SGLT2 inhibitors for type 2 diabetes: Clinical considerations
Medications used to manage type 2 diabetes
FDA has approved three sodium–glucose cotransporter 2 (SGLT2) inhibitors in the last 2 years: canagliflozin (Invokana—Jansssen), dapagliflozin (Farxiga—AstraZeneca), and empagliflozin (Jardiance—Boehringer Ingelheim). Many clinicians are interested in learning where these agents fit into the armamentarium of medications used to manage type 2 diabetes, key differences within the class, and appropriate patient selection.
SGLT2, which is expressed in the proximal renal tubule, is responsible for the reabsorption of filtered glucose from the tubular lumen. Inhibition of SGLT2 results in reduced reabsorption of filtered glucose and increased urinary glucose excretion.
“At first I was hesitant to use these agents after reading about the potential for dehydration and genital infections. But once I started using them in my patients, I have had positive results, and patients seem to really like being on these agents,” said Jennifer D. Smith, PharmD, CPP, BC-ADM, CDE, Associate Professor, Campbell University College of Pharmacy & Health Sciences, and Clinical Pharmacist Practitioner, Wilson Community Health Center.
Smith noted differences among the SGLT2 inhibitors. Hyperkalemia is a concern with canagliflozin, and bladder cancer is a warning on the dapagliflozin label.
Patients with moderate renal impairment and those taking medications that may also cause hyperkalemia—such as ACE inhibitors or angiotensin receptor blockers—are at greater risk for elevated potassium levels with canagliflozin.
Bladder cancer is a warning specific to dapagliflozin. According to the labeling, data from 22 clinical studies showed that newly diagnosed bladder cancer was reported in 0.17% of patients treated with dapagliflozin (n = 10/6045) compared with 0.03% of patients treated with placebo or a comparator (n = 1/3512).
Appropriate patient selection
“An ideal patient for these agents would be one who needs additional glycemic control and is overweight and has elevated blood pressure,” Smith told Pharmacy Today.
The SGLT2 inhibitors have been shown to reduce glycosylated hemoglobin (A1C) by about 0.7%–1%, lower blood pressure, and result in weight loss. These agents cause intravascular volume contraction, resulting in modest reductions in blood pressure. In terms of weight loss, Smith added, “We have seen about a 5- to 10-lb weight loss” in patients taking these agents.
Smith continued that baseline assessment and close monitoring of renal function are another factor that clinicians need to consider. These medications are effective only in those with sufficient renal function; canagliflozin and empagliflozin are not recommended for patients with an estimated glomerular filtration (eGFR) rate of less than 45 mL/min/1.73 m, and dapagliflozin is not recommended for those with an eGFR less than 60 mL/min/1.73 m.
Concurrent medications also need to be assessed. Smith noted that the use of loop diuretics may further increase the risk for dehydration and hypotension. The increased risk of genital mycotic infections with the SGLT2 inhibitors also must be considered, especially in patients who have a history of these types of infections.
The 2015 American Diabetes Association Standards of Medical Care in Diabetes are fairly consistent with previous recommendations in terms of selecting pharmacotherapy for patients. Metformin remains the preferred option for those with type 2 diabetes, used in combination with behavioral modifications, for patients who do not have contraindications to this agent. For patients who do not attain A1C targets after 3 months of metformin monotherapy, a two-drug regimen is recommended, which can include the addition of an SGLT2 inhibitor.
Within the standards, the SGLT2 inhibitors are characterized as having intermediate efficacy, a low risk for hypoglycemia, weight loss, genitourinary and dehydration adverse effects, and an associated high cost. These agents are also listed as an option for patients who require select three-drug regimens and as initial monotherapy for patients with contraindications to metformin.
Key counseling points should focus on proper administration and potential adverse effects, according to Smith. Patients should be informed that the medications should be taken in the morning with or without food, but that canagliflozin’s label specifically states it should be taken before the first meal of the day.
“To help prevent dehydration, patients should be encouraged to drink one to two extra glasses of water per day above what they usually drink,” Smith said. “Patients should also have a thorough understanding of the risks of genital mycotic infections and potential signs and symptoms indicative of these types of infections.”