Pharmacological treatment in type 2 diabetes

Abstract

The pharmacological treatment of type 2 diabetes mellitus (T2DM) has undergone a paradigm shift that transcends the historical goal of isolated glycemic control. The approach has evolved from a vision focused strictly on glycemic control to a new paradigm based on cardiovascular and renal protection and comprehensive risk management. This shift recognizes that T2DM is a systemic challenge that requires early interventions to reduce morbidity and mortality.

Metformin remains the first-line cornerstone for most patients, given its efficacy, safety profile, low cost, and weight-neutral profile, provided there are no contraindications. However, the current algorithm prioritizes pharmacological selection based on the presence of specific comorbidities, regardless of initial HbA1c levels.

For patients with atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular risk, GLP-1 receptor agonists (GLP-1 RAs) are the early choice of therapy due to their proven ability to reduce major adverse cardiac events (MACE). Meanwhile, in individuals with heart failure (HF)—regardless of ejection fraction—or chronic kidney disease (CKD), SGLT-2 inhibitors (SGLT-2 iSGIs) are positioned as central therapy due to their nephroprotective effect and impact on reducing HF hospitalizations. Both classes are also valuable tools in the management of obesity, promoting weight loss, a critical pillar for disease control.

DPP-4 inhibitors (DPP-4 iSGIs) offer a safe and well-tolerated alternative, being weight-neutral and with a very low risk of hypoglycemia, making them ideal for combination therapy or in patients for whom metformin is not tolerated. Regarding sulfonylureas (SUs), guidelines recommend prioritizing the latest generation (gliclazide, glimepiride) to minimize the risk of hypoglycemia, while maintaining them as an accessible and potent option for glycemic control.

Thiazolidinediones (pioglitazone) retain a role in selected patients, such as those with hepatic steatosis or a history of stroke, although their use requires caution in the presence of heart failure.

An emerging concept of increasing clinical relevance is that of diabetes phenotype, which proposes subclassifying patients according to the predominance of insulin resistance, beta-cell deficiency, obesity, or hereditary component, thus guiding pharmacological selection beyond the classic linear algorithm. This individualized approach—which integrates comorbidities, risk of hypoglycemia, renal function, and metabolic phenotype—constitutes the central axis of current therapeutic decision-making.