or that treat high blood pressure and blood levels of lipids, such as renin-angiotensin-system inhibitors and statins, have organ-protective effects in patients with T2DM. Amongst patients with T2DM treated with these traditional drugs, randomized clinical trials have confirmed the additional cardiorenal benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA) and nonsteroidal mineralocorticoid receptor antagonists. The cardiorenal benefits of SGLT2i extended to patients with heart failure and/or chronic kidney disease without T2DM, whereas incretin-based therapy (such as GLP1RA) reduced cardiovascular events in patients with obesity and T2DM. However, considerable care gaps exist owing to insufficient detection, therapeutic inertia and poor adherence to these life-saving medications. In this Review, we discuss the complex interconnections of cardiorenal-metabolic diseases and strategies to implement evidence-based practice. Furthermore, we consider the need to conduct clinical trials combined with registers in specific patient segments to evaluate existing and emerging therapies to address unmet needs in T2DM.