SGLT2 Inhibitors: Pros, Cons, Comparisons, and Considerations

The FDA has approved two oral diabetic medications that are first in class: canagliflozin (Invokana®) and dapagliflozin (Farxiga®). These agents work by inhibiting the receptor sodium-glucose cotransporter 2 (SGLT2) in proximal renal tubules thereby reducing glucose reabsorption and increasing urinary excretion of glucose. SGLT2 inhibitors are only approved for the management of type 2 diabetes mellitus (T2DM). Here, a review of potential advantages and disadvantages, comparison with other oral agents of HgbA1c- [A1c-] lowering power, and recommended dosage adjustments for patients with impaired renal function.^1,2

Potential advantages^1-3

   1. SGLT2 inhibitors lower both fasting and post-prandial glucose levels: Not all oral diabetic medications decrease both numbers. (See Table 1 for comparison of A1c reduction among oral anytihyperglycemic agents.)

   2. There is a low risk of hypoglycemia: Since these medications do not stimulate pancreatic insulin secretion, hypoglycemia risk is lower compared to oral medications, and particularly sulfonylureas. However, the risk of hypoglycemia increases if patients use the cotransporter class with other oral medications or insulin.

   3. They cause weight loss: These agents led to a 2- to 3-kg weight loss when compared to placebo, especially in patients taking the maximum prescribed dose.

   4. They lower systolic blood pressure: A diuresis occurs with this class by virtue of its primary action on the renal tubules and can decrease systolic blood pressure by 3 to 5 mm Hg.

Table 1. A1c Reduction Comparison Among Oral Antidiabetic Medications^1-3,7

^{*NOTE: The A1c reduction is based on data reported in clinical trials. This effect is influenced by
several factors including: baseline HgbA1c of patients in clinical trials, duration and severity of disease
(beta-cell function remaining), and drug’s mechanism of action. Therefore, this HgbA1c lowering effect
may vary with each patient.}

Potential disadvantages^1-3

   1. Vulvovaginal candidiasis and mycotic infections can be a problem: In phase 3 clinical trials, this was the most common reported side effect, specifically for females. The incidence of these infections was approximately 10%.

   2. Osmotic diuresis may lead to reductions in intravascular volume and orthostatic hypotension. The glucose excreted in the urine drags water and solute with it. In this way, they act like a diuretic.

   3. Hyperkalemia and renal insufficiency may occur as a result of a diuresis. Follow-up labs in 1 to 2 weeks are necessary after starting SGLT2 inhibitors.

   4. Dosing of SGLT2 inhibitors must be based on kidney function: The drugs were studied using estimated glomerular filtration rate (eGFR) versus estimated creatinine clearance (eCrCL) with the Cockgroft-Gault equation. Also, there are higher renal dosing cut-offs (Table 2).

   5. They are pricey: These medications are expensive without insurance and may be associated with higher prescription co-pays for those with insurance.

   6. The drugs increase LDL cholesterol: Phase 3 clinical trials with these agents showed an increase in LDL of 2% to 3%. The mechanism is unknown. There are trials with canagliflozin and dapagliflozin studying whether these medications are effective at reducing cardiovascular events. If they do, the small increase in LDL will not mean much.^4,5
 

Table 2.  SGLT2 Inhibitor Dosage Adjustments Based on Renal Function^1,2

Which patients are ideal candidates for SGLT2 inhibitors?

While there are several advantages to these medications compared to other oral diabetic medications, the side effect profile of the SGLT2 inhibitors may limit their use to a smaller patient population. These agents are more likely to be effectitve in younger patients with good renal function and stable blood pressure. Also, patients may not want to take a drug that mimics symptoms of hyperglycemia (genitourinary infection and increased urinary excretion).

What do the leading professional organizations say about these agents? (ie, American Association of Clinical Endocrinologists [AACE], American Diabetic Association [ADA] and European Association for the Study of Diabetes [EASD])

The 2013 treatment algorithm from the AACE recommends SGLT2 inhibitors with caution as monotherapy in patients with A1c < 7.5% and as part of dual or triple therapy in patients with A1c 7.5% to 9.0%. Other oral diabetic medications the AACE recommends with caution include sulfonylureas, meglitinides, and thiazolidinediones. The ADA and EASD published their last joint position statement and treatment algorithm in 2012. This article did not include the SGLT2 inhibitors because they were not FDA approved.^6,7

References:

• Invokana®[package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013.
• Farxiga® [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2014.
• Stenlof K, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013; 15: 373-82.
• ClinicalTrials.gov. Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) http://clinicaltrials.gov/show/NCT01730534
• ClinicalTrials.gov. CANVAS - CANagliflozin cardioVascular Assessment Study http://clinicaltrials.gov/ct2/show/NCT01032629?term=CANVAS&rank=1
• Garber AJ, Abrahamson MH, Barzilay JI, et al. American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19:327-336.
• Inzucchi SE, Bergenstal RM, Buse JB, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).Diabetes Care. 2012;35:1364-1379.