For SGLT2 inhibitors, big benefits come with some trade-offs

BOSTON — The overall profile of sodium-glucose cotransporter 2 inhibitors suggests they are a reliable, second-line therapy choice for adults with type 2 diabetes; however, the class is associated with possible side effects that should be carefully considered, according to a speaker at the Cardiometabolic Health Congress.

“Both GLP-1 (receptor agonists) and SGLT2s have shown a mortality benefit, more so than, really, any other class of diabetic glucose-lowering drug in people with type 2 diabetes,” George L. Bakris, MD, director of the ASH Comprehensive Hypertension Center at University of Chicago Medicine, said during a presentation. “Given the overall profile, they definitely would be preferred second-line agents, absolutely over sulfonylureas, and probably over [thiazolidinediones] and some other agents as well.”

George L. Bakris

Previous studies assessing intensive therapy vs. standard care, such as the STENO-2 trial, have demonstrated the benefits of intensive therapy even 2 decades after the original intervention ended, Bakris said. More recently, large outcome studies of GLP-1 receptor agonists, such as the LEADER trial, and SGLT2 inhibitors, such as the EMPA-REG OUTCOME trial, revealed that patients assigned liraglutide (Victoza, Novo Nordisk) or empagliflozin (Jardiance, Boehringer Ingelheim), respectively, experienced reduced BP and CV benefit vs. those assigned a placebo.

The most recent glycemic control algorithm released by the American Association of Clinical Endocrinologists and the American College of Endocrinology in 2016 reflects the shifting trend in favor of the two drug classes, Bakris said. SGLT2 inhibitors, he said, have “skyrocketed” to the top of the recommended therapies’ list, second only to GLP-1 receptor agonists, for patients with an HbA1c of at least 7.5% already taking metformin or another first-line therapy.

“If you look at empagliflozin and put it with other SGLT2s, what are the effects?” Bakris asked. “Certainly, you’re reducing [BP], it does reduce sympathetic nervous system activity, it does reduce uric acid, it reduces glucagon, reduces oxidative stress, and of course, it reduces glucose. All these factors could theoretically contribute to the [BP] lowering effect of this agent, this class.”

“It’s important to keep in mind that these two new classes of agents have really hit the ground running, with a lot of good data,” Bakris said. “They’ve already been incorporated in these guidelines. What the [American Diabetes Association] is going to [recommend], I have no idea, but they will have to at least give them some lip service.”

Renal benefits in trial

Data from the EMPA-REG OUTCOME trial, published in September 2015, revealed that empagliflozin significantly reduced the risk for CV death and all-cause mortality in adults with type 2 diabetes and an established history of CVD. When combined with standard care, empagliflozin reduced the risk for CV death by 38% vs. placebo, with no significant difference in the risk for nonfatal MI or stroke. Patients treated with empagliflozin also experienced a 32% reduction in all-cause mortality risk and what Bakris called “a whopping 35% risk reduction” in risk for hospitalization for HF.

“[This is] very clear evidence — even stronger then, I would argue, in SPRINT, that by using this agent as part of a cocktail that is already treating [BP], lipids and glucose, you’re getting a huge volume benefit on [HF] reduction,” Bakris said.

In EMPA-REG OUTCOME subgroup analysis, there are a few key results that stand out, Bakris said. Adults aged at least 65 years, those with an HbA1c of 8.5% or less, and those with a BMI of 30 kg/m² or less all fared better with liraglutide vs. patients who were younger than age 65 years, had a higher HbA1c or a BMI greater than 30 kg/m². In addition, patients with kidney disease assigned empagliflozin experienced fewer renal events, and ongoing follow-up analyses suggest that the drug further slows nephropathy progression, Bakris said.

“If you look at the decline in [estimated glomerular filtration rate], you can see the placebo group had a sustained decline over the 192-week follow-up compared to empagliflozin,” Bakris said. “With empagliflozin, you get this acute decline in eGFR, similar to what you see in ACE inhibitors.”

BP reduction

A recent systematic review of 27 randomized controlled trials assessing BP outcomes with all SGLT2 inhibitors (n = 12,960) showed that the class reduced both systolic BP (weighted mean difference, -4 mm Hg; 95% confidence interval, -4.4 to -3.5) and diastolic BP (weighted mean difference, -1.6 mm Hg; 95% confidence interval, -1.9 to -1.3) from baseline. Only canagliflozin had a significant dose-response relationship with systolic BP, Bakris said.

SGLT2 inhibitors had no significant effect on the incidence of orthostatic hypotension, he added.

“So in case you want to call these diuretics, you would only be partially correct,” Bakris said. “They don’t work as diuretics. They are osmotic diuretics, but why are you getting good effects on BP with a eGFR of 40, when in fact the glucose-lowering effect at that point is very minimal? So, there are some limitations.”

Risks to consider

When prescribing an SGLT2 inhibitor on a diuretic, Bakris said, there is a risk for hypotension — not from the SGLT2 inhibitor alone, but from the interaction between the two drugs.

“Older people, generally, either stop the diuretic or cut the diuretic dose in half, because then, you will be in trouble,” Bakris said.

SGLT2 inhibitors are also associated with certain genital infections, Bakris said. He recommended the drug not be prescribed to uncircumcised men due to the risk of balanitis; women using an SGLT2 have an increased risk for vulvovaginitis.

“If [patients] have frequent urinary tract infections, this drug is probably not so good, because it will increase that risk,” he said. – by Regina Schaffer

Reference:

Bakris GL. SGLT2s: Should They Be Second-Line Therapy? Presented at: Cardiometabolic Health Congress; Oct. 5-8, 2016; Boston.

Disclosure: Bakris reports receiving consultant fees from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Medtronic, Novartis and Takeda.