Type 2 diabetes mellitus (T2DM) is a chronic and complex metabolic disease characterized by chronic hyperglycemia due to insufficient insulin signaling due to defective insulin secretion and insulin resistance. It is also related to increased endogenous glucose production (EGP) or glucagon. Patients with type 2 diabetes mellitus have a two to three-fold increased risk of cardiovascular disease, which is further amplified in the presence of chronic renal impairment. In addition to atherosclerotic cardiovascular disease, patients with T2DM have an increased risk of developing diabetic kidney disease (DKD) and heart failure (HF). As our awareness of the underlying pathophysiological deficiency grows, so do the treatment choices for T2DM.

SGLT2 inhibitors can help in weight loss and improve hyperuricemia, blood lipids, and blood pressure while lowering glycate hemoglobin (HbA1c) without increasing the risk of hypoglycemia. The review aimed to examine the clinical role, clinical advantages, safety, and tolerability of SGLT2 inhibitors.

According to review data, SGLT2 inhibitors reduce HbA1c by approximately 0.6–1.0% and enhance renal and cardiovascular outcomes in T2DM patients, particularly those with a history of cardiovascular events, chronic kidney disease (CKD), or heart failure (HF). Furthermore, a meta-analysis of 58 trials found that SGLT2 inhibitors improved HbA1c levels (mean difference (MD) from placebo was 0.66%; the active comparator was 0.06%). When compared to other medicines, SGLT2 inhibitors reduced body weight (1.80 kg) and systolic blood pressure (4.45 mm Hg). Also, SGLT2 inhibitors do not affect insulin secretion but have been clinically shown to improve cell function and improve insulin sensitivity.

Additionally, the effect of the SGLT2 inhibitor on blood lipids is manifested as an increase in low-density lipoproteins (18%) and high-density lipoproteins (20%) and a decrease in triglycerides (0.12 mmol/L). Compared with pioglitazone, dapagliflozin significantly reduced the fatty liver index. Overall, it was found that SGLT2 inhibitors may be the preferred drug for T2DM patients with NAFLD.

The cardiovascular benefits (e.g., HHF and cardiovascular death) of SGLT2 inhibitors are diverse, however, the effect of SGLT2 inhibitors on the risk of non-fatal stroke or myocardial infarction was neutral. SGLT2 inhibitors have been clearly shown in multiple trials to improve renal outcomes in patients with CKD or DKD. Results of an exploratory analysis of EMPA-REG OUTCOME indicated that changes in hemoglobin and hematocrit mediated 48.9% and 51.8% of the effect of empagliflozin vs. placebo on the risk of cardiovascular death, while HbA1c, fasting plasma glucose (FPG) and uric acid were less regulated (29.3%). SGLT2 inhibitors were also able to reduce all-cause mortality, and comparative literature suggested that SGLT2 inhibitors reduced deaths by 5–48 per 1000 patients over 5 years.

Genital or urinary tract infections, amputations, fractures, osmotic diuresis, ketoacidosis, sarcopenia, and hypotension are common with SGLT2 inhibitors. SGLT2 inhibitors have a lower risk of hypoglycemia than glimepiride. The FDA has also issued a safety warning for canagliflozin and dapagliflozin, which may cause AKI or fractures. Therefore, the balance between benefits and risks, along with risk mitigation strategies for SGLT2 inhibitors, should be carefully considered.

Reference: Xu, B., Li, S., Kang, B. et al., Cardiovasc Diabetol 21, 83 (2022). https://doi.org/10.1186/s12933-022-01512-w