AACE/ACE Position Statement on SGLT2 Inhibitors

In spite of the FDA warning a year ago, the American association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) has taken a strong position in opposition to the FDA warning.

This position paper represents the official position of the AACE and ACE and is meant to provide guidance. It is not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

The FDA warning in May 2015 that SGLT-2 inhibitors may lead to ketoacidosis, generated considerable attention. Now, AACE/ACE have issued a joint position statement concluding that the incidence of diabetic ketoacidosis in patients with type 2 diabetes taking an SGLT-2 inhibitor is no greater than the low levels occurring in the general diabetes population. While this is true, the cases are not considered similar to what develops in those with type 1 diabetes. The AACE/ACE concluded that the risk of DKA when using inhibitors is infrequent and the risk-benefit ratio favors continued use.

In an interview with Endocrine Today, study co-author Zachary T. Bloomgarden, MD, MACE, stated that “There is no definite evidence that these agents are associated with DKA in type 2 diabetes, and some reports have actually described patients with ketosis, or even just ketonuria, which likely are not clinically significant. The DKA cases that have been reported generally involve patients with type 1 diabetes, although reports in atypical diabetes (such as that with pancreatic disease) and in patients with longstanding type 2 diabetes who require multiple-dose insulin treatment similar to that used in type 1 diabetes suggests that a necessary mediator of DKA is marked insulin deficiency.”

The consensus group reviewed over 82 DKA cases from the literature, including those involving SGLT-2 inhibition and those cases occurring before SGLT-2 inhibitor therapy was available. In patients taking an SGLT-2 inhibitor, DKA occurred most often in insulin-deficient individuals, including those with longstanding type 2 diabetes, type 1 diabetes or latent autoimmune diabetes in adults. SGLT-2 inhibitors are not FDA approved for patients with type 1 diabetes, and 7 out of 9 patients in the American case series that prompted the FDA safety warning had type 1 diabetes, the authors wrote.

Nonetheless, the authors urge further study of SGLT-2 inhibitors in type 1 diabetes because initial studies have shown promise in glycemic regulation for patients with type 1. For future T1D trials, lower SGLT-2 inhibitor doses should be considered and insulin doses should not routinely be reduced when SGLT-2 inhibitors are begun, but adjusted based on the individual response.

Further, the position statement notes that almost all cases of SGLT-2 inhibitor-associated DKA occurred in patients challenged with metabolically stressful events, which acted as precipitants of DKA, such as surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting, and other stressful physical and medical conditions.

The statement recommends that SGLT-2 inhibitors be stopped at least 24 hours before planned stressful events, such as surgery, or very intensive exercise, such as running a marathon. Patients prescribed SGLT-2 inhibitor therapy should also avoid excess alcohol intake and very low carbohydrate diets, both of which are potentially ketogenic, the researchers wrote.

Once diagnosis of DKA is suspected, the SGLT-2 inhibitor should be stopped immediately and a DKA protocol initiated, including fluids, insulin and other standard interventions.

DKA diagnosis may be missed or delayed due to atypical presentation involving lower-than-anticipated glucose levels or other misleading laboratory values. This presentation has been seen with SGLT-2 inhibitors, but has also been observed for decades before the introduction of these agents. Gaps in understanding call for more studies of the mechanisms behind the metabolic effect of SGLT-2 inhibitors as well as more healthcare professional education focused on the proper diagnosis and treatment of DKA.

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.

Diabetes Ketoacidosis with SGLT2 Inhibitors

The European Medicines Agency (EMA) is alerting doctors and other healthcare professionals to the possibility of atypical cases of diabetic ketoacidosis (DKA) associated with use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, a relatively new class of oral medications used to treat type 2 diabetes and some type 1 diabetes patients. The announcement follows a review, conducted by the EMA's Pharmacovigilance Risk Assessment Committee (PRAC), and aims to help minimize the risk of DKA associated with the use of this class of drugs.

The issue initially came to light in May 2015, when the US Food and Drug Administration issued a notice on the basis of 20 cases of DKA associated with SGLT2 inhibitors reported to the agency's adverse-event reporting system. A month later, the EMA initiated its review and identified 101 cases worldwide associated with type 2 diabetes.

Diabetic ketoacidosis is a serious complication of diabetes caused by low insulin levels. The issue is of considerable concern because ketoacidosis is not typically observed in patients with type 2 diabetes. "Rare cases of this condition, including life-threatening ones, have occurred in patients taking SGLT2 inhibitors for type 2 diabetes, and a number of these cases have been atypical, with patients not having blood sugar levels as high as expected," states EMA.

Patients with type 1 diabetes who have DKA typically have very high glucose levels.

An atypical presentation of DKA can delay diagnosis and treatment, so doctors and others treating diabetes patients should therefore consider the possibility of ketoacidosis in those taking SGLT2 inhibitors who have symptoms consistent with the condition, even if blood glucose levels are not high, the EMA adds.

And "patients taking any of these medicines should be aware of the symptoms of DKA, including rapid weight loss, nausea or vomiting, abdominal pain, excessive thirst, fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odor to urine or sweat."

If they have any of these symptoms, patients should contact a healthcare professional. If DKA is suspected or confirmed, treatment with the SGLT2 inhibitor should be stopped immediately, and should not be restarted unless another cause for the ketoacidosis is identified and resolved.

For their part, when considering SGLT2 therapy, EMA says, “medical perscribers should exercise caution in patients with risk factors for ketoacidosis and inform patients of the risk factors.”

These include low reserve of insulin-secreting cells, conditions that restrict food intake or can lead to severe dehydration, a sudden reduction in insulin, or an increased requirement for insulin due to illness, surgery, or alcohol abuse.

In addition, the PRAC recommends temporarily stopping SGLT2-inhibitor treatment in patients in the hospital for major surgical procedures or due to serious illness.

European Medicines Agency, Published February 12, 2016. This can be read here.

SGLT2 Dangerous for Causing Diabetic Ketoacidosis

Allen and I were talking to a person with type 1 diabetes this last weekend and he was bragging about being on an oral medication for type 2 people with diabetes. I said that the doctor was prescribing it “off label” and there were some serious side effects to the SGLT2 medication. He asked what the side effects could be. Allen said that DKA (diabetic ketoacidosis) was the side effect and that it was not the same as that experienced generally by people with type 1 diabetes.

The person laughed and said he was not aware of any problems. Fortunately, I had just read this and had my wife's laptop with me. I pulled up the article and the definition for euglycemic, which is a condition or state in which the blood glucose level is within the normal range. See also glycemia. As reported…the presence of euglycemia appeared to delay correct diagnosis in some of the patients in their series.

• Euglycemic DKA may be associated with the use of a SGLT2-inhibitor in type 1's.
• Volume depletion associated with SGLT2-inhibitor use could exacerbate the problem by further increasing glucagon, cortisol, and epinephrine.
• If insulin levels are low and glucagon and other counterregulatory hormones are high, a perfect storm exists.

Now we had his attention and he asked to read the article. When he finished, he said that then he could be in trouble as he was scheduled to a surgery on Monday, June 29. He said that it is recommended that he be off the medication for three days before any surgery.

Then I opened the Medscape article and had him read that article. His first question was how he could get access to either article, as he was not aware of either source. I said he would have to join both sites to have access to them and that they were free. Allen said it would be good to be a journalist when applying, but that there was good information, he would email him some of the links for diabetes and other information, and then he could explore for his favorite topics.

He called his doctor at his home and informed the doctor of what he had read and that he needed to postpone this surgery at least two days if possible. He asked the doctor for his email address and sent the doctor the two links and his phone number and then the doctor called him and said he would see that the surgery was set back for at least two days. He went back to talking with us.

Next, he thanked both of us and said he was sorry he had acted so badly when we started the conversation. He explained that he had always felt that people type 2 diabetes had no interest in helping people with type 1 diabetes. I said that type 1 takes enough grief from people ignorant of the difference and accused them of many of the problems that type 2 people face on a regular basis. I said we need to work together to end the ignorance and help each other at every opportunity. He agreed and thanked us again.

I said that I had sent him the links for the two articles and would send him any more that I found. I said I was aware of at least one more, but I would need to get on my home computer to find it.

Then he asked to read the first article again. He said that he had not been counseled by his doctor when he started the medication as was recommended and was happy we could show him information. He was going to have a long discussion with his doctor and consider not taking the medication. He said that it was helping in the management of his daily blood glucose levels so the decision would be difficult without the doctor understanding what could happen.

He asked if anyone we knew was using the SGLT2 medication. Allen said no, as the members of our support group only used metformin or insulin. I added that we have a few members that have been able to stop all medications after lifestyle changes. They continue the monitor their blood glucose levels and have been successful so far.

He said he needed to head home and repeated his thanks and said he would stay in touch.

SGLT2 Inhibitors Seem to Increase Glucose Production

Paradoxes do happen and this is a surprise. Researchers discovered this while studying the newest class of diabetes drugs, sodium glucose cotransporter 2 SGLT2 inhibitors. The result was obtained from dapagliflozin (Farxiga), one of the two FDA approved drugs in the class.

“Although they increase the amount of blood sugar dumped into the urine, the newest class of diabetes drugs appears to increase endogenous (proceeding from within; derived internally) glucose production, two studies found.”

The researchers are wisely calling for additional studies to confirm the results they found. The first study was done at the University of Texas Health Sciences Center in San Antonio and involved 18 men. The second study was done at the University of Pisa in Italy, and used the drug empagliflozin. The Italy study used 66 type 2 patients.

The researchers found that the drugs did what they were designed for; increase the glucose excretion in the urine and lower plasma glucose levels. This is when the researchers discovered the substantially increased endogenous glucose production, which was accompanied by an increase in glucagon levels. Patients on the placebo had no change in these levels.

The researchers reported that the increase in endogenous glucose production offset about half of the amount of glucose dumped into the urine. In other words, if the endogenous glucose production could have been prevented, the decrease in glucose caused by dapagliflozin and empagliflozin would have been about double.

By having others replicate this finding, the researchers are suggesting that clinicians may want to use the SGLT2 inhibitors in tandem with incretin therapies, which have effects on glucagon and could reduce the increase in endogenous glucose production. The researchers then ask for further metabolic studies for verification of this.

This research does point to potential problems for SGLT2 and clinicians need to use caution in prescribing this medication until the full effects are understood. As people with diabetes, I would also urge caution in accepting this medication until the full effects are determined. This is one paradox that may have long-term harmful effects.

SGLT2, A New Class of Diabetes Drugs

A new class of diabetes drug was approved in 2013. The class is SGLT2 and the brand name is Invokana with as generic name of canagliflozin. Canagliflozin is to improve glycemic control in adults with type 2 diabetes in cooperation with diet and exercise. The drug has been studied as monotherapy and in combination with other common treatments for type 2 diabetes including metformin, sulfonylurea, pioglitazone, and insulin. The manufacturer is Johnson and Johnson.

The FDA is requiring J&J to perform five post marketing studies with canagliflozin, including a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; and a bone safety study. This is more than any previous drug and indicates the FDA is being tough on J&J.

The most common side effects include vaginal yeast and urinary tract infections which if treated early have not been difficult to manage. The FDA states that canagliflozin is not to be used to treat people with type 1 diabetes, people with diabetic ketoacidosis, or people with severe renal disease. Over 10,000 patients in clinical trials with type 2 diabetes shows that canagliflozin improved A1C levels and fasting plasma glucose levels.

SGLT2 is short for sodium-glucose co-transporter-2 inhibitors that lower blood glucose by blocking the reabsorbtion of glucose and passing it in urine. A clinical study of patients at especially high risk of cardiovascular disease showed that within the first 30 days, 13 patients taking canagliflozin suffered a major cardiovascular event compared with just one patient taking a placebo. After that, the imbalance was reversed. The drug also caused a slight increase in unhealthy LDL cholesterol.

Canagliflozin comes in 2 different pill sizes, a 100-mg tablet and a 300-mg tablet. It is recommended that patients should take it first thing in the morning before breakfast. As an analogy, I think of giving this drug a little bit like using a diuretic, because it is going to make them a little bit glycosuric (excretion of glucose in the urine) and it will have a little bit of a diuretic effect. Therefore, take it in the morning so patients don’t urinate all night long when they're getting used to it. Clinicians should start patients at 100 mg. If that dose is tolerated then up-titrate to 300 mg, and that's the dose the patient continues to take.

David Spero writing for Diabetes Self Management has an excellent discussion on SGLT2 and what he finds as concerns.   Read his blog here.