Recent studies show that the Invokana amputation risk was shown to increase twofold when compared to other type-2 diabetes drugs.

Invokana (canagliflozin) is a type-2 diabetes medication and is part of the drug class SGLT2 inhibitors.

In May 2017, the U.S. Food and Drug Administration (FDA) revealed that Invokana treatment may increase the risk of lower limb amputation – including toe and foot amputations. The announcement was prompted by the results of two CANVAS trials.

The CANVAS and CANVAS-R clinical trials provided evidence for the increased risk, although the trials originally aimed to examine cardiovascular and renal risks with Invokana.

In the CANVAS trial, 5.9 out of every 1,000 patients treated with Invokana reportedly had a lower limb amputation compared to 2.8 out of 1,000 in the control group. In the CANVAS-R trial, 7.5 out of 1,000 Invokana patients had a lower limb amputation compared to 4.2 out of 1,000 in the placebo group.

“Amputations of the toe and middle of the foot were the most common; however, amputations involving the leg, below and above the knee, also occurred. Some patients had more than one amputation, some involving both limbs,” the FDA noted.

The FDA’s announcement regarding the Invokana risks prompted new boxed warnings to be added to the labels of canagliflozin products. However, the warnings regarding lower limb amputations may need to be expanded to other medications in the drug class.

In November 2018, a study of Swedish and Danish patients revealed that being treated with SGLT2 inhibitors doubled the risk for lower limb amputations. According to lead researcher Peter Ueda of the Clinical Epidemiology Division for the Karolinska Institute’s Department of Medicine, the real world, large scale study adds to existing evidence which suggested an Invokana amputation risk and expands the risk to all SGLT2 inhibitors.

“Our study adds to the data on the safety of these drugs by assessing the association between SGLT2 inhibitor use and serious adverse events in a substantially different population as compared to those included in the clinical trials — a population representative of routine clinical practice,” Ueda told Medscape Medical News.

The results of Ueda’s study reportedly align with the findings of the CANVAS trial program that prompted the FDA’s 2017 safety announcement regarding the increased Invokana amputation risk.

“Our findings should lead to further emphasis on the importance of counseling patients on routine preventative footcare,” Ueda stressed when discussing patient counseling.

Diabetic amputations may be the result of a diabetic foot ulcer that refused to heal. Lack of circulation and sufficient blood flow in the feet can make it harder for these ulcers to heal – thereby increasing the chance of infection and gangrene. When diabetic patients on SGLT2 inhibitors take care of their feet, they may be able to get ahead of any risks and seek medical treatment before amputation is the only option.

SGLT2 Might Cause Hypovolemia

The reason Invokana is associated with an increased risk of amputations has been under debate since the results of the CANVAS study was released.

Ronan Roussel, MD, PhD, chief of the endocrinology, diabetes, and nutrition department at Group Hopital Bichat, Ap-HP in Paris, France, said that like diuretics, SGLT2 inhibitors might have a hypovolemia effect, and that this effect could increase a patient’s risk of amputation.

Hypovolemia is an abnormal decrease in the volume of blood plasma, which can inhibit circulation of the blood. Dehydration can result in hypovolemia.

Roussel presented results of an observational study of patients with type 2 diabetes at the European Association for the Study of Diabetes 2018 Annual Meeting in October 2018. The study looked at 1468 patients with a median follow-up of 7.2 years at which time the diuretic users were found to have double the risk of lower limb amputations compared with non-users.

He said that some previous studies actually have shown a link between the use of diuretics and an increased risk of lower limb amputation. He said the same reduction in plasma volume that leads to a doubled risk of amputations among those who take diuretics could translate to the same increased risk for patients taking SGLT2 inhibitors.

Although he said his findings were just “hypothesis-generating” and not conclusive, he said patients who are already at an increased risk for amputation should use caution with diuretics and SGLT2 inhibitors.

Roussel said, “The hypovolemia hypothesis could provide an explanation for the increased risk of lower limb amputation observed with SGLT2 inhibitors.”