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Sodium-glucose cotransporter-2 inhibitors in type 2 diabetes


Preclinical and clinical pharmacology

The potential role of SGLT2 inhibitors in the treatment of type 1 diabetes mellitus

Sodium-glucose co-transporter (SGLT)-2 inhibitors are cardio- and renal protective in type 2 diabetes mellitus (T2DM). Clinical data indicate these benefits may extend to type 1 DM (T1DM).

Summary points
  • ​​​​​​​SGLT2 inhibitors improve blood glucose control in T1DM as well as in T2DM.
  • There is low risk of hypoglycaemia due to the compensatory activity of SGLT1 and the body’s metabolic counter-regulation, both of which persist during SGLT2 inhibition.
  • In the key EMPA-REG OUTCOME trial in patients with T2DM, empagliflozin reduced the risks of nephropathy by 39%, progression to end-stage renal disease by 55%, cardiovascular (CV) death by 38%, all-cause death by 32%, and heart failure hospitalization by 35% versus placebo.
  • Similar effects were observed for canaglifozin in the CANVAS Program.
  • CV and renal protective actions also relevant in T1DM patients include reduced glomerular filtration, blood pressure, volume overload, body weight, and blood glucose; and mild ketosis which may be organ protective.
  • Three double-blind, randomized, double-blind trials have showed SGLT2 inhibitors to reduce HbA1c, body weight and daily insulin doses in patients with T1DM.
  • Ketoacidosis is an especial risk in T1DM patients.

Fattah H, Vallon, V. Drugs 2018; 78: 717–726. doi: 10.1007/s40265-018-0901-y

SGLT2 inhibitors: Benefit/risk balance

An evaluation of the benefit/risk profile of the sodium-glucose cotransporter-2 (SGLT2) inhibitors canagliflozin, dapagliflozin and empagliflozin.

Summary points
  • Three sodium-glucose cotransporter-2 (SGLT2) inhibitors are currently available in the US and Europe: canagliflozin, dapagliflozin, and empagliflozin.
  • Benefits of SGLT2 inhibitors include reductions in glycated hemoglobin (with a minimal risk of hypoglycemia), body weight, blood pressure, and serum uric acid.
  • Empagliflozin use showed positive renal outcomes and remarkable reductions in cardiovascular and all-cause mortality in patients with previous cardiovascular disease.
  • The most common adverse effects with SGLT2 use are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rare.
  • Concerns about ketoacidosis and bone fracture risk deserve caution and further evaluation.

Scheen AJ. Curr Diab Rep 2016; 16: 92. doi: 10.1007/s11892-016-0789-4

Sodium glucose cotransporter-2 inhibitors: A review of their basic and clinical pharmacology

Sodium-glucose cotransporter-2 inhibitors reduce hyperglycemia by increasing urinary glucose excretion independently of insulin secretion or action. This review describes their biological rationale, mode of action, and clinical pharmacology.

Summary points
  • Sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent reabsorption of glucose in the kidney and facilitate its excretion in urine. As glucose is excreted, its plasma levels fall leading to an improvement in all glycemic parameters.
  • Three of these agents, canagliflozin, dapagliflozin and empagliflozin, are available in the USA and Europe.
  • They are associated with a variety of non-glycemic benefits, including reductions in body weight and blood pressure.
  • Potential adverse effects include genitourinary infections, symptoms of volume depletion, and deleterious effects on the skeleton.
  • SGLT2 inhibitors do not exhibit any clinically relevant drug–drug interactions, including with other anti-diabetic drugs and diuretics.
  • The efficacy of SGLT2 may be suboptimal in individuals with advance renal disease.
  • SGLT2 inhibitors are a reasonable treatment option if an additional glucose-lowering effect is needed beyond metformin monotherapy, and can be used as initial monotherapy in persons in whom metformin is not indicated, or not tolerated.

​​​​​​​Kalra S. Diabetes Ther 2014;5:355–366. doi:10.1007/s13300-014-0089-4

Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion

Bonner et al. demonstrate that sodium-glucose cotransporter-2 inhibitors increase the secretion of glucagon by means of a direct effect on pancreatic alpha cells, which may, at least in part, offset their effect on glucose reabsorption in the kidney.

Summary points
  • Treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors in subjects with type 2 diabetes increases both plasma glucagon and endogenous glucose production (EGP) by unknown mechanisms; increased EGP is the main cause of fasting hyperglycemia in type 2 diabetes (T2D).
  • Data from this study reveal that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets, and suggest that sodium-glucose co-transport by SGTL2 is essential for the appropriate regulation of glucagon secretion.
  • Inhibition of SGLT2 via dapagliflozin treatment in human islets increases glucagon secretion through KATP channel activation, explaining the hyperglucagonemia previously reported in T2D individuals treated with dapagliflozin.
  • These results identify a heretofore unknown role of SGLT2. The effect of SGLT2 inhibitors on alpha cells may counter their effect on glucose reabsorption in the kidney.

Bonner C et al. Nat Med 2015; 21: 512–517. doi: 10.1038/nm.3828

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