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Non-glycemic lowering FDA indications and warnings for SGLT2 inhibitors

 
Sodium-glucose cotransporter 2 (SGLT2) inhibitors were first developed to treat hyperglycemia in patients with type 2 diabetes. They exert their action by blocking glucose reuptake in the proximal tubule and lowering blood glucose by promoting urinary loss.¹ There is currently four SGLT2 inhibitors approved by the FDA which are all indicated for glycemic control in patients with type 2 diabetes mellitus. Based on outcomes from clinical trials on medications in this class and subsequent results showing benefit in risk reduction outside of antihyperglycemic effects, the FDA has approved new indications seen in table 1.^2-4 Risk reductions included reducing risk of cardiovascular disease, diabetic kidney disease, and heart failure related events. The proposed mechanism of action for reducing cardiovascular disease and heart failure related events is that the inhibitors also prevent reabsorption of sodium. This leads to an increase in urine production, a decrease in plasma volume, and a decrease in systolic blood pressure. This mechanism causes a lowering effect in the pre- and afterload of the heart as well as downregulation of sympathetic activity.⁴ The mechanism for reducing diabetic kidney disease is by an increase in tubuloglomerular feedback and a reduction in intraglomerular pressure.²

Table 1: non-glycemic FDA approved indications and approval dates^2-4

Canagliflozin (Invokana) was approved to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease on October 30, 2018. The canagliflozin cardiovascular assessment study (CANVAS) was a randomized, parallel, placebo controlled, multi-center, multi-national, double blind trial conducted to assess the safety and efficacy of canagliflozin. The primary endpoint of the trial was a composite cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Canagliflozin reduced the relative risk of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke by 14% compared to placebo. This was statistically significant in the primary prevention group and overall population. The incidence was found to be 26.9 versus 31.5 per 1000 patient-years.⁵ The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial studied the efficacy of canagliflozin in preventing kidney and cardiovascular outcomes in patients with diabetes and kidney disease. The trial was a multinational, randomized, double blind, placebo-controlled trial with a primary endpoint of composite end stage kidney disease (ESKD), doubling of serum creatinine, and renal or cardiovascular death. The primary endpoint was evaluated as “time to first occurrence.” The results of the trial showed that canagliflozin significantly reduced the risk in progression to ESKD, doubling of serum creatinine and cardiovascular death (HR: 0.70; 95% CI: 0.59, 0.82; p<0.0001).⁶ The event rate for canagliflozin treatment group was 4.3 per 100 patient years versus placebo event rate of 6.1 per 100 patient years.⁶

Empagliflozin (Jardiance) was also approved to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease. The trial that allowed for this approval was the EMPA-REG Outcome trial, which was a multicenter, multi-national, randomized, double-blind parallel group trial. The primary endpoint was defined as the time to the first occurrence of a major adverse cardiac event in empagliflozin treatment group versus placebo. The empagliflozin treatment group showed a statistically significant reduction in the risk of cardiovascular death (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction) with no change in the risk of non-fatal myocardial infarction or non-fatal stroke.⁷ The risk of CV death, nonfatal myocardial infarction, and nonfatal stroke was significantly reduced by 14% compared to placebo. It also reduced all-cause mortality by 32% and death from CV causes by 38%.^7,8

Dapagliflozin (Farxiga) has received the most attention in the past year. The most recent approval is to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (NYHA class II-IV). This approval makes dapagliflozin the first and only approved SGLT2 inhibitor for patients with heart failure with reduced ejection fraction (HFrEF).⁹ More interesting is that is can be a treatment option for patients with HFrEF with or without type II diabetes mellitus. In the landmark trial called Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), patients with HFrEF were randomized to receive dapagliflozin or placebo. The trial was international, multi-center, randomized, and double blind. The primary composite endpoint looked at cardiovascular death, hospitalization for heart failure, and urgent heart failure visit. Patients in the dapagliflozin treatment group had significantly reduced incidence in the primary composite endpoint. The primary composite endpoint occurred in 386 patients (16.3%) in the dapagliflozin group and in 502 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). The results were consistent when comparing HFrEF patients with and without type 2 diabetes.¹⁰ Before the DAPA-HF trial, dapagliflozin was studied in the Dapagliflozin Effect on Cardiovascular Events Trial (DECLARE), to determine the effect when added on to current therapy. This study allowed for the indication to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors. Dapagliflozin was found to be superior to placebo at reducing the risk of hospitalization in heart failure patients (hazard ratio, 0.73; 95% CI, 0.61 to 0.88) but was noninferior to placebo with respect to the composite safety outcome of cardiovascular death, myocardial infarction, or ischemic stroke.¹¹

             
Prior to initiation of therapy, the patient’s risk for adverse effects with this class of medications should be evaluated. Since the mechanism of action leads to increased excretion of glucose in the urine, the most common side effect is genital mycotic infections such as vulvovaginal candidiasis in women and Candida balanitis in men. These patients also experience an increase in urinary tract infections. Therefore, SGLT2i therapy in patients with a history of recurrent genitourinary infection is not preferred, and therapy should be stopped if new or worsening genitourinary infections occur while on therapy.  One can also expect that due to the osmotic diuresis effects, these drugs can cause polyuria, dehydration, dizziness, and hypotension.¹¹ Therefore, patients should be counseled to drink plenty of fluids while on therapy and report any signs or symptoms of hypotension.  Another adverse effect is known as Fournier’s gangrene which is a rare form of necrotizing fasciitis of the perineal soft tissue and genitalia.¹² The incidence of Fournier’s gangrene is 1.6 cases per 100,000.¹³

             
The FDA has issued a few warnings about these medications. The most serious black box warning is for canagliflozin. FDA warned that the medication causes an increased risk of leg and foot amputations.¹⁴ Results showed that over a year that the risk of amputation was 5.9 out of 1,000 in patients treated with canagliflozin compared to 2.8 out 1,000 patients in the placebo group.⁵ One study reviewed the risk of amputations in patients treated with SGLT2 inhibitors compared to DPP-4 inhibitors. There was a higher rate of amputations among the SGLT2i patients, but it was not statistically significant.¹⁵ In a meta-analysis review, SGLT2 inhibitors were not significantly associated with amputation risk but the subgroup analysis showed an increased incidence of amputation in participants using canagliflozin.¹⁶ Ways to minimize risk of amputation is to counsel the patient on checking their feet every day, properly caring for wounds, following their treatment regimen, and maintaining a healthy lifestyle. The FDA strongly warns about increase risk of bone fractures. The CANVAS trial showed an increase risk of fractures, but many occurred after a fall and thus could be attributed to dizziness and orthostatic hypotension.^5,8 It is important to counsel patients on the importance of regular exercise and a healthy diet to reduce the risk of fractures. Another warning the FDA advises about is the risk for diabetic ketoacidosis.¹⁷ Ketoacidosis related to SGLT2 inhibitors presents uniquely because glucose levels do not go over 250 mg/dL due to urinary glucose excretion therefore it can be referred to as euglycemic ketoacidosis. There have only been a few cases reported and remains rare but patients should be educated on the symptoms of diabetic ketoacidosis. Most cases have been reported in patients with type 1 diabetes mellitus, which is not a currently approved use by the FDA therefore this SGLT2 inhibitors should not be used in patients with type 1 diabetes mellitus.^8,18

In the American Diabetes Association Standards of Care 2020, SGLT2 inhibitors are now recommended in addition to metformin for patients when atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease predominates independent of A1C.¹⁹ SGLT2 inhibitors and GLP1RA shown to decrease risk for ASCVD events are recommended for patients with established or high risk ASCVD. Other classes of medications known to decrease risk for ASCVD events should also be used based on guideline-recommended therapy including statins, ACEi/ARBs, and antiplatelet therapy as these were also utilized in patients described in the studies above.²⁰ SGLT2 inhibitors are preferred in addition to metformin in patients with CKD (including albuminuria) and CHF. In patients without established ASCVD, CHF, or CKD, they are recommended to be used in patients that desire weight loss.^8,21 The amount of weight loss expected varies between individuals but patients lose 2-3 kg on average.²²

SGLT2 inhibitors are a great treatment option for patients with diabetes as they have benefits beyond glycemic lowering. For each patient, benefits of treating patients with SGLT2 inhibitors should be weighed against patient-specific risks. Education is key to help patients know how the medications can affect them and when they should contact a health provider to minimize potential adverse effects.

For a complete list of references or further questions, please reach out via emails below:

Taylor Jaramillo, PharmD Candidate
tnhayes2@central.uh.edu

Bernadette Asias-Dinh, PharmD, BCACP, BCPS, CDCES
bdasias@central.uh.edu