SGLT2 Being Investigated by EMA

After the last blog, I am not surprised that the European Medicines Agency (EMA) is continuing the investigation of SGLT2 diabetes drug. This time after an increase in amputations, mostly of the toe, was observed in a large ongoing clinical trial of the drug.

Cases of lower-limb amputation occurred in both the active drug and placebo groups in the Canagliflozin Cardiovascular Assessment Study (CANVAS), which is the cardiovascular-outcomes trial for this agent and is randomizing just over 4000 type 2 diabetes patients to canagliflozin 100 mg or 300 mg daily or to placebo, slated for completion in 2017.

“The EMA Pharmacovigilance Risk Assessment Committee (PRAC) has requested more information from the company to assess whether canagliflozin causes an increase in lower-limb amputations and whether any changes are needed in the way this medicine is used in the European Union.”

The EMA notes that patients with diabetes, and especially those with poorly controlled diabetes and preexisting vascular problems are at increased risk of infection and ulceration, which result in lower-limb amputations. In 12 other completed clinical trials, there was a statistically nonsignificant increase in the number of amputations.

Both CANVAS and CANVAS-R involve patients at high cardiovascular risk. The PRAC will also ask for data on other medicines in the SGLT2 inhibitor class, which include dapagliflozin (Farxiga, Forxiga, AstraZeneca) and empagliflozin (Jardiance, Lilly/Boehringer Ingelheim).

"Based on this, the PRAC may decide to extend the scope of the review to cover these medicines," the EMA notes.

Combination products containing SGLT2 inhibitors with metformin are also available in the European Union.

While the review on canagliflozin is ongoing, healthcare professionals will receive a letter reminding them about the importance of routine foot care among diabetic patients to avoid cuts or sores of the feet and to treat them promptly should they occur to prevent infection and ulceration.

Patients at increased risk of amputation (such as those who have had a previous amputation) should be carefully monitored. As a precautionary measure, doctors may consider stopping treatment with canagliflozin in patients who develop significant foot complications.

"Patients who have any questions should speak to their doctor or pharmacist. It is important that patients with diabetes continue to take their prescribed treatment and not stop treatment without first consulting a healthcare professional," the EMA notes.

The incidence of lower-limb amputation in CANVAS is currently seven in 1000 patient-years with canagliflozin 100 mg daily and five in 1000 patient-years with canagliflozin 300 mg daily, compared with three in 1000 patient-years with placebo, EMA indicates.

Patients in the study have so far been followed up for an average of 4.5 years.

In CANVAS-R, a study on the effects of canagliflozin on renal end points in adults with type 2 diabetes, the incidence of lower-limb amputation is seven in 1000 patient-years with canagliflozin and five in 1000 patient-years with placebo. This difference is not statistically significant. Patients in this study have so far been followed up for an average of 0.75 years.

The independent data monitoring committee for CANVAS and CANVAS-R has recommended that the trials should continue.

Our Group's February Meeting

With two relatives doing the topics for this meeting, I had to be there. Yes, I had several emails from them and a few phone calls asking questions about what we had discovered in our meetings and if there was a lot of secrecy among our new members.  Both said Tim had warned them that this could be a possibility and I had to agree with Tim. I did say that our long time members would not be a problem and that some of the new members would not be either.

Beverly asked if she should avoid calling on people and I suggested that she ask for volunteers the first time. I knew the topic she had planned and knew some of our new members might not appreciate the topic. Suzanne said she had several minor topics to discuss and would see how Beverly was received before using one of her topics.

Saturday, February 7, arrived and everyone was present plus a few from the third support group in our town. Tim called the meeting to order and thanked the group for being present. He introduced Beverly and she started her program. She explained that she was a nurse that assisted several surgeons during operations, but that in the last two months she had been part of a team involved in amputations. She continued that before you tune me out, I have been informed about the last meeting you had with two podiatrists and I think you have a great group that cares and this should prevent the members from needing this surgery in the future.

Next, she asked A.J and Jerry to stand and explain what had happened that possibly had prevented them from needing an amputation. A.J said he and I had been talking about diabetes and while he had not wanted to hear what I was saying, when I described some of the symptoms of diabetes; he knew that he had better listen. When I had mentioned sores that were slow to heal, A.J said he had to show Bob a sore on my leg. A.J said I had not hesitated, but had called his doctor for an appointment and told the nurse about the symptoms he had and made a special point of telling her about his sore.

A.J said the doctor had carefully cleaned the sore and applied a gel to the sore and told him to bring his diabetes under quick management to help it heal. He covered the sore with breathable gauze and had told him how to take care of it with the prescription he gave me. Next, he started me on insulin for managing diabetes and within 30 days, my sore was healed. I still have a small scar to know that it was there, but I am a lot more careful now with sores.

Next Beverly asked Jerry to talk about his problem. Jerry said he had a foot ulcer and A.J had asked Bob to have a look at it. They had me see a doctor that day and the doctor had discovered a new ulcer developing on my other foot. The doctor had prescribed medications and coverings for both ulcers. The new one was gone in three weeks, and the bad one is almost completely healed and Jerry said he has been given permission to walk on that foot without crutches before having his shoe fitted with orthotics later this month. He explained that he still uses his mirror to look at his feet daily, but is thankful that A.J and I have been there for him when he needed assistance.

Gale was next and she was still using crutches, but was happy to have a ride to the meeting. She explained that she had never thought about foot problems until she noticed blood in her slipper. She said she had called Sue for help and had also been taken to the doctor immediately. She said that she was sorry for missing the last meeting, but felt that even with crutches, she should not come. She commented that she was still using medication for her foot ulcer and had a mirror to look at her feet now. She commented that belonging to this group was a good thing as they wanted to help and went out of their way to help when other members were in need.

Beverly thanked them and said this is the way to prevent problems and avoid amputations. She explained that she had been present at six amputations and the problems following the operations. She believed five of them could have been prevented if those people had been members of a support group like this. Four were from sores on a leg and two were from foot ulcers that had not been cared for properly or early enough.

Next, she opened the discussion up for questions and questions that took the rest of the meeting. Suzanne had a few questions as well and she answered them. She said she would schedule anyone that wanted help after Valentines Day. Tim was ready to end the meeting, but I took the floor and asked Beverly to introduce her husband, Tom, to the group and she did, explaining that he had type 2 diabetes and was taking metformin. Tom then asked if we were taking new members, as he was not aware of any groups in the town they lived in that were this positive or active.

Tim thanked him for asking and asked him a couple of questions. Then Tim asked our members for a vote and it was unanimous. Tom was accepted and Tim said the meeting was over. Questions happened for another half-hour and people started leaving. Beverly and Tom came to talk to me. Tom said I am about finished reading your blogs, and asked if I took suggestions. I said yes, but some topics are difficult and if he has a topic with articles, I do ask for a copy of the article. Tom said he had my email address and would send me a couple of articles. Tim then obtained Tom's email address and told him about the summary of the meeting that he would receive even when he was in attendance. We did this for everyone and this way people could miss a meeting if they needed to and still be kept up to date on the meetings. With that, we left the meeting.