SGLT2 Inhibitors Double the Risk for Diabetic Ketoacidosis

Miriam E Tucker

June 07, 2017

The risk of developing diabetic ketoacidosis (DKA) among type 2 diabetes patients initiating a sodium–glucose cotransporter 2 (SGLT2) inhibitor medication is about double that seen among patients starting a dipeptidyl peptidase-4 (DPP-4) inhibitor, but the overall risk is still low, new research suggests.

Findings from the largest study conducted to date to investigate the issue were published as a research letter in the June 8 issue of the New England Journal of Medicine by Michael Fralick, MD, and colleagues at the Brigham and Women's Hospital, Boston, Massachusetts.

"We found a doubling in the risk of DKA, which sounds frightening, but the absolute risk is quite small.…I still think this is a very good class of medications and for certain patients will continue to be. Now we just have a little more information to add to the discussion when the risks and benefits are being considered," Dr Fralick told Medscape Medical News.

He estimates that between 5 and 8 patients per 1000 initiating SGLT2 inhibitors will develop DKA.

And he advises that patients be strictly monitored for signs of DKA after starting on SGLT2 inhibitors, noting, "This is something that can happen relatively quickly, so that's why I think it's important right after patients are started on these drugs that they're closely monitored and the clinician considers ordering bloodwork."

But overall, Dr Fralick, a general internist, supports use of the SGLT2 inhibitor class for selected patients with type 2 diabetes, given the recent results from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study showing reduction in cardiovascular deaths, as well as renal protection, with empagliflozin (Jardiance, Boehringer Ingelheim/Lilly).

"I completely agree that these medications have significant benefits," he commented.

All eyes will be on the results from another cardiovascular-outcomes trial with a different SGLT2 inhibitor, canagliflozin (Invokana, Johnson & Johnson) to be reported on Monday at the American Diabetes Association (ADA) 2017 Scientific Sessions.

Results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) program will reveal whether the cardiovascular protection observed with empagliflozin in EMPA-REG OUTCOME is a class effect or not.

And the findings will further inform on some of the side effects so far associated with this drug class, including DKA, as well as fracture risk and a doubling of amputations of the lower limb, already identified with canagliflozin compared with placebo in CANVAS, which resulted in the Food and Drug Administration adding a boxed warning to this effect to the product label.

Largest Study of Its Kind  

For the current study, Dr Fralick and colleagues used a claims database of commercially insured US patients (Truven MarketScan) and identified 50,220 type 2 diabetes patients who had received a new prescription for an SGLT2 inhibitor and 90,132 initiating a DPP-4 inhibitor (chosen as the comparator class because it is used similarly to SGLT2 inhibitors, as second-line after metformin for type 2 diabetes, but has no known link to DKA).

The primary outcome was hospitalization for DKA — the unadjusted rate within 180 days of SGLT2 inhibitor initiation was 4.9 per 1000 person-years, compared with 2.3/1000 person-years following DPP-4–inhibitor initiation (hazard ratio, 2.1).

After propensity score matching with 38,045 patients in each arm to account for confounders such as age, comorbidities, use of other medications, and healthcare utilization, the hazard ratio for hospitalization for DKA with SGLT2 inhibitors vs DPP-4 inhibitors was still significant at 180 days (4.9 vs 2.2/1000 person-years; HR, 2.2), as well as at 30 days (7.5 vs 3.3/1000 person-years; HR, 2.3) and 60 days (5.6 vs 2.3; HR, 2.5).

The DKA risk at 180 days was also significantly higher with SGLT2 inhibitors among patients not taking insulin (2.5 vs 1.0; HR, 2.5).

"Still So Much Work to Be Done"

Once the investigators had the data, they strove to get them published as quickly as possible — hence in a research letter rather than a full paper, Dr Fralick told Medscape Medical News, adding, "There's still so much work to be done to identify specific risk factors."

Meanwhile, the group is using the same database to examine the risk of amputations with canagliflozin; results are expected in a few weeks.

The study was supported by the division of pharmacoepidemiology and pharmacoeconomics, department of medicine, Brigham and Women's Hospital, Harvard Medical School, Boston. Dr Fralick reports grants from the University of Toronto Clinician Scientist Program and Clinician Investigator program and grants from the Detweiller Traveling Fellowship funded by the Royal College of Physicians and Surgeons of Canada, outside the submitted work. Disclosures for the coauthors are listed on the journal website.

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N Engl J Med. 2017;376:2300-2302. Article


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