Sodium-Glucose Cotransporter 2 Inhibitors
October 2020
Volume 4, Issue 5


Welcome from J. Michael Gonzalez-Campoy, MD, PhD, FACE

The accumulation of fat mass leads to overweight and obesity. Adiposopathy, the pathophysiological changes in adipose tissue that develop with excess fat mass, contributes to the development of metabolic diseases. For years, it was dogma that improving glycemic control would cause weight gain. This posed a dilemma for clinicians because it created a vicious cycle of weight gain, leading to loss of glycemic control, and the need to escalate the pharmacological management of diabetes.

The development of medications that can both improve glycemic control and help the weight loss process has changed diabetes management. Metformin, the first of these compounds to become available for the treatment of diabetes, has become the first-line therapy for most patients with type 2 diabetes. The glucagon-like peptide-1 (GLP-1) agonists carry the benefit of associated weight loss, but they need to be administered via subcutaneous injection.

The newer sodium-glucose cotransporter 2 (SGLT2) inhibitors act on the proximal tubule of the nephron, inhibiting the active transport of glucose from the tubular lumen to the interstitium. This causes glucosuria, which both improves glycemic control and leads to the urinary excretion of calories that would otherwise be made available to the body. The pharmacological glucosuria caused by SGLT2 inhibitors causes weight loss, and also a mild osmotic diuresis that lowers the blood pressure. These pharmacological effects of SGLT2 inhibitors place this class of medications high up in the diabetes armamentarium.

In this issue of Diabetes Scan, we review the first of the SGLT2 blockers to come to market in the United States, canagliflozin (Invokana). The first paper documents an additional mechanism of action for canagliflozin: it delays the intestinal absorption of glucose, thereby decreasing postprandial glucose peaks. This provides canagliflozin with an additional mechanism of action that is similar to the alpha-glucosidase inhibitors.

Canagliflozin is effective as initial monotherapy for type 2 diabetes mellitus, without the risk of hypoglycemia. This agent also is effective as a second agent added to metformin, with hemoglobin A1c reductions similar to those seen with a sulfonylurea, but with much less hypoglycemia. Furthermore, canagliflozin is effective as a third-line agent added to a regimen of metformin and a sulfonylurea, faring better than the dipeptidyl peptidase-4 inhibitor sitagliptin in glycemic control, body weight, and blood pressure. Of note, whenever a glucose lowering medication is added to sulfonylureas or insulin, there is the real possibility of hypoglycemia. Patients must be cautioned of this risk, and the doses of insulin and sulfonylureas should be adjusted downwards to minimize this risk.

Given the mechanism of action of the SGLT2 blockers, one concern that has been raised is that the higher amount of glucose in the urine may predispose patients to urinary and genital tract infections. In a study specifically designed to document the incidence of asymptomatic bacteriuria and symptomatic urinary tract infection, the incidence of these side effects with canagliflozin was no different than that with placebo, despite significantly increasing urinary glucose excretion.

This is not a universal observation, and in some of the registration trials for canagliflozin the incidence or urinary tract infections was higher than that for placebo. When canagliflozin is prescribed, patients should be informed of the potential for urinary and genital tract infections.

The mild osmotic diuresis seen with canagliflozin is an attribute and not a deterrent. Both in patients with chronic kidney disease and the elderly, canagliflozin is well-tolerated and effective in improving glycemic control. The osmotic diuresis lowers the blood pressure gently, without significant risk of dehydration or orthostatism.

From my perspective as a bariatric endocrinologist, the reduction in body weight is what makes the SGLT2 inhibitors highly desirable—they treat the hyperglycemia and also the underlying adiposopathy that causes it. The beneficial effect on blood pressure makes canagliflozin’s benefits outweigh its risks.

First Article:
Safety and Efficacy Study of Canagliflozin in Older Patients
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