3. Blood glucose-lowering therapies – Non-insulin options for type 2 diabetes

Key points Globally, poor glycaemic control is common in people with type 2 diabetes mellitus (T2DM) and improving glycaemic control remains an unmet need and a key diabetes care priority. Early and intensive glycaemic control in T2DM not only reduces micro-and macrovascular complications but also has a legacy effect that lower risk for decades. Intensive multifactorial risk management, including blood glucose, blood pressure, and lipids, decreases long-term cardiorenal events and overall mortality. Recent cardiovascular outcome trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated significant cardio-renal protection, prompting debate about balancing the focus on glycaemic control and organ protection, particularly for individuals at low risk of cardio-renal complications. Global availability, access, and affordability of blood glucoselowering therapies (BGL) vary widely and impact treatment options in lower resource settings. The majority of cardio-renal outcome studies have added trial therapies to usual care with placebo as the comparator and outcome data from head-to-head studies comparing blood glucose-lowering therapies are limited. Initiating therapy should be personalised based on individual characteristics, comorbidities, and shared decision-making, with lifestyle interventions (e.g., self-management education, nutrition, and exercise) as essential components. Metformin remains the recommended first-line monotherapy due to its global availability, efficacy, safety profile, low hypoglycaemia risk, and cost-effectiveness, along with demonstrated long-term cardiovascular benefits. Emerging data support the early use of SGLT2 inhibitors and GLP-1 receptor agonists, usually added to metformin, to mitigate the adverse consequences of poor glycaemic control and improve cardio-renal outcomes, although evidence supporting their role as first-line monotherapy is limited. Initial combination therapy may increase durability of glycaemic control compared with stepwise addition of BGL therapies. Timely treatment intensification is crucial to overcome clinical inertia, while deintensification should be considered in individuals at or near glycaemic targets, especially in the elderly and those prone to hypoglycaemia. Therapy choices should factor in management of coexisting conditions such as cardio-renal complications, metabolic dysfunction-associated steatotic liver disease, and weight control.