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Sodium-glucose cotransporter-2 inhibitors in type 2 diabetes


Effects on non-glycemic outcomes

Combination treatment of SGLT2 inhibitors and GLP-1 receptor agonists: Symbolic effects on metabolism and cardiorenal risk

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce body weight and promote metabolic benefits. This paper reviews treatment in combination.

Summary points
  • ​​​​​GLP-1 receptor agonists may improve cardiac function by decreasing inflammation, improving endothelial function and slowing atheroma formation.
  • Evidence from two prospective clinical studies and four retrospective analyses in patients with type 2 diabetes indicates that SGLT2 inhibitors and GLP-1 agonists have additive effects with respect to lowering glycated hemoglobin, blood pressure and body weight.
  • Similar effects on body weight and blood pressure were also observed in obese adults without diabetes.
  • This combination treatment may reduce major cardiovascular events and slow the progression of renal disease beyond that seen with either class of agent alone or in combination with other hypoglycemic treatments.
  • The risk of ketoacidosis with SGLT2 inhibitor treatment may be lessened by coadministration with a GLP-1 agonist.

Goncalves E, Bell DSH. Diabetes Ther 2018; 9: 919–926. doi: 10.1007/s13300-018-0420-6

Sodium-glucose transporter as a novel therapeutic target in disease

The sodium-glucose cotransporter (SGLT) is being found to be involved in increasing numbers of diseases. This review explores the role of SGLT in select diseases and its value as a therapeutic target.

Summary points
  • Cerebral SGLTs may exacerbate cerebral ischemia in hyperglycemic conditions.
  • Excessive sodium influx through SGLTs may be associated with post-ischemic, hyperglycemia-induced exacerbation of neuronal damage.
  • Inhibition of SGLT1 or activation of SGLT3 may have therapeutic potential in cerebral ischemia.
  • SGLT2 inhibitors may be suitable for treating cancers, especially in those expressing epidermal growth factor receptor.
  • Cardiac SGLT1 plays a key role in cardiac ischemia, and SGLT1 inhibitors may be potential treatments for cardiomyopathy.
  • Targeting SGLT1 could promote the survival of epithelial cells in intestinal ischemic disease.

Yamazaki et al. Eur J Pharmacol 2018; 822: 25–31. doi: 10.1016/j.ejphar.2018.01.003

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

This pooled analysis of trial data shows that empagliflozin reduces albuminuria by a clinically meaningful amount in patients with type 2 diabetes and either micro- or macroalbuminuria.

Summary points
  • This pooled analysis examined the effect of sodium-glucose co-transporter 2 (SGLT2) inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes.
  • SGLT2 inhibition lowers HbA1c, systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension.
  • As lowering HbA1c, SBP, weight and intraglomerular pressure is associated with anti-albuminuric effects in diabetes, the authors hypothesized that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent.
  • The authors examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 30–300 mg/g; n = 636) or macroalbuminuria (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomized clinical trials.
  • In patients with type 2 diabetes and either micro- or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount.
  • This effect was largely independent of the known metabolic or systemic hemodynamic effects of this drug class.

Cherney D et al. Diabetologia 2016; 59: 1860–1870. doi: 10.1007/s00125-016-4008-2

Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes

Pooled data suggest that reductions in glycated hemoglobin (HbA1c) and systolic blood pressure with canagliflozin occur by both weight-loss-independent and weight-loss-associated mechanisms.

Summary points
  • This pooled analysis investigated the contribution of weight loss resulting from treatment with the sodium-glucose cotransporter-2 inhibitor canagliflozin to HbA1c and systolic BP (SBP) reductions in patients with type 2 diabetes.
  • Canagliflozin 100 and 300 mg reduced mean body weight, HbA1c and SBP compared with placebo (p < 0.001 for each), and more patients had body-weight reductions >0%, ≥5% and ≥10% with canagliflozin treatment than with placebo.
  • Weight-loss-independent and weight-loss-associated mechanisms contributed to HbA1c and SBP lowering with canagliflozin: ~85% of HbA1c lowering and ~60% of SBP lowering was independent of weight loss.
  • In patients with type 2 diabetes, canagliflozin provided clinically meaningful body-weight reductions, and the weight loss contributed to reductions in HbA1c​​​​​​​ and SBP.

Cefalu WT et al. Diabetologia 2015; 58: 1183–1187. doi: 10.1007/s00125-015-3547-2

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