The personal injury attorneys at Parker Waichman LLP are investigating potential lawsuits over sodium-glucose cotransporter-2 (SGLT2) Type 2 diabetes medications and a variety of serious adverse events, including amputations. Other side effects associated with this class of drugs include heart attack, stroke, renal failure, and diabetic ketoacidosis. If you or someone you know suffered adverse reactions following treatment with Invokana, our personal injury attorneys would like to hear from you.
Invokana is a drug in the SGLT2 inhibitor class and is manufactured by Janssen Pharmaceuticals, a unit of Johnson & Johnson. Other drugs in this class include dapagliflozin, which is sold under the trade name Farxiga and is manufactured by Astra Zeneca, as well as empagliflozin, which is sold by the trade name Jardiance and is manufactured by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly.
FDA Warns that Janssen Pharmaceuticals’ Invokana, Invokamet Linked to Amputations in Clinical Trial
On May 18, 2016, the U.S. Food and Drug Administration (FDA) issued a “Drug Safety Communication” warning that the diabetes medicine, Invokana/canagliflozin, may be linked to a higher risk of leg and foot amputations. The alert was based on the interim safety results of an ongoing clinical trial. Canagliflozin is sold under the brand names Invokana (canagliflozin) and Invokamet (canagliflozin and metformin).
According to the interim data, patients were twice as likely to suffer amputations while using Invokana and Invokamet compared to patients taking a placebo. The FDA alert indicates that the risk equated to five of every 1,000 patients taking a 300-milligrams daily. In patients taking a 100-milligram daily dose, the risk equated to seven of every 1,000 patients.
Amputations involved toes, feet, and legs. Agency officials noted that they are looking into if canagliflozin elevates amputation risks. “Patients taking [canagliflozin] should notify their health care professionals right away if they notice any new pain or tenderness, sores or ulcers, or infections in their legs or feet,” the agency wrote.
CANVAS Study Reveals that Canagliflozin Reduces CV Events, but Amputations Increased
Invokana does reduce cardiovascular events by 14 percent and renal decline by 40, but doubles risks for lower limb amputation, according to new cardiovascular-outcomes trial data Medscape Medical News reported June 12, 2017. Combined results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS–Renal (CANVAS-R) studies were presented at the American Diabetes Association (ADA) 2017 Scientific Sessions and were simultaneously published in the New England Journal of Medicine. According to the Journal, “All three components of the primary outcome—death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke—showed point estimates of effect that suggested benefit, although the individual effects did not reach significance.”
The statistic that stood out for Invokana concerns the two-fold increase in rates of lower extremity amputations. The risk was first seen in 2016 when an independent data monitoring committee discovered the risk. Since then, the FDA has added a black-box warning to Invokana’s label. Still, within the SGLT2 class, amputation is a risk that appear unique to Invokana as far as investigators currently know, according to Fierce Pharma.
In a cardiovascular outcomes trial, Invokana was similar to Jardiance at reducing a combined measure of cardiovascular risks with a 14 percent reduction. FiercePharma pointed out that 14 percent is the same mark Jardiance reached in 2015. Although Invokana reduced cardiovascular death by 13 percent, that is more than is nearly three-fold less that its competitor drug, Jardiance. According information released in early June 2017 at the American Diabetes Association’s annual meeting.
These data show the second time cardiovascular benefit has been demonstrated in an FDA–mandated cardiovascular outcomes trial for an SGLT2 inhibitor. The first was the landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). That research demonstrated a major reduction in both all-cause and cardiovascular death among high-risk patients who took Jardiance in September 2015.
The CANVAS data now suggest that cardiovascular and renal benefits are a class effect, according to lead investigator, Bruce Neal, MB, ChB, PhD, professor of medicine, University of New South Wales Sydney, and senior director, the George Institute for Global Health, Sydney, Australia, Medscape Medical News reported. Meanwhile, the CANVAS data also revealed a significant doubling in amputation risks, primarily of the toe or metatarsal (6.3 vs. 3.4 cases per 1000 patient-years; hazard ratio, 1.97), according to Medscape Medical News. That risk, which had been identified, led to a boxed warning by the FDA for canagliflozin, as well as a warning on the labels of all SGLT2 inhibitors by the European Medicines Agency (EMA).
“Prescribers and patients will need to balance the positive and negative events from the CANVAS trial in clinical decision-making. Certainly it is a more complicated calculus than with the results of the EMPA-REG trial,” LEADER principal investigator John Buse, MD, of the University of North Carolina, Chapel Hill, told Medscape Medical News.
The “CANVAS program” combined data from both CANVAS and CANVAS-R and involved 10,142 patients diagnosed with Type 2 diabetes and increased cardiovascular risk. CANVAS patients were randomized 1:1:1 to canagliflozin 300 mg or 100 mg or placebo, and the CANVAS-R patients to 100 mg (with option to increase to 300 mg after week 13) or placebo. Mean follow-up was 188 weeks (median, 126.1 weeks), Medscape Medical News explained.
Unlike the EMPA-REG and LEADER studies, in which all subjects were diagnosed with established cardiovascular disease, in CANVAS, two-thirds did and the remainder did not. Dr. Neal presented an analysis indicating that use of canagliflozin reduces risk of major cardiovascular adverse events (MACE) per 1,000 patients over five years by 23, risk of hospitalization for heart failure by 17 per 1,000, and renal events by 16. At the same time, amputations occur in 15 more patients per 1,000 over five years, according to Medscape Medical News. Amputation data were not reported in the EMPA-REG research.
More research is needed to determine if the amputation risk seen in Invokana is a class effect. Dr. Neal pointed out that amputation is “certainly something under intense scrutiny.” He also said that “there might be challenges collecting the data retrospectively” from EMPA-REG, according to Medscape Medical News.
In February 2017, the European Medicines Association (EMA) indicated in a statement that, “An increased [amputation] risk has not been seen in studies with other medicines in the same class, dapagliflozin and empagliflozin. However, data available, to date, are limited and the risk may also apply to these other medicines. Further data are expected from ongoing studies with canagliflozin, dapagliflozin, and empagliflozin.”
American Diabetes Association (ADA) 2017 Scientific Sessions Confirms Invokana Amputation Risks
Information at the American Diabetes Association’s (ADA) 2017 Scientific Sessions revealed a massive 20-fold increase in amputation risks in patients treated with Invokana who suffered a prior amputation.
The fact that increased amputation risk has not been picked up in clinical trials of other SGLT-2 inhibitors (Jardiance and Farxiga) is unusual and has experts believing amputation may be a class effect that may involve all SGLT-2 inhibitors. Because the mechanism of the action that leads to amputation is not yet known; however, it is likely that research will reveal evidence of amputations in the trials being conducted on other SGLT-2 inhibitors.
The CANVAS study was presented at the conference as having “proved its primary objective of demonstrating cardiovascular safety with superiority.” There was also a suggestion by the researchers that Invokana has a reno-protective (protects the kidneys)effect that prevented progression and induced regression of albuminuria (symptom of kidney disease), and also reduced renal function loss events. Shockingly, Invokana was also found to increase amputation risk independent of any risk factors. This increased risk was two-fold; however, if the patient had a prior amputation, canagliflozin increased the risk of lower-extremity amputation 20-fold.
Amputation was added to the study at the suggestion of a data monitoring committee in 2016. The FDA issued its drug safety communication regarding increased risk of amputation with canagliflozin, and the European regulatory pharmacovigilance risk assessment committee noted that amputation events were not “systematically captured” within the completed large cardiovascular study of another SGLT-2 inhibitor, empagliflozin. Because of this, it is not yet possible to know if this increased risk of amputation is a class effect; however, caution is advised for high-risk patients. What’s more, over five years, some 15 more patients per 1,000 will suffer amputation compared to placebo. The 15 amputations involved five above the ankle and 10 toes and metatarsals. There is also a possible increased low-impact fracture risk.
The Invokana prescribing information and patient guides do not currently mention the amputation risk.
FDA Strengthens Warning on Invokana and Invokamet Due to Bone Fracture Risk
In September 2015, the FDA strengthened the warning on Invokana and Invokamet, to include information about the increased risk of bone fractures. The agency also added additional information about reduced bone mineral density. In light of this information, the FDA advises health care professionals to consider whether patients are already at increased risk for bone fractures before prescribing Invokana or Invokamet.
The warning label indicates that bone fractures have been reported in patients taking canagliflozin occurring as early as 12 weeks after starting treatment. Invokana has been linked to reduced bone mineral density at the hip and lower spine.
Health care professionals should discuss risk factors for bone fractures, the FDA notes. The agency also indicated that it, “is continuing to evaluate the risk of bone fractures with other drugs in the SGLT2 inhibitor class,” including Farxiga and Xigduo XR (dapagliflozin) and Jardiance, Glyxambi, and Synjardy (empaglifozin), to determine if additional label changes or studies are needed.
Additionally, the FDA required two pediatric studies under the Pediatric Research Equity Act (PREA) to evaluate whether Invokana/Invokamet is safe and effective in children. Based on trial findings, the FDA warned of increased risk of bone fracture associated with canagliflozin in 2015.
The FDA approved canagliflozin in March 2013 to treat patients with Type 2 diabetes. Along with its approval, the agency mandated several post-marketing studies to evaluate the risk of certain adverse events, including cardiovascular events, cancer, pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, adverse pregnancy outcomes, and bone safety.
Legal Help for Victims of the SGLT2 Inhibitor-Related Amputation
If you or someone you know suffered amputation following use of a SGLT2 Type 2 diabetes drug, you may have valuable legal rights, including filing an Invokana amputation lawsuit. For a free lawsuit evaluation with a personal injury attorney, please fill complete our online form or call 1-800-YOURLAWYER (1-800-968-7529) today.
New York City, Long Island, New Jersey, and Florida
Our NYC personal injury attorneys are here to help you when you need it the most.