Is an SGLT2 inhibitor right for your patient with type 2 diabetes?

BP reduction. Although the mean baseline BP was controlled in most studies, SGLT2 inhibitors have been shown to significantly reduce BP. Reductions in BP with all 3 SGLT2 medications range from approximately 2 to 5 mm Hg systolic and 0.5 to 2.5 mm Hg diastolic, which may be due to weight loss and diuresis.^{4-8,10-16,20-23} While the reductions were modest at best, one study involving empagliflozin reported that more than one-quarter of patients with uncontrolled BP at baseline achieved a BP <130/80 mm Hg 24 weeks later.⁵ While these agents should not be used solely for their BP lowering effects, they may help a small number of patients with mildly elevated BP achieve their goal without an additional antihypertensive agent.

Weight reduction. Modest weight loss, likely due to the loss of calories through urine, was seen with SGLT2 inhibitors in most studies, with reductions persisting beyond one year of use. In most studies, including those involving obese patients on insulin therapy,^15,17,21 patients’ body weights were reduced by approximately 2 to 4 kg from baseline.^{3-16,18,21-23,26}

Lipid effects. Although the mechanism is unclear, use of SGLT2 inhibitors can have varying effects on lipid panels. In most studies, total and LDL cholesterol levels were increased with elevations ranging from 0.7 to 10 mg/dL.^{3,7,8,18,19,22,23} Conversely, at least one study demonstrated mild reductions in total and LDL cholesterol levels with higher doses of empagliflozin.¹³ Additionally, modest reductions in triglycerides and increases in HDL across all doses of canagliflozin, dapagliflozin, and empagliflozin have been seen.^8,9,13,15,19 While the clinical relevance of these lipid changes is unknown, monitoring is recommended.²

These agents are well tolerated

SGLT2 inhibitors were generally well tolerated in studies. The most common adverse effects include mycotic infections (2.4%-21.6%) and urinary tract infections (UTIs) (4.0%-19.6%) (both with higher incidences in females); volume-related effects such as dizziness and hypotension (0.3%-8.3%); and nasopharyngitis (5.4%-18.3%).^{4-14,16-23,26-28} Hypoglycemia was observed more often when an SGLT2 inhibitor was used in combination with a sulfonylurea or insulin therapy.^{4-14,16-23,26-28} The number of times adverse events led to discontinuation was low and similar to that in control groups.^{4-14,16-23,26-28}

Mycotic and urinary infections should be diagnosed and treated according to current standards of care and do not require discontinuation of the SGLT2 inhibitor. Canagli-flozin therapy was associated with electrolyte abnormalities including hyperkalemia, hypermagnesemia, and hyperphosphatemia.²⁵ Thus, levels should be monitored periodically, especially in patients predisposed to elevations due to other conditions or medications.²⁵

Two additional warnings are worth noting

Diabetic ketoacidosis (DKA) has been reported with all 3 agents, and bone fractures have been reported with canagliflozin.

The FDA issued a warning in May 2015 regarding the increased risk of DKA with the use of SGLT2 inhibitor single and combination products.²⁹ This warning was prompted by several case reports of DKA with uncharacteristically mild to moderate glucose elevations in patients with type 1 diabetes mellitus (T1DM) and T2DM who were taking an SGLT2 inhibitor. The absence of significant hyperglycemia delayed diagnosis in many cases. Therefore, patients should be counseled on the signs and symptoms of DKA, as well as when to seek medical attention.

SGLT2 inhibitors can reduce BP by about 2 to 5 mm Hg, systolic, and 0.5 to 2.5 mm Hg, diastolic.

Patients with diabetes and symptoms of ketoacidosis (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, and fatigue) should be evaluated regardless of current blood glucose levels, and SGLT2 inhibitors should be discontinued if acidosis is confirmed. Identified potential triggers include illness, reduced food and fluid intake, reduced insulin dose, and history of alcohol intake. Use of SGLT2 inhibitors should be avoided in patients with T1DM until safety and efficacy are established in large randomized controlled trials. The European Medicines Agency announced that a thorough review of all currently approved SGLT2 agents is underway to evaluate the risk for DKA.³⁰

In addition, the FDA called for a revision of the label of canagliflozin to reflect a strengthened warning about an increased risk of bone fractures and decreased bone mineral density (BMD).³¹ Fractures can occur as early as 12 weeks after initiating treatment and with only minor trauma.³¹

Over a 2-year period, canagliflozin also significantly decreased BMD in the hip and lower spine compared to placebo.³¹ Patients should be evaluated for additional risk factors for fracture before taking canagliflozin.³¹ The FDA is continuing to evaluate whether the other approved SGLT2 inhibitors are associated with an increased risk for fractures.

Drug interactions: Proceed carefully with diuretics

The number of drugs that interact with SGLT2 inhibitors is minimal. Because these agents can cause volume-related effects such as hypotension, dizziness, and osmotic diuresis, patients—particularly the elderly and those with renal impairment—taking concomitant diuretics, especially loop diuretics, may be at increased risk for these effects and should be monitored accordingly.^2,25