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Canagliflozin ‘not your mother’s diabetes lowering drug’ due to kidney benefits
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CHICAGO — The protective benefits for the kidney and cardiovascular system from SGLT2 inhibitor therapy may be more critical than the more traditional diabetes treatment effects of this medication class, according to a speaker at the Cardiometabolic Health Congress.
“You’ve been hearing about SGLT2s and what I’m hoping to convince you of is this is not your mother’s diabetes lowering drug,” George L. Bakris, MD, FASN, FAHA, professor of medicine and director of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago Medicine, said during a presentation. “This is a special class of agents we don’t fully understand yet, but we have significant data as strong for the kidney as the heart.”
CREDENCE clarifies
Much of that significant data is from the CREDENCE trial, which evaluated the use of the SGLT2 inhibitor canagliflozin (Invokana, Janssen) against placebo. Results from the trial were “very consistent” in yielding renal benefits, according to Bakris. For example, participants in the trial who took canagliflozin experienced a 32% greater decrease in albuminuria (95% CI, –36 to –28) compared with those who took placebo. Bakris noted that this is a particularly important finding of the trial.
“If you get a greater than 30% reduction in albuminuria that is sustained for greater than a year, then that is validated surrogate territory that something positive is happening to the kidney,” Bakris said. “You’ll never get an indication for it but you’re moving in the right direction.”
In addition to decreasing albuminuria, canagliflozin proved effective in addressing other renal endpoints including the composite risk of end-stage renal disease, doubling of serum creatinine, renal death and CV death (HR = 0.7; 95% CI, 0.59-0.82) as well as ESRD by itself (HR = 0.68; 95% CI, 0.54-0.86) compared with placebo. Bakris also said there was less degradation of estimated glomerular filtration rate with canagliflozin compared with placebo.
“A little bit of a reduction initially but the key is not what’s happening acutely — the key is what’s happening long term,” Bakris said. “Decline of kidney function is essentially stabilized with canagliflozin.”
According to Bakris, these results held regardless of baseline eGFR, albuminuria, diabetes status and history of CVD, amputation or heart failure. In addition, demographic differences between patients did not affect the outcomes.
Beyond the renal benefits, canagliflozin also produced positive effects for multiple CV endpoints in the CREDENCE trial. For example, in comparison with those taking placebo, participants taking canagliflozin experienced a 31% decrease in risk for CV death and hospitalization for heart failure (HR = 0.69; 95% CI, 0.57-0.83) and a 20% decrease in risk for major adverse CV events such as CV death, myocardial infraction and stroke (HR = 0.8; 95% CI, 0.67-0.95).
Despite significant renal and CV benefits, Bakris said canagliflozin’s effect on glucose and blood pressure were mild, although those with the lowest eGFRs at baseline experienced the largest decreases in BP. Consistent with the class’ adverse event profile, Bakris noted that genital mycotic infections were common. An increased risk for below-the-knee amputations, first observed during the CANVAS program, was not significant in CREDENCE, he said, adding there was no signal for increased fracture risk.
The importance of these findings and the work done in the CREDENCE trial stems from the fact that there has been a paucity of data on renal outcomes with many diabetes medications, especially DPP-IV inhibitors and GLP-1 receptor agonists, with most trials providing no evidence of a benefit for chronic kidney disease. More has been done in the area of SGLT2 inhibitors, particularly in the EMPA-REG and CANVAS trials, but Bakris noted that “these were exploratory analyses. They were not analyses that would ever give an indication.”
Some of the unique aspects of the CREDENCE trial also make the findings that much more important. The trial, which was “stopped early for overwhelming efficacy,” according to Bakris, included an overwhelming majority of participants already using renin-angiotensin-aldosterone system blockers. Bakris also noted that a baseline eGFR of 45 mL/min/1.73 m2 or lower was identified in nearly one-third of participants, whereas 300 mg albuminuria or more was identified in 88% of participants.
“There’s no one in the world that’s not going to say this is not kidney disease,” Bakris said.
Mechanistic explanations lacking
Although the renal benefits of canagliflozin therapy are clear, the mechanisms that lead to these benefits still must be determined.
“If you think we knew how this drug is working, if somebody tells you they know, they’re hallucinating or they’re delusional,” Bakris said. “It’s one of the two because we’re still trying to figure out what’s going on.”
According to Bakris, some potential explanations include how SGLT2 inhibitors interact with the distal tubule and macula densa as well as how they may decrease oxidative stress and inflammation.
“Increased oxidative stress stimulates NLRP3 inflammasome activity, and NLRP3 inflammasome activity is literally like lighting an exploding fire in the mitochondria in the cells and really causes all kinds of damage,” Bakris said. “If you can reduce oxidative stress, everybody calms down and that’s essentially what these drugs are doing.”
Even with this lack of clarity, the treatment of certain renal and CV outcomes with canagliflozin was recently approved by the FDA, as Endocrine Today previously reported, which follows Bakris’ argument that reducing HbA1c is not all that canagliflozin and other SGLT2 inhibitors bring to the table.
“[SGLT2 inhibitors] acts both hemodynamically and as an anti-inflammatory mechanism and there’s good evidence to support both of those,” Bakris said. “If you think of that, then you come up with a conclusion that SGLT2s are cardiorenal risk-reducing agents that have glucose lowering as a beneficial side effect.” – by Phil Neuffer
Reference:
Bakris GL. SGLT2 Inhibitors and Renal Preservation. Presented at: Cardiometabolic Health Congress; Oct. 10-13, 2019; Chicago.
Disclosure: Bakris reports he has received research funding from Bayer, Janssen, Novo Nordisk and Vascular Dynamics, served as a consultant for AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Relypsa, Sanofi and Vascular Dynamics, and as editor for the American Journal of Nephrology, as the nephrology and hypertension section editor of UpToDate and as associate editor of Diabetes Care and Hypertension Research.