CREDENCE: First Renal Outcomes Trial Finds Canagliflozin Cuts Risk of Renal Failure, Death; Prompts ADA Updates

CREDENCE, the first of a coming wave of dedicated renal outcomes trials for sodium glucose cotransporter 2 (SGLT2) inhibitors, has reported 2 sets of results that

suggest there is more news to come for the drug class that has already changed diabetes care since reaching the market in 2013.¹

Investigators for CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), reported on April 14, 2019, that canagliflozin cut the risk of renal failure or death by 30% in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD).² These results, unveiled at the International Society of Nephrology 2019 World Congress of Nephrology in Melbourne, Australia, were simultaneously reported in the New England Journal of Medicine.²

Canagliflozin is sold as Invokana by Janssen Pharmaceutical Companies of Johnson and Johnson.

The findings prompted the American Diabetes Association (ADA) to update its Standards of Medical Care in Diabetes on June 3, 2019,³ in 2 chapters that deal with cardiovascular (CV) disease and risk management⁴ and microvascular complications and foot care.⁵

Then, on June 11, 2019, during the Scientific Sessions in San Francisco, California, CREDENCE coprincipal investigator Kenneth Mahaffey, MD, of Stanford University Medical Center, shared additional data on what the results mean for primary and secondary prevention—namely, how well canagliflozin prevented renal decline in individuals with T2D who had been diagnosed with CV disease or had experienced an event (secondary prevention) as well as those who had neither (primary prevention).⁶

After a series of CV outcomes trials (CVOTS) showed a class effect for CV benefits for SGLT2 inhibitors,^7-9 there was plenty of interest at the 79th Scientific Sessions not only for CREDENCE, but also for secondary findings on renal outcomes from the CVOTS for rival drugs. Other manufacturers have their own dedicated renal outcomes trials in process: AstraZeneca has Dapa-CKD for dapagliflozin (Farxiga),¹⁰ due to report in November 2020, and Boehringer Ingelheim and Eli Lilly have sponsored EMPA-KIDNEY for empagliflozin (Jardiance), due to report in June 2022.¹¹ Various dedicated trials exploring the therapeutic value of SGLT2 inhibitors

in heart failure for patients with and without diabetes are also under way.¹²

SGLT2 inhibitors lower blood glucose by targeting a protein that affects reuptake of glucose by the kidneys back into the bloodstream. Patients who take these drugs excrete glucose out of the body through the urine, and this unique system for discharging extra blood glucose accounts for the drugs’ protective effects on the renal system. As described by Christoph Wanner, MD, in a 2017 article, “The potential mechanisms responsible are likely multifactorial, and direct renovascular and hemodynamic effects are postulated to play a central role.”¹³

Although an early completion date of CREDENCE had suggested positive results,¹⁴ the magnitude of the benefit surprised some. While moderating a press briefing at the 79th Scientific Sessions, Robert H. Eckel, MD, of the University of Colorado, exclaimed, “CREDENCE—that just knocks your socks off, doesn’t it?”

Initial Findings Show No Amputation Risk

Phase 3 results reported in Melbourne show that CREDENCE easily achieved its primary end point; compared with placebo, canagliflozin reduced a composite of (1) the progression to end-stage renal disease (ESRD), defined as the need for chronic dialysis or renal transplant; (2) doubling of serum creatinine; and (3) renal or CV death.² This was not unexpected, given the June 2018 announcement that the trial was ending early after independent evaluators determined the primary end point had been met.¹⁴

CREDENCE did not show the elevated risk of lower extremity amputation seen in CANVAS,⁸ the CVOT for canagliflozin that caused the FDA to issue a boxed warning, even though the same trial found benefits that led to an indication for lower risk of CV events.¹⁵ When asked if these results would prompt the drug maker to seek removal of the warning, Janssen officials said in an email that the new data are “reassuring” because they “show no imbalance” in either fractures or amputations between the canagliflozin or placebo arms; the company will be working with the FDA, “to reflect these safety findings in the Invokana label.”

Janssen is seeking an additional indication for canagliflozin, based on the CREDENCE findings.¹⁶

CREDENCE was a double-blind trial that randomized 4401 patients with a median follow-up of 2.62 years. Patients had a mean age of 63 years (± 9.2 years) and had lived with T2D for an average of 15.8 years (± 8.6 years). All patients had an estimated glomerular filtration rate (eGFR) of 30 to <90 mL per minute per

1.73 m² of body surface area and albuminuria. All were being treated with standard of care, renin-angiotensin system blockade.

Findings included²:

• The relative risk (RR) of the primary outcome was 30% lower for those taking 100 mg of canagliflozin compared with placebo; event rates were 43.2 and 61.2 per 1000 patient-years (hazard ratio [HR], 0.70; 95% CI, 0.59-0.82; P = .00001).

• The RR for the renal-specific elements of the primary end point—excluding CV death&mdash;was 34% lower for those taking canagliflozin (HR, 0.66; 95% CI, 0.53-0.81; P <.001).

• The RR of ESRD was 32% lower for those taking canagliflozin (HR, 0.68; 95% CI, 0.54-0.86; P = .002).

• Among secondary end points, the risks of CV death, myocardial infarction, or stroke (HR, 0.80; 95% CI, 0.67-0.95; P = .01) and for hospitalization for heart failure (HR, 0.61; 95% CI, 0.47-0.80; P <.001) was lower among those taking canagliflozin. The authors wrote that these measures may have been limited when the trial ended early, but they were consistent with other randomized controlled trials and real-world studies in SGLT2 inhibitors.

No significant differences were seen in rates of amputations or fractures. In amputation, the HR was 1.11 (95% CI, 0.79-1.56) and in adjudicated fractures, the HR was 0.98 (95% CI, 0.70-1.37).

Lower limb amputation rates were 12.3 for canagliflozin versus 11.2 for placebo per 1000 patient-years. There has been much speculation about whether the amputation findings in CANVAS were due to the makeup of the study population. Authors in CREDENCE wrote that the population in this trial was at high risk for CV events, and they discussed the disparity from the CANVAS findings.

“Whether the increased risk of lower limb amputation in the CANVAS Program was due to differing trial populations or protocols or to chance remains unclear,”

they wrote. “The overall safety profile in our trial is otherwise consistent with the known adverse effects associated with canagliflozin.”²

A Breakthrough With Potential Savings to the Health System

“Canagliflozin is the first medical breakthrough in nearly 20 years proven to slow the progression of chronic kidney disease in patients with diabetes at high risk of developing kidney failure,” the study’s lead author, Vlado Perkovic, MBBS, PhD, FASN, FRACP, said in a statement.¹⁷

Perkovic, who is cochair of the CREDENCE Steering Committee and executive director of The George Institute for Global Health, Australia, said, “These impressive results from the CREDENCE study have significant clinical implications for preventing kidney failure and improving health for millions of people living with chronic kidney disease and type 2 diabetes.”

Researchers and physicians familar with the CREDENCE trial have hinted as far back as the summer of 2017 that the renal outcomes suggested in CANVAS-R (the renal component of CANVAS) would be fully demonstrated in these results.18 With T2D being the top cause of kidney failure, a treatment to prevent patients with T2D from needing dialysis or transplant would potentially save millions of dollars for Medicare. A 2018 report from the US Renal Data System (USRDS) found that 1% of the patients in Medicare have ESRD, but they account for 7% of Medicare fee-for-service costs.¹⁹

When the first CVOT, EMPA-REG OUTCOME,⁷ reported that empagliflozin reduced the risk of CV death in 2015, it “changed the landscape in diabetes management,” as Julie R. Ingelfinger, MD, and Clifford J. Rosen, MD, wrote in their editorial that accompanied publication of the study.²⁰ EMPA-REG OUTCOME and subsequent CVOTs showed that SGLT2 inhibitors reduced the risk of hospitalization for heart failure, suggesting that the drugs were not only beneficial to patients, but could also reduce one of the high-cost items in healthcare, just as health systems were being graded on their ability to avoid repeat hospitalizations for this condition.

SGLT2 inhibitors have been shown to reduce hypertension and promote modest weight loss. Existing evidence showing prevention of renal decline last month prompted the American College of Cardiology and the American Heart Association to include the class, with glucagon-like peptide-1 receptor agonists, in an updated primary prevention guideline.²¹ Ingelfinger and Rosen wrote that, although several T2D medications show benefits beyond lowering blood glucose, “the SGLT2 inhibitors appear to be the most promising.”²⁰

CREDENCE shows that canagliflozin has the potential to achieve savings in an area of huge importance to policy makers. Few items tax the health system as much as ESRD, which affects 750,000 individuals in the United States. The USRDS estimates the cost of a year of dialysis at $89,000 per patient¹⁹, and, as Ingelfinger and Rosen wrote, the ranks in need of dialysis and kidney transplants are growing due to rising levels of obesity.²⁰ They noted that the investigators estimate that among

1000 patients treated over 2.5 years,²¹ would need to be treated with canagliflozin to avoid dialysis or transplant, doubling the serum creatinine level, or renal or CV death.² Dialysis and kidney transplant care are so costly that patients with CKD who reach this stage automatically qualify for Medicare at any age; most Medicare Advantage plans do not accommodate these patients unless they have a special needs plan that handles ESRD.²²

However, the CREDENCE investigators noted that they did not study patients who already had advanced CKD at baseline, or kidney disease believed to have been caused by conditions other than T2D.

Evidence in Both Primary, Secondary Prevention

At the 79th Scientific Sessions, Mahaffey presented a series of slides during a symposium that included the CREDENCE results showing CV and renal outcomes for patients with and without existing CV disease, based on screening the patients at the start of the trial. Those in the secondary prevention group had a history of coronary, cerebrovascular, or peripheral vascular disease, procedures, or events^6,23

The primary prevention group had 49.6% of the participants, was younger, and had more women, but had similar measures of glycated hemoglobin and low-density lipoprotein cholesterol. As expected, the secondary prevention group began the trial with higher rates of hypertension, heart failure, CV disease, peripheral vascular disease, and amputations. The 2 groups had similar duration of T2D and level of renal function, according to Mahaffey’s presentation.²³

Overall, the data Mahaffey shared showed that canagliflozin demonstrated “important reductions in CV death and hospitalization for heart failure,” in

both the primary and secondary prevention groups:23

• There was a 26% reduction in hazard of CV death or hospitalization for heart failure in the primary prevention group.
• There was a 34% reduction in the hazard of CV death or hospitalization for heart failure in the secondary prevention group.
• For the combined end point of CV death, myocardial infarction or stroke, there was a 32% reduction in the primary prevention group, and a 15% reduction in the secondary prevention group.
• For CV death, Mahaffey said there were “very similar” HRs, translating into a 25% reduction in the primary prevention group and a 21% reduction in the secondary prevention group.

“These data show, for the first time, important reductions in these end points with an agent to treat [T2D] and [CKD] in both primary and secondary prevention groups,” Mahaffey said.

Data showed similar results for the composite renal end point between the primary and secondary prevention groups, “very different from the [CV] results,” he said.

In a statement, Mahaffey said the new analysis shows that canagliflozin can manage serious complications from T2D, including CV and kidney disease. “We’re particularly excited about this new analysis, because it’s the first time a [T2D] medicine has shown a [CV] benefit in patients who did not have pre-existing CV disease. This is an important, clinically meaningful finding as it uncovers the potential of canagliflozin to offer a protective effect in this patient population.”²⁴ References

1. 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-approvesinvokana-canagliflozin-for-the-treatment-of-adults-with-type-2-diabetes. Accessed June 17, 2019.

2. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi: 10.1056/NEJMoa1811744.

3. American Diabetes Association issues critical updates to the 2019 Standards of Medical Care in Diabetes [press release]. Arlington, VA: American Diabetes Association; June 3, 2019. diabetes.org/newsroom/press-releases/2019/updates-standards-medical-care-diabetes.html. Accessed June 16, 2019.

4. American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2019. Diabetes Care. 42(suppl 1):S103-S123. doi: 10.2337/dc19-S010.

5. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes—2019. Diabetes Care. 42(suppl 1):S124-S138. doi: 10.2337/dc19-S011.

6. Petrovic V, Rosenstock J, chairs. CREDENCE and CARMELINA—results from two major clinical trials in kidney and cardiovascular disease in diabetes. Symposium presented at: 79th Scientific Sessions of the American Diabetes Association; San Francisco, California: June 7-11, 2019.

7. Zinman B, Wanner C, Lachin JM, et al; 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.

8. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.

9. Wiviott SD, Raz I, Bonaca MP, et al; DECLARE—TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi: 10.1056/NEJMoa1812389.

10. A study to evaluate the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease (Dapa-CKD). Clinical Trials website. clinicaltrials.gov/ct2/show/NCT03036150. Updated April 29, 2019. Accessed June 16, 2019.

11. EMPA-KIDNEY (the study of heart and kidney protection with empagliflozin). Clinical Trials website. clinicaltrials.gov/ct2/show/NCT03594110. Updated June 10, 2019. Accessed June 17, 2019.

12. Kosiborod M, Caffrey M. Time for a “new goalpost’ in cardiovascular outcomes trials, Kosiborod suggests. Am J Manag Care. 2018;24(spec No. 14):SP602-SP604.

13. Wanner C. EMPA-REG OUTCOME: the nephrologist’s point of view. Am J Med. 2017;130(6S):S63-S72. doi: 10.1016/j.amjmed.2017.04.007.

14. Phase 3 CREDENCE renal outcomes trial of INVOKANA (canagliflozin) is being stopped early for positive efficacy findings [press release]. Raritan, NJ: PRNewswire; June 16, 2018. prnewswire.com/news-releases/phase-3-credence-renal-outcomes-trial-of-invokana-canagliflozin-is-being-stopped-early-for-positive-efficacy-findings-300681634. html. Accessed June 17, 2019.

15. FDA approves CV events indication for Invokana. Healio website. healio.com/endocrinology/diabetes/news/online/%7B2bc50980-9d8e-4787-962a-3a9fff676e21%7D/fda-approves-cv-events-indication-for-invokana.Published October 31, 2018. Accessed June 17, 2018.

16. Janssen submits supplemental New Drug Application to US FDA for INVOKANA (canagliflozin) for the treatment of chronic kidney disease in patients with type 2 diabetes [press release]. Raritan, NJ: Janssen; March 28, 2019. janssen.com/janssen-submits-supplemental-new-drug-application-us-fda-invokanar-canagliflozin-treatment-chronic. Accessed June 17, 2019.

17. Invokana (canagliflozin) significantly reduces the risk of renal failure in patients with type 2 diabetes and chronic kidney disease in the landmark phase 3 CREDENCE study [press release]. Melbourne, Australia: PRNewswire; April 14, 2019. prnewswire.com/news-releases/invokanacanagliflozin-significantly-reduces-the-risk-of-renal-failure-in-patients-with-type-2-diabetes-and-chronic-kidney-disease-in-the-landmark-phase-3-credence-study-300831777.html. Accessed June 16, 2019.

18. Product theater: experts present evidence and advice on canagliflozin. Am J Manag Care. 2017;23(spec No. 11):SP458-SP459.

19. US Renal Data System (USRDS). 2018 Annual Data Report. USRDS website. usrds.org/adr.aspx. Published 2018. Accessed June 16, 2019.

20. Ingelfinger JR, Rosen CJ. Clinical credence—SGLT2 inhibitors, diabetes, and chronic kidney disease. N Engl J Med. 2019;380(24):2371-2373. doi:

10.1056/NEJMe1904740.

21. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published online March 17, 2019]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2019.03.009.

22. Signing up for Medicare if you have ESRD. Medicare website. medicare.gov/information-for-my-situation/signing-up-for-medicare-if-youhave-

esrd. Accessed June 17, 2019.

23. Perkovic V, Agarwal R, Jardine MJ, Neal B, Mahaffey K, Zinman B. Updated CREDENCE results presented by Vlado Perkovic at the American Diabetes

Association on June 12, 2019. The George Institute website. georgeinstitute.org/media-releases/new-breakthrough-treatment-for-kidney-disease-

offers-hope-for-hundreds-of-millions-0. Accessed June 21, 2019.

24. Invokana (canagliflozin) significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes and chronic kidney disease in new CREDENCE analysis. [press release]. San Francisco, CA: Janssen; June 11, 2019. janssen.com/invokana-canagliflozin-significantly-reduced-major-cardiovascular-events-and-kidney-failure. Accessed June 17, 2019.

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