SGLT2 Inhibitors Heavily Promoted at ADA

The 2016 ADA conference in New Orleans was the showcase for the latest research on SGLT2 Inhibitors. The Diabetes-in-Control team was at the conference and state the SGLT2Inhibitors had over 150 poster presentations on this class alone. The article says they will cover the new research in depth over the coming weeks.

For now, here’s a taste of some of the breaking news from the sessions:

1. Research pertaining to the kidneys was a major topic. Researchers concluded that canagliflozin slows the progression of kidney function decline compared to glimepirde at almost equal glycemic control. This suggests that canagliflozin’s beneficial effect on kidney function is independent of its glycemic effects.
2. Janssen presented results from a Phase 2, randomized study showing glycemic improvements in adults with type 1 diabetes mellitus (T1DM), when treated with canagliflozin (Invokana) plus insulin.
3. Two study results pertaining to AstraZeneca’s Farxiga were presented. In one study, Farxiga was shown to decrease body weight and blood pressure among patients with kidney problems,
4. In the other study, Farxiga was used in combination with a potassium-sparing diuretic. A1C, body weight and blood pressure were reduced, with no significant increase in potassium levels. This reduces the risk for hyperkalemia.

In other news, the results of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial was major news at the conference on Monday, June 13. The results showed that liraglutide (Victoza), in patients identified with cardiovascular disease, lowered the combined risk of heart attack, stroke and death from cardiovascular causes by 13%. While a reduction in CV risk with a GLP-1 treatment is an exciting development, there’s not a yet any real evidence of a class effect.

Meanwhile, multiple SGLT-2 drugs are undergoing further testing to explore the possibility that SGLT-2 inhibitors as a class can reduce cardiovascular risk.

Amputation Risk Up for Canagliflozin Users

The FDA had continued to issue new warnings for the sodium-glucose cotransporter 2 (SGLT2) inhibitor class of drugs. This last warning for the diabetes drug canagliflozin which has been linked to an increase in leg and foot amputations. Canagliflozin is marketed as a stand-alone drug therapy under the name of Invokana and as part of a combo therapy under the name of Invokamet.

The Canagliflozin Cardiovascular Assessment Study (CANVAS), a 4.5-year research project which will finish up in 2017 is the basis for the latest warning.

Researchers have found a slightly elevated amputation risk among those who took the drug. The rate of amputation was seven for every 1000 patients taking 100 mg of canagliflozin and five for 1000 patients for those taking 300 mg of the drug. Those in the placebo group saw an amputation risk of three per 1000 patients.

There are many 'what if's' missing from the above analysis. What if the amputations were for people that had the highest A1cs? What is the comparison of A1cs between those patients taking 100 mg and those taking 300 mg. I am talking about those that needed amputations and not the 1000 patients in each group.

The article does say there are many questions raised by this study that still need to be answered. For example, a follow-up study did not yield the same increased rate of amputations for those taking the drug. I have to wonder how a follow-up study can be completed before the CANVAS study is complete. Also, FDA regulators are not certain if the drug was what caused the increased amputation risk. Still, out of an abundance of caution, they are warning doctors to watch for possible foot issues with patients taking canagliflozin and for other SGLT2 drugs.

I am writing about several other issues with the sodium-glucose cotransporter 2 (SGLT2) inhibitor class of drugs. Never assume that oral diabetes drugs are safe and many of the latest drugs are still being found to have serious side effects.

FDA Strengthens Warnings for Two SGLT2 Drugs

The US Food and Drug Administration (FDA) has strengthened its drug label warnings about the risk for acute kidney injury that can result from the use of the type 2 diabetes prescription medications canagliflozin (Invokana, Invokamet, Janssen) and dapagliflozin (Farxiga, Xigduo XR, AstraZeneca), according to an agency news release. The revised warnings include information about acute kidney injury and recommendations for minimizing this risk.

These medications are sodium-glucose cotransporter-2 (SGLT2) inhibitors and are used with diet and exercise to lower blood sugar in adults with type 2 diabetes. The dangers are beginning to show now that these drugs have been in use for over two years. I can just about bet there will be other problems come to the fore over the next five years.

The FDA approved canagliflozin in March 2013 and dapagliflozin was approved in January 2014. In these cases, approximately half of the patients experienced acute renal injury within one month of beginning the medication, and some were younger than 65 years. Most improved after discontinuing the drug. Some of the affected patients were dehydrated, had low blood pressure, or were taking other drugs that can affect the kidneys. Some of these patients required hospitalization and dialysis. The FDA believes there are additional cases that have not been reported.

There is no mention of any warning with another SGLT2 inhibitor, empagliflozin (Jardiance, Boehringer Ingelheim) in this FDA communication, but it has not been on the market long enough.

The FDA does advise healthcare professionals to consider factors that may predispose patients to acute kidney injury before starting them on either of the medications. These factors include decreased blood volume; chronic renal insufficiency; congestive heart failure; and taking medications such as diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and nonsteroidal anti-inflammatory drugs.

Clinicians should assess the patient's kidney function before beginning canagliflozin or dapagliflozin and monitor it periodically after the patient begins either medication. Clinicians should discontinue the medication promptly and treat the renal impairment if acute kidney injury occurs.

SGLT2 inhibitors have also been associated rarely with fractures and diabetic ketoacidosis, and the FDA strengthened the warning with regard to fracture and canagliflozin specifically last September.

Patients who experience signs and symptoms of acute kidney injury should seek immediate medical attention, says the FDA. These can include decreased urination or swelling in the legs or feet. The FDA warns patients that acute renal injury is a serious condition in which the kidneys abruptly stop working and dangerous levels of waste can accumulate in the body.

The warnings do instruct patients not to discontinue their medication without first talking to their healthcare providers because uncontrolled blood glucose levels can develop. Patients are instructed to read the medication guide that comes with their canagliflozin or dapagliflozin prescriptions.

Healthcare professionals and patients should report adverse events or side effects related to the use of these medications to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.fda.gov/MedWatch/report
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the preaddressed form, or submit by fax to 1-800-FDA-0178

SGLT2 Therapy Does Not Prevent Diabetic Bone Disease

And yet another problem with SGLT2 diabetes drugs. Doctors are being told to take bone density and history of osteoporosis into consideration when prescribing SGLT2 inhibitors. Both type 1 and 2 diabetes patients are at increased risk of bone fractures.

It is believed that the cause is the chronic hyperglycemia state that leads to a decrease in bone density, and this in turn puts diabetes patients at risk for osteopenia and osteoporosis. Osteopenia is a condition of bone in which decreased calcification, decreased density, or reduced mass occurs. Therefore, bone microarchitecture and strength could be potentially amplified by down-regulating patients’ blood glucose levels.

Using sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors), seems to lower blood glucose levels only by 0.7 to 1.0 percent which is helpful but not great in the overall blood glucose lowering needs. They work by blocking sodium-glucose cotransporter 2 in the proximal tubules of the kidneys and reducing the reabsorption of filtered glucose from the tubular lumen, which lowers glucose levels in the blood. The added benefit of this group of medications is a slight weight loss.

Paradoxically, previous studies indicated that treatment with the SGLT2 inhibitor canagliflozin could actually worsen the bone structure and increase the risk for bone fractures by 30%.

While recent studies have all be on rodents, the findings do suggest an association between the increased risk for bone fractures and using medications like canagliflozin, and caution in using them in a group of patient at high risk for bone fracture.

Because of the rodent studies, we definitely need more studies that involve human participants who would challenge these findings. The significance of the results may increase since, currently, SGLT2 inhibitors are approved by the FDA only for type 2 diabetes patients, but it may change as new studies are being conducted on type 1 patients.

Doctors are being advised that SGLT2 inhibitors can contribute to increased risk of bone fractures in diabetes patients. In diabetes patients with a history of multiple bone fractures or osteoporosis, it may be wise to stay away from SGLT2 inhibitors and try other groups of medications first. Physicians are encouraged to report any known incidents of sudden unexpected worsening of bone density in patients who recently got started on SGLT2 inhibitor therapy.

SGLT2 Post Marketing Studies

This is so typical for “experts” and especially those on the receiving end of money from Big Pharma.

Dave Joffe, Editor-in-chief of Diabetes-in-Control makes this statement, “One of the problems that can occur in these postmarking studies is the lack of good controls and patient choices. This means that a lot of great drugs can get a bum rap because of external influences.”

I must wonder what he has in mind in his support of Big Pharma. The above statement is about the SGLT2 drugs. These drugs have not been on the market long enough to know what all the side effects are and whether the benefits outweigh the risks.

Apparently a few legal firms believe otherwise as they are trying to get patients involved in class action lawsuits especially against Invokana. Jardiance has been advertising heavily on TV, as has been Farxiga.

AACE and ACE are calling upon pharmaceutical companies to continue to investigate the mechanisms behind the metabolic effect of SGLT2i (sodium-glucose cotransporter-2 inhibitors). They also make note that the diagnosis of DKA is often missed or delayed due to atypical presentation involving lower-than-anticipated glucose levels or other misleading laboratory values.

In addition, AACE and ACE encourages all associated stakeholders including medical societies, insurance companies, the pharmaceutical industry, hospitals, patient associations, and other interested parties to initiate educational activities to teach physicians and other related healthcare professionals who manage diabetes, on the proper ways to identify and treat DKA.

For people with type 2 diabetes there is one way to avoid DKA (diabetic ketoacidosis), and that is to not take any of the SGLT2i medications. This may seem harsh, but I would rather be safe than rely on “experts” on the payroll of Big Pharma and those receiving money from Big Pharma.

An international panel convened by AACE and ACE concludes that the risk-benefit ratio overwhelmingly favors continued use of SGLT2i. I cannot accept this and do wish that they could have been a little more cautious. I could not take any of the SGLT2i because of the conflicts I would have with my kidneys.

The one missing point in the panel discussion that is missing is the listing of conflicts of interest and what the panel members receive in compensation from the manufacturers of the three drugs.