According to a recent Scandinavian cohort study, slightly more amputations and ketoacidosis occur under SGLT2 inhibitors than under GLP1 receptor agonists. Overall, however, the risk of serious adverse events seems manageable.
Do gliflozines, also known as SGLT2 inhibitors, deliver in practice what they have promised in clinical pivotal or safety studies for antidiabetic and cardiovascular protective effects? And is their use justified, despite some of the risks discussed, which are indicated by data from clinical trials, observational studies, and case reports?
As it appears from the data available so far, both questions can probably be answered with "yes" at the bottom line. However, the evidence base can still be expanded; so far there have only been four large-scale observational studies. Another one has now been added.
A few days ago, a Scandinavian cohort study was published in the British medical journal BMJ (see source 1). The Stockholm-based Karolinska Institute and its affiliated university hospital were in charge of the study. Between July 2013 and December 2016, the scientists looked at registry data collected from Sweden and Denmark.
Using the statistical methodology of propensity score matching, they compared 17,213 new users of SGLT2 inhibitors (SGLT2i) with the same number of to users of GLP1 receptor agonists (GLP1-RA) with comparable patient properties. The primary objective of the study was to compare hospital data on the occurrence of seven serious adverse events.
The result of propensity analysis: Amputations of the lower limbs and ketoacidosis occurred more than twice as frequently under SGLT2 inhibitors compared to GLP1 receptor agonists, with the absolute risk being low. The other serious side effects, which are currently the focus of interest, did not, however, lead to an increased risk.
In detail, the results of the cohort study are as follows (incidence per 1,000 person-years SGLT2i vs. GLP1-RA; hazard ratio; 95% confidence interval):
On a positive note, the risk of acute pancreatitis does not appear to increase among gliflozines. The statistical power had not been sufficient in previous clinical studies to answer this question.
Is the increased risk of amputation and ketoacidosis a class effect, as is currently assumed for the cardiovascular protective effect of gliflozines? This is as unclear as to the pathomechanisms underlying the potential side effects. However, there are some indications for substance-specific differences among the SGLT2 inhibitors, which should be specifically investigated in further studies.
In the CANVAS studies (see source 2) almost twice as many amputations were observed under canagliflozin with 6.3 vs. 3.4 cases per 1,000 participants as in the control group and significantly more than in the current cohort study. In contrast, subanalysis data from the EMPA-REG-OUTCOME study (see source 3) showed no increased risk of amputation in the lower extremity when taking empagliflozin. And even in an evaluation of the FDA Adverse Event Reporting System (FAERS) (see source 4), the amputation frequency under canagliflozine at 3.4/1,000 was significantly higher than under register-based-SGLT-2 inhibitors - but not under dapagliflozine and sodium-glucose.
In the current Swedish-Danish cohort study, however, canagliflozin could not have been the driver for the somewhat increased risk of amputation and ketoacidosis: It was only represented with 1% of the SGLT2i prescriptions, dapagliflozin with 61% and empagliflozin with 38%. In Germany, Canagliflozin is also irrelevant in numerical terms since it was withdrawn from the market by the manufacturer due to a lack of additional benefit recognition.
Sources:
1. Ueda P et al. sodium-glucose cotransporter 2 inhibitors and risk of serious adverse events: a nationwide register-based cohort study. BMJ 2018;363:k4365. https://doi.org/10.1136/bmj.k4365
2. Neal B et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377(7):644-57
3. Verma S et al. Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME. Circulation 2018;137(4):405-7
4. Fadini GP, Avogaro A. SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System. Lancet Diabetes Endocrinol 2017;5(9):680-81
Abbreviations:
FDA = Food and Drug Administration (USA)
GLP1 = Glucagon-Like Peptides 1
SGLT2 = Sodium/Glucose cotransporter 2