Invokana: First Oral Medication Approved for Diabetes and Cardiovascular Events

Diabetes medication now indicated to help patients lower their A1C levels AND protect them from cardiovascular events.

Invokana MedicationThe FDA gives new indication for Invokana, the first oral diabetes medicine to improve blood sugar levels and protect against potentially adverse cardiovascular problems.

The FDA has approved canagliflozin (Invokana, Invokamet—canagliflozin plus metformin) to reduce the risk of major adverse cardiovascular events including stroke, heart attack and cardiac death in patients with type 2 diabetes and established cardiovascular disease. It is the first oral diabetes medication to gain this indication, according to an announcement1 from drug manufacturer Janssen Pharmaceutical Companies.

Invokana is an sodium-glucose cotransporter-2 inhibitor (SGLT2) which works with the kidneys to remove some excess sugar through urination.

Two other glucose-lowering drugs have received FDA approval for cardiovascular benefit in patients with type 2 and cardiovascular disease. They include empagliflozin (Jardiance), another SGLT2 inhibitor shown to reduce  cardiovascular death and liraglutide (Victoza), a glucagon-like peptide (GLP-1) receptor agonist, an injectable medication approved for protection against heart attack, stroke and cardiovascular death.

“It is an important step forward for patients and the physicians who treat them,” said James List, MD, PhD, with the Cardiovascular & Metabolism Division of Janssen Research & Development. “Not only does Invokana enable patients to control their diabetes symptoms by lowering their A1C levels, but it now also helps protect them from potentially devastating cardiovascular events."

Expanded Indication Supported by Trail

The expanded indication was based on the CANVAS trial, which was published in the New England Journal of Medicine2. That study included over 10,000 participants with type 2 diabetes and either established cardiovascular disease (65%) or at least two cardiovascular risk factors (35 %).

Treatment with the drug versus a placebo— in addition with standard-of-care therapy—was associated with a 14%  reduction in the combined risk of cardiovascular death, stroke or heart attack. In patients with established cardiovascular disease, Invokana achieved an 18% reduction compared to placebo medication.

Overall, nonfatal heart attacks were reduced by 15%, strokes by 10% and cardiovascular deaths by 13%.

Patients with Kidney Disease, Take Note

In 2016, the FDA issued a warning label on Invokana, citing cases of acute kidney injury, where the kidney can stop working suddenly.

The problem is that in patients taking Invokana who have sudden onset of kidney disease, Invokana can quickly worsen the problem, says Dr. Daniel Rosenberg, an endocrinologist in Willow Grove, Pennsylvania. “In very, very rare cases, the dehydrating effect of the drug can cause additional problems and cause the kidney to shut down,” he says.

However, save for those rare examples, and in cases where type 2 diabetes patients already have severe kidney disease, people without kidney disease don’t normally get this condition, says Dr. Katalin Susztak, MD, PhD, nephrologist, and professor of medicine at the Perelman School of Medicine, University of Pennsylannia.

“I feel the benefits of this drug to be far greater than the complications,” says Dr. Susztak. “If patients have very severe or advanced kidney disease, we usually say that they should not take it, because this additional filtration can cause problems, but if people have mild kidney disease we recommend them taking the medicine and monitoring them because taking the drugs can reduce the risk of ending up on dialysis or needing a kidney transplant by 40%.”

Other Side Effects

Other serious side effects of Invokana can include the risk of lower limb amputations, dehydration and genital infections from excess sugar being stored in the bladder.

EndocrineWeb reported that the FDA (in May 2016) called attention to the increased incidence of amputations among people taking the medication compared to people taking a placebo in the CANVAS trial. (Over a year's time, the amputation risks were evaluated to be 7 of every 1,000 treated with 100 milligrams of the drug, versus 3 of every 1,000 on placebo.)

As a result, the FDA required the most prominent black-box warning to be added to the canagliflozin drug label to describe the risk. (Patients should be aware of problems in the extremities and know that the areas most affected are the toe and middle foot. Awareness of problems in the extremities is key. The FDA urges patients to contact their health care provider immediately if they notice new pain or tenderness, sores, ulcers or infections in the legs or feet.)

However a new study presented in June at the American Diabetes Association (ADA) 2018 Scientific Sessions by John B. Buse, MD, PhD, director of the Diabetes Center at the University of North Caroline School of Medicine in Chapel Hill, North Carolina found no increased risk of amputation seen among patients taking canagliflozin compared with other SGLT2 inhibitors or other glucose-lowering drugs. (The observational study—OBSERVE-4D—looked at more than 700,000 patients with type 2 diabetes.)

Dr. Buse noted that the CANVAS amputations occurred primarily in people with risk factors for amputation, including prior amputations, peripheral vascular disease, severe neuropathy or high A1Cs.

"If I had a patient with a prior amputation and had a choice of an SGLT2 inhibitor, I would pick one that doesn't have amputation in the label. It would be crazy to do otherwise," he said in Medscape.

Experts Say Rewards Outweigh the Risks

The more recent FDA approval for Invokana builds on recent consensus reports from the ADA and the American Association of Clinical Endocrinologists (AACE) that support the use of the drug across a broad range of patients.3,4

The ADA recommends SGLT2 medications that specifically show a cardiovascular benefit for patients with type 2 diabetes and cardiovascular disease, while the AACE notes that for appropriate patients, Invokana has been shown to reduce major adverse cardiovascular events.

"Americans living with type 2 diabetes are two to three times more likely to die from heart disease than adults without diabetes," said Ralph DeFronzo, MD, a diabetes specialist who was not involved in the CANVAS study but who was quoted in Janssen’s news release. "With this approval, Invokana now plays an even more important role in the overall treatment mix with its demonstrated ability to reduce the risk of potentially devastating cardiovascular events.”

Updated on: November 19, 2018
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