SGLT2 Inhibitor Q & A

1. What is the mechanism of action of SGLT2 inhibitors?

A. They inhibit a glucose transporter in the proximal renal tubule.

B. They bind to a receptor in the pancreas that results in signaling that increases insulin synthesis and release.

C. They suppress hepatic gluconeogenesis.

D. They competitively inhibit post-prandial hormones that results in increased insulin secretion and decreased glucagon.

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Answer: A. They inhibit a glucose transporter in the proximal renal tubule.

SGLT2 inhibitors bind to sodium glucose transporter 2, a low-affinity, high capacity glucose transporter, responsible for 90% of glucose reabsorption. The SGLT2  sodium-glucose transporter is upregulated in diabetes. Inhibition of the transporter decreases glucose reabsorption in the proximal tubule, increasing its excretion in the urine, and resulting in reduced hyperglycemia. SGLT2 inhibitors also improve phase I insulin release from pancreatic beta cells and increase peripheral insulin sensitivity and uptake. Option B is the mechanism of action of GLP-1 agonists; option C is the mechanism of metformin; option D is the mechanism of action of DPP-4 inhibitors.

2. What is the range of A1c reduction that has been described with monotherapy with SGLT2 inhibitors?A. -0.1 to -0.3%

B. -0.6 to -1%

C. -0.9 to 1.2%

D. -1.2 to 1.5%

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Answer: B. -0.6 to -1%

The average A1c reduction is dose-dependent and varies based on the specific SGLT2 inhibitor used. However, in clinical studies to date, canagliflozin reduced mean A1c by 0.77% (100 mg dose) to 1.03% (300 mg dose) and dapagliflozin by 0.58% (2.5 mg dose), 0.77% (5 mg dose) and 0.89% (10 mg dose). Interestingly, in a study of cangliflozin in type 2 diabetes patients aged 55 to 80 years, those <65 years had a more robust A1c reduction (-0.65% and -0.82%) compared to those ≥65 years (-0.45% and -0.5%) for the 100 mg and 300 mg doses, respectively. Patients with moderately impaired renal function (GFR between 30-50 mL/min/1.73m²), however, responded with a lower A1c reduction compared to those with normal or mildly impaired renal function. This suggests that, because the drug acts in the kidney, there may be some heterogeneity by age and renal function that ought to be considered when the decision to use an SGLT2 inhibitor is made.

3. Which of the following parameters should be periodically monitored in patients with renal impairment who are on an SGLT2 inhibitor?

A. GFR

B. Serum potassium

C. Calcium

D. Blood pressure

E. A and B

F. B and D

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Answer: F.B. Serum potassium and B. Blood pressure.

Because SGLT2 inhibitors induce osmotic diuresis, patients at risk for intravascular volume depletion (ie, elderly patients who may be on other antihypertensives) should be carefully monitored for symptomatic hypotension. In addition, the SGLT2 inhibitors’ action on a sodium-glucose transporter in the setting of renal impairment can affect serum potassium, magnesium, and phosphate levels. Serum potassium levels should be periodically checked, until a stable dose and stable renal function have been achieved.

4. Which of the following is a known side effect of SGLT2 inhibitors?

A. Weight gain

B. Edema

C. Urogenital infections

D. Hypertension

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Answer: C. Urogenital infections

Because they induce incraesed glucosuria, the SGLT2 inhibitors predispose patients to both genital mycotic infections and urinary tract infections (compared to placebo) with the highest risk occurring in females and uncircumsized males. These drugs deplete intravascular volume and are therefore associated with lower blood pressure and less edema. In addition, weight loss of 2.5 to 3.3 kg has been observed in those receiving this drug in clinical trials.