Indications and Mechanism of SGLT2 Inhibitors in Type 2 Diabetes

1. The American Association of Clinical Endocrinologists (AACE) recommends which of the following for type 2 diabetes (T2DM) patients?

A. Initiating therapy with metformin, a glucagon-like peptide 1 (GLP- 1) receptor agonist, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a sodium glucose cotransporter 2 (SGLT2) inhibitor, or an alpha-glucosidase inhibitor for patients with an entry A1C ≥7.5%.

B. Initiating treatment with metformin (unless contraindicated) plus a second agent (GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, TZD, or basal insulin) with entry A1C levels >7.5%.

C. Initiating insulin therapy alone or in combination with metformin or other oral agents for patients with an entry A1C >9.0% who have symptoms of hyperglycemia.

D. All of the above

E. None of the above

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Answer: D. All of the above

The AACE recommends choice of therapy to be based on entry hemoglobin A1C (HbA1c) as well as individualized for each patient according to the side effect profile. For example, in a T2DM patient who has frequent episodes of hypoglycemia, sulfonylureas and glinides are the least desirable alternative due to their increased risk of hypoglycemia. In such patients, insulin analogs glargine and detemir may also be preferred over intermediate-acting neutral protamine Hagedorn (NPH) because analog insulins are associated with less hypoglycemia. Alternatively, in a diabetic patient who is obese, a GLP-1 receptor agonist may be a great choice because it results in weight loss. Minimizing hypoglycemia and weight gain should be priorities when deciding on choice of therapy, but additional issues, such as patient compliance, method of deliver (PO vs. injection), frequency of dosing, and cost must also be considered.

Reference: Handelsman Y, et al.  American Association of Clinical Endocrinologists and American College of Endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015 - Executive Summary. Endocr Pract. 2015;21(4):413-437.

2.  For each of the following, select whether SGLT2 inhibitors exert a neutral, mild, moderate, or marked effect:

Fasting plasma glucose (FPG)

Postprandial glucose (PPG)

Nonalcoholic fatty liver disease (NAFLD)

Hypoglycemia

Weight (magnitude and effect)

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Answers: The magnitude of effects of SGLT2 inhibitors on each of the following parameters:

FPG: moderate

PPG: mild

NAFLD: neutral

Hypoglycemia: neutral

  Weight: mild, weight loss      

         SGLT2 inhibitors bind to an SGLT2, which is a low-affinity, high capacity glucose transporter that is responsible for 90% of glucose reabsorption. The SGLT2 sodium-glucose transporter is upregulated in diabetes. Therefore, by inhibiting this transporter, there is decreased glucose resorption in the tubule and increased excretion into the urine, resulting in less hyperglycemia. In addition to this mechanism of action, SGLT2 inhibitors also improve phase I insulin release from beta cells and increase peripheral insulin sensitivity and uptake. SGLT-2 inhibitors have multiple beneficial effects and have been shown to result in a decrease in blood pressure and weight and have a very low incidence of hypoglycemia when used alone or in combination with metformin. 

Reference: Handelsman Y, et al. American Association of Clinical Endocrinologists and American College of Endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015 - Executive Summary. Endocr Pract. 2015;21(4):413-437.

 3. SGLT2 mediates approximately what percentage of renal glucose transport? 

 A. 10%

 B.  30%

 C.  50%

 D.  70%

 E.  90%

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      Answer: E.       90%

Although SGLT2 mediates approximately 90% of renal glucose reabsorption in the renal tubule, SGLT2 inhibitors in clinical practice are only able to inhibit approximately 30-50% of the glucose load filtered by the kidneys. Surprisingly, early in vitro studies suggested that these agents would provide near complete inhibition of their targets and of glucose reabsorption. However, this has not panned out in clinical trials in humans. The mechanism of this discrepancy is largely incompletely understood. However, some experts have postulated that these findings may be a result of secretion and/or active reabsorption of the drug in the proximal tubule (ie, glomerular filtration cannot deliver sufficient levels of SGLT2 inhibitors to their targets in the renal tubule over a long period even when systemic high doses of the drugs are given). Since the drug is acting within the renal tubule and is also being cleared by the kidneys, its efficacy is exquisitely sensitive to its own pharmacokinetics/pharmacodynamics. Another mechanism of a lower than expected result may be related to a slow off-rate of these inhibitors from the target (the SGLT2 receptor).

Reference: Liu J, et al. Why do SGLT2 inhibitors inhibit only 30–50% of renal glucose reabsorption in humans? Diabetes. 2012;61(9):2199-2204.