SGLT2 Inhibitor-Amputation Link in Diabetes -- Is it Hypovolemia?

Miriam E. Tucker

October 02, 2018

BERLIN – Use of diuretics may increase the risk for lower limb amputations in people with diabetes, and the same hypovolemic effect might help explain the increased risk of amputations seen with the sodium-glucose cotransporter type 2 (SGLT2) inhibitor canagliflozin (Invokana, Janssen), new data suggest.

Results from a large prospective observational cohort of patients with type 2 diabetes were presented October 2 here at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting by Ronan Roussel, MD, PhD, chief of the endocrinology, diabetes, and nutrition department at Group Hôpital Bichat, AP-HP, Paris, France.

The mechanism behind the finding of an increased risk of lower-limb amputation in patients taking canagliflozin in the Canagliflozin Cardiovascular Assessment Study (CANVAS) has been much debated. Findings from observational trials of canagliflozin have conflicted regarding the amputation risk, and the effect hasn't been seen with other SGLT2 inhibitors.

But, assuming the amputation risk is a class effect, one theory about the mechanism is that the reduction in plasma volume from SGLT2 inhibitors could lead to decreased perfusion, especially in patients who already have reduced lower limb perfusion. "If true, we hypothesized that diuretics would show a similar safety profile," Roussel explained.

In fact, he noted, a few previous retrospective studies have shown an association between diuretic use and lower-limb amputation (Pharmacoepidemiol Drug Saf. 2004;13:139-146). 

In the current study, after propensity matching and adjustment for multiple confounders, Roussel and colleagues found a doubling of risk for amputation with diuretic use.

"This is a strong signal," he told Medscape Medical News in an interview, adding that the data suggest diuretics should be used with caution in patients who are at increased risk for amputation, such as those with critical ischemia.

Regarding his extrapolation to SGLT2 inhibitors, he emphasized that the new findings are merely "hypothesis-generating" and not conclusive. However, "If this observation [is accurate], it's probably a class effect," he said.

Asked to comment, session comoderator Anna Katharina Trocha, MD, chief physician at the department of diabetology at Elisabeth Hospital, Essen, Germany, urged caution about interpretation of the findings as heart failure wasn't one of the factors in the propensity score adjustment because of lack of available data.

"I think, from a retrospective cohort, you can't draw these conclusions. Patients may have been on diuretics a long time...They only looked at vascular disease, not heart failure. Patients with heart failure have a higher risk for amputations…Diuretics might just be a surrogate marker."

Is the Relationship Causal?

The new data come from 1468 participants in the prospective, single-center SURDIAGENE study, with a median follow-up of 7.2 years. Propensity score matching was performed for 1074 of the total 1468 participants to account for the fact that the diuretic users and nonusers differed in significant ways, particularly with regard to cardiovascular risk.

There were 537 matched participants each in the diuretic and no-diuretic groups, balanced for factors such as age, diabetes duration, previous cardiovascular disease, LDL cholesterol, and kidney function, but not heart failure.

During a median follow-up of 7.2 years, the primary composite outcome of first lower-limb amputation or lower-limb revascularization occurred in 12.7% of the diuretic users versus 7.2% of nonusers, a significant difference (P = .001).

After propensity score matching and adjustment for additional unbalanced covariates (baseline hypertension and use of RAAS blockers, beta blockers, and statins), the hazard ratio (HR) for composite lower limb events for those taking versus not taking diuretics was 1.60 (P = .027).

When the two outcomes were examined separately, the risk for lower limb amputations was doubled with diuretic use (HR, 2.13; P = .013) but lower limb revascularizations were not significantly elevated (HR, 1.12; P = .6443).  

Adjustment for death as a competing factor didn't change the results, nor did a sensitivity analysis done for the full cohort of 1468 participants.

Roussel acknowledged that the single-center population, lack of information on the date of drug initiation, and potential for residual confounding even after the propensity matching, among other issues, were all limitations, noting "further studies are needed to explore the role of drug-induced hypovolemia in the association between the use of diuretics and lower-limb events."

Nonetheless, he concluded, "The hypovolemia hypothesis could provide an explanation for the increased risk of lower limb amputation observed with SLGT2 inhibitors."

Asked whether she believes patients taking a diuretic should be prescribed an SGLT2 inhibitor, Trocha responded, "We don't know. We have to work on that."

Roussel has reported disclosures for Janssen, Merck, Sanofi, AstraZeneca, and Boehringer Ingelheim. Trocha has reported no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 2018 Annual Meeting; October 2, 2018; Berlin, Germany. Abstract OP-02.

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