Product Theater: Experts Present Evidence and Advice on Canagliflozin

Three physicians, 2 in academic medicine and 1 in family medicine, recently reviewed studies involving the type 2 diabetes (T2D) therapy canagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor sold by Janssen Pharmaceuticals, Inc, as Invokana.

The review included a 2016 meta-analysis of 38 studies, which found the 300-mg dose of canagliflozin reduced glycated hemoglobin (A1C), fasting plasma glucose, and systolic blood pressure better than other drugs in the class “at any dose.”¹ The review also covered new results from the Cardiovascular Assessment Study (CANVAS) and CANVAS Renal (CANVAS-R) trials, which were presented June 12, 2017, at the 77th Scientific Sessions of the American Diabetes Association in San Diego, California.

The combined results of CANVAS and CANVAS-R trials, reported in the New Journal of Medicine (NEJM), found a 14% reduction in the combined primary endpoint of nonfatal heart attacks, nonfatal strokes, and cardiovascular (CV) death.² These results also found that patients taking canagliflozin had a lower risk of hospitalization for heart failure, less loss of kidney function, and a lower risk of progression to albuminuria.

Janssen officials said at that time the CANVAS and CANVAS-R results showed “a positive risk-benefit profile” for both CV and renal endpoints.³ One commentator called these results highly statistically significant for noninferiority and statistically significant for superiority.⁴ Since the CANVAS results were announced, CVS Caremark has listed canagliflozin as the preferred SGLT2 inhibitor on its 2018 formulary.⁵

The physicians’ presentation, which welcomed questions from family practice physicians who treat most patients with T2D, featured Carol Wysham, MD, clinical professor of medicine at the University of Washington; Christian Mende, MD, FACP, FACN, FASN, FASH, clinical professor of medicine at the University of California, San Diego; and Eden Miller, DO, a practitioner of family medicine and a codirector of Diabetes Nation in Bend, Oregon.

SGLT2 inhibitors, which thus far are approved only for the treatment of T2D, have a unique mechanism of action that causes the body to excrete excess glucose through the urine. Reviewing the mechanism, Mende said that for a person with diabetes, the result can be the loss of 100 mg of glucose a day.

Mende and Wysham explained that canagliflozin goes to work immediately, and physicians must instruct patients to drink water and eat while taking the drug. In many cases, physicians should reduce or eliminate antihypertensive therapy, especially diuretics.

Patients starting canagliflozin “should drink an extra quart of water a day to stay hydrated,” Mende said. If a patient must fast for a medical procedure, such as a colonoscopy, canagliflozin should be stopped temporarily. The rule of thumb, he said, is: “No food, no drink, no drug.”

The physicians covered results from both randomized clinical trials and real-world evidence. Miller, the family physician, said real-world evidence includes claims, registry, and observational studies, which she said can be examined with clinical trial results to “synergistically inform us to make better decisions.”

Results included the following:

• In lowering A1C, canagliflozin outperforms sitagliptin, a top-selling dipeptidyl peptidase-4 inhibitor, and patients on canagliflozin lost about 5 pounds.⁶

• Real-world results show patients were more likely to stay on canagliflozin than comparators.

• Safety data showed that canagliflozin compared well with its competitors, except for an increased risk of hypoglycemia if patients were also on insulin and sulfonylureas.

Results From the Meta-analysis

A 2016 study funded by the United Kingdom’s National Institute for Health Research reviewed results from 38 randomized controlled trials for the 3 approved SGLT2 inhibitors—canagliflozin, empagliflozin (Jardiance), and dapagliflozin (Farxiga). The meta-analysis involved 23,997 patients in trials that lasted at least 24 weeks.

Wysham noted that while the trials differed in some of the reported metrics, all recorded changes in A1C, and the average baseline A1C was within a narrow range of 8.0% to 8.2%. Citing an article by Zaccardi et al that appeared in Diabetes, Obesity and Metabolism,¹ the physicians explained that the meta-analysis found the following mean A1C reductions, compared with placebo:

• -0.9% (95% CI, -1.0 to -0.8) for canagliflozin 300 mg

• -0.8% (95% CI, -0.9 to -0.7) for canagliflozin 100 mg

• -0.7% (95% CI, -0.8 to -0.6) for empagliflozin 25 mg

• -0.6% (95% CI, -0.7 to -0.5) for empagliflozin 10 mg

• -0.7% (95% CI, -0.7 to -0.6) for dapagliflozin 10 mg

• -0.6% (95% CI, -0.6 to -0.4) for dapagliflozin 5 mg

“Comparisons among SGLT2 inhibitors showed greater [A1C] reductions with canagliflozin 300 mg compared with all SGLT2 drugs…and no significant differences between dapagliflozin and empagliflozin at different doses,” the authors found.

CANVAS and CANVAS-R

Both CANVAS and CANVAS-R arose from a 2008 FDA requirement that manufacturers of new diabetes, obesity, and cholesterol therapies conduct CV outcomes trials to show that the drugs are safe. As Wysham explained, the CANVAS started before canagliflozin was approved in March 2013,7 while CANVAS-R began after approval.

In total, the 2 studies covered 10,142 patients, making the pool of patients larger than a comparable study of empagliflozin.⁸ Patients’ mean age was 63, and their mean time living with T2D was 13.5 years.

Wysham explained that because CANVAS was created to find out whether the drug was safe for high-risk patients, by design the population was sicker than the typical patients physicians will see in family practice: To participate, patients had to have a history of atherosclerotic CV disease or be at least 50 years old with 2 or more CV risk factors. In the canagliflozin group, close to a third had a diagnosis of neuropathy (30.8%2), 17.2% had nephropathy,2 and Wysham said half were on insulin; 2.3% had already experienced an amputation.² (According to the NEJM study, the mean body mass index for the canagliflozin group was 31.4 kg/m².)

While all arms of the study started with baseline A1C of 8.2%, the canagliflozin group dropped to a mean of 7.5% at week 26 and then slowly rose over the long follow-up period while maintaining a difference of -0.58%, along with a mean body weight difference of -1.60 kg. Wysham stated that the findings showed an increased risk in lower limb amputations, of the toe and forefoot; she clarified that while the risk was double that of placebo, the overall numbers were extremely small (6.3 vs 3.4 participants per 1000 patient years²).

Miller explained the significance of CANVAS to family physicians who see the typical patient with T2D. “One thing CANVAS and CANVAS-R really did demonstrate was this 3-point MACE [major adverse CV events, which is a composite measure of reduction in heart attacks, strokes, and hospitalization for heart failure]. We saw these positive benefits from it, including a signal in the reduction in hospitalization for heart failure. This really matters at the primary care level and for treating all their comorbidities.”

“The endocrinologist treats the sugar, but it’s the primary care physician who keeps the patient alive,” she said.

Clarifying Amputation Risk

During the question-and-answer period, Amy Carroll, PhD, medical science liaison for Janssen, asked Wysham to further clarify what the amputation risk means for physicians in family practice.

Wysham emphasized that the patients in CANVAS, as a group, were very high risk, including those with established peripheral vascular disease who were at risk for amputation. “These individuals were pretty sick to begin with,” she said. Wysham noted that this signal did not emerge in the earlier phase 3 and phase 4 trials for the drug.⁹

Trial protocols in CANVAS called for seeing the full effects of canagliflozin on blood pressure and lipids, which Wysham said “was actually probably not the best advice.” Wysham and Mende said it is apparent the problem was a volume depletion issue, and Mende added that there were amputation signals in trials for other SGLT2 inhibitors, just not the differential with placebo. “To me, it’s a placebo issue,” he said.

For family physicians, the best advice is to emphasize the importance of drinking water, especially when starting canagliflozin, and Wysham emphasized the need for regular foot exams.

“Excited About the Kidney”

CANVAS confirmed previous results of increased rates of infections of male genitalia and mycotic genital infections in women. The physicians agreed that almost all these infections occur when patients are starting the drug, and physicians typically send patients home with a prescription for a barrier cream or one to treat the infection, in case it is needed. “A very small percentage are at risk of recurrent yeast infection,” Wysham said.

In addition to the positive CV data, the renal results seen in CANVAS-R are promising. Both Mende, a nephrologist, and Miller say they are encouraged by the opportunity to preserve renal function with the drug. Miller said the purpose of CANVAS was to show cardiac safety, “and the data are showing there’s some protective effect…but I’m just as excited about the kidney [function] and hospitalizations for CHF [congestive heart failure].” Mende said he, too, is looking forward to the results of the CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) trial, which is ongoing and expected to conclude in June 2019.¹⁰

Janssen’s Carroll asked the physicians: What sets canagliflozin apart from other SGLT2 inhibitors? “It was the first, it’s had the greatest, by far, experience, it has the best A1C reduction overall,” Wysham said. Because it is on most formularies, “I use what’s easiest to get, with the understanding that Invokana is going to give us the greatest A1C reduction.”

Added Mende, “You look at the data, and you have to make your own decision,” For nephrologists, there’s going to be a lot of news about renal data, he said. “Stay tuned.”

“It’s going to give us the biggest bang for the buck,” Miller said. “I’m looking for more than blood sugar control.”

References

1. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab 2016;18(8):783-794. doi: 10.1111/dom.12670.

2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes [published online June 12, 2017]. N Engl J Med. 2017. doi: 10.1056/NEJMoa1611925.

3. Invokana (canagliflozin) significantly reduces the combined risk of cardiovascular death, myocardial infarction and stroke in the CANVAS program [press release]. Raritan, NJ, and San Diego, CA: Janssen Pharmaceuticals; June 12, 2017. janssen.com/invokana-canagliflozin-significantly-reduces-combinedrisk-cardiovascular-death-myocardial. Accessed August 15, 2017.

4. AJMC® Insights with John Buse, MD. Results from the CANVAS trial. The American Journal of Managed Care® website. ajmc.com/peer-exchange/diabetes-therapy-and-cardiovascular-outcomes-an-update/results-from-thecanvas-trial. Published August 10, 2017. Accessed August 15, 2017.

5. Brennan T. 2018 formulary strategy. CVS Health Payor Solutions website. payorsolutions.cvshealth.com/insights/2018-formulary-strategy. Published August 1, 2017. Accessed August 15, 2017.

6. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea [published correction in Diabetes Care. 2013;36(12):4172]. Diabetes Care. 2013;36(9):2508-2515. doi:10.2337/dc12-2491.

7. US FDA approves INVOKANA™ (canagliflozin) for the treatment of adults with type 2 diabetes [press release]. Raritan, NJ: Johnson and Johnson; March 29, 2013. jnj.com/media-center/press-releases/us-fda-approves-invokanacanagliflozin-for-the-treatment-of-adults-with-type-2-diabetes. Accessed August 21, 2017.

8. Zinman B, Wanner C, Lachin JM, EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.

9. Cada DJ, Ingram KT, Levien TL, et al. Canagliflozin. Hosp Pharm. 2013;46(10): 855-867. doi: 10.1310/hpj4810-855.

10. Janssen Research & Development LLC. Evaluation of the effects of canagliflozin on renal and cardiovascular outcomes in participants with diabetic nephropathy (CREDENCE). clinicaltrials.gov/ct2/show/NCT02065791. NLM identifier: NCT02065791. Accessed August 15, 2017.

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