Issue: February 2022
Disclosures: Disclosures: Bakris reports he receives honoraria from AstraZeneca, Merck, Novo Nordisk and Relypsa. DeFronzo reports receiving research support, advisory or speaking fees from AstraZeneca, Bayer, Boehringer Ingelheim and Janssen. Stanton reports serving on an advisory board for Bayer in 2020. Tuttle reports receiving grants, personal fees or nonfinancial support from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Goldfinch Bio, Gilead, Novo Nordisk and Travere. Michos reports serving on advisory boards for Astra Zeneca, Amarin, Bayer, Boehringer Ingelheim, Esperion, Norvartis and Novo Nordisk.
December 20, 2021
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New drugs bring dual benefits for ‘intertwined’ diabetic kidney disease, CVD

Issue: February 2022
Disclosures: Disclosures: Bakris reports he receives honoraria from AstraZeneca, Merck, Novo Nordisk and Relypsa. DeFronzo reports receiving research support, advisory or speaking fees from AstraZeneca, Bayer, Boehringer Ingelheim and Janssen. Stanton reports serving on an advisory board for Bayer in 2020. Tuttle reports receiving grants, personal fees or nonfinancial support from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Goldfinch Bio, Gilead, Novo Nordisk and Travere. Michos reports serving on advisory boards for Astra Zeneca, Amarin, Bayer, Boehringer Ingelheim, Esperion, Norvartis and Novo Nordisk.
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Diabetic kidney disease is the leading cause of end-stage renal disease in the U.S., and 50% of adults initiating renal replacement therapy have diabetes, according to the CDC.

Additionally, subclinical cardiovascular disease affects two-thirds of people with type 2 diabetes at the time of diagnosis, with CVD manifesting approximately 15 years earlier among people with type 2 diabetes vs. those without. Chronic kidney disease in type 2 diabetes increases CV mortality threefold.

“Diabetic kidney disease (DKD) and CVD go hand in hand, and it is very difficult to disassociate the two,” Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center at San Antonio, told Endocrine Today. “Once you are dealing with diabetic nephropathy, you are also dealing with CVD. We also say that you really cannot make the diagnosis of DKD unless there is retinopathy. That means you are also dealing with a complication of blindness. It is a bad combination we want to avoid.”

Until recently, there were no proven therapies that could substantially alter the timeline to ESRD or CV death for this population. Now, new agents are upending the treatment paradigm for DKD, offering the promise of delaying or even preventing dialysis, along with significant reduction in heart failure hospitalization risk and CV death.

In September 2019, the FDA approved a new indication for the SGLT2 inhibitor canagliflozin (Invokana, Janssen) to reduce risks for ESRD, worsening of kidney function, CV death and hospitalization for heart failure among adults with type 2 diabetes and DKD. That was followed by a new FDA-approved indication for another SGLT2 inhibitor, dapagliflozin (Farxiga, AstraZeneca), to reduce risks for kidney function decline, kidney failure, CV death and hospitalization for heart failure in adults with CKD. In August 2021, the agency approved a novel nonsteroidal mineralocorticoid receptor antagonist, finerenone (Kerendia, Bayer), for reducing risks for kidney and heart complications for adults with CKD associated with type 2 diabetes.

Erin D. Michos

“Because patients with diabetes are at such high risk for not only progression of kidney complications, but CV complications, a multipronged approach is needed, including glucose control, but also controlling other traditional risk factors like blood pressure and dyslipidemia,” Erin D. Michos, MD, MHS, associate professor of medicine and director of women’s cardiovascular health at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, told Endocrine Today. “Now we have three therapies, if you include [angiotensin-converting enzyme] inhibitors or [angiotensin receptor blockers], SGLT2 inhibitors and finerenone, that help the heart and the kidney. These patients are at very high risk, and they should be treated aggressively.”

Aggressive treatment will also require clinicians across specialties to work together more than ever before, according to Katherine R. Tuttle, MD, FASN, FACP, FNKF, professor of medicine and co-principal investigator at the Institute of Translational Health Sciences at the University of Washington.

“These three conditions are so intertwined that it is almost impossible to untangle them,” Tuttle, also executive director for research at Providence Health Care, told Endocrine Today. “When you treat one, you treat the others. Patients do not come in and say, ‘I am a heart,’ or ‘I am a kidney.’ They come in as a whole person. Admittedly, one clinician cannot do everything. This should be coordinated care.”

Traditional treatment changing

DKD, sometimes called diabetic nephropathy, is defined by continual albuminuria and a progressive lowering in renal function, or both, along with the presence of retinopathy in a person with type 1 or type 2 diabetes. The National Institute of Diabetes and Digestive and Kidney Diseases, the American Society of Nephrology and Kidney Disease: Improving Global Outcomes (KDIGO) all use the threshold of an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower to diagnose CKD.

George L. Bakris

For those with kidney disease attributed to diabetes, when albuminuria is present, the longstanding standard of care has been glucose control along with maximally tolerated angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker therapy to manage BP, according to George L. Bakris, MD, professor of medicine and director of the American Heart Association-accredited Comprehensive Hypertension Center at the University of Chicago Medicine.

“Data clearly show you need systolic BP control to less than 130 mm Hg, you need glycemic control with an HbA1c around 7%, and you need lipid control with LDL cholesterol well below 100 mg/dL,” Bakris told Endocrine Today. “If you can do those things, consistently for years, you will see absolute risk reduction of 20% for developing kidney disease. That is huge.”

Even with those recommendations, many people with DKD continue to experience renal decline and develop CV complications; experts cite poor implementation of therapies or lack of patient or provider education.

“People manage BP, but are not really paying attention,” Bakris said. “Physicians try to manage HbA1c, but you need patient participation. The best way to do that is explain the consequences of not doing it. That takes time, and it is not being done. You cannot assume people understand that.”

Genetic factors may also play a role in DKD progression, according to Robert C. Stanton, MD, chief of the kidney and hypertension section at Joslin Diabetes Center and associate professor of medicine at Harvard Medical School.

“We treat everyone with diabetes as if they could develop kidney disease — one of the holy grails, of course, is figuring out who actually will,” Stanton told Endocrine Today. “In type 1 [diabetes], the risk is anywhere from 20% to 40%. For type 2 [diabetes], risk is more like 10% to 20%. It is a relatively small proportion of those who go on to end-stage kidney disease.”

New DKD options

A series of large CV outcomes trials previously mandated by the FDA to show CV safety for any diabetes drug yielded surprising CV and renal benefits for two drug classes — SGLT2 inhibitors and some long-acting GLP-1 receptor agonists. Several dedicated kidney outcomes trials for these drugs followed, some still ongoing.

Robert C. Stanton

CREDENCE, the first trial for an SGLT2 inhibitor with a primary renal outcome, evaluated the efficacy and safety of canagliflozin vs. placebo in 4,401 adults with type 2 diabetes, an eGFR between 30 mL/min/1.73 m2 and 90 mL/min/1.73 m2, and albuminuria.

Participants assigned canagliflozin were 30% less likely to experience a composite endpoint of ESRD, doubling of serum creatine and renal or CV death compared with placebo. A renal composite of ESRD, doubling of serum creatine or renal death occurred for 224 patients who took placebo and 153 patients who took canagliflozin, for an HR of 0.66 with canagliflozin. Researchers also observed a 32% risk reduction of ESRD among patients who took canagliflozin as well as a 28% risk reduction for starting dialysis, having a kidney transplant or renal death. The large benefits led the CREDENCE steering committee to announce an early stop of the study in July 2018, based on the achievement of prespecified efficacy criteria.

“CREDENCE was a big success; not only did canagliflozin reduce the primary kidney outcome, but it also reduced the secondary CV outcomes, notably CV death and hospitalization for HF,” Michos said.

The DAPA-CKD study, assessing the benefit of dapagliflozin for adults with CKD with or without diabetes, was similarly stopped early in March 2020 after investigators reported an “overwhelming benefit” for reduction in worsening renal function or renal death compared with placebo. Data presented at the 2020 European Association for the Study of Diabetes Annual Meeting showed participants in the dapagliflozin group had a 39% lower risk for the primary endpoint — a composite of sustained decline in eGFR of at least 50%, ESRD or CV or renal death — compared with the placebo group (HR = 0.61; 95% CI, 0.51-0.72), with a number needed to treat to prevent one primary outcome event of 19.

The study entry criteria for DAPA-CKD also further lowered the eGFR threshold to 25 mL/min/1.73 m2 to 75 mL/min/1.73 m2 (CKD stages 2-4) and albuminuria.

“The CV outcomes trials are just the gift that keeps on giving,” Tuttle said. “We will always be grateful to the FDA for requiring these safety studies. We see the albuminuria and eGFR criteria continue to drop for SGLT2 inhibitors. You are going to see that continue to move. We do have to follow the labeled indication, because that is where we have data on safety and efficacy.”

In EMPA-KIDNEY, researchers are studying the effect of empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on kidney disease progression or CV death compared with placebo in 6,609 participants with CKD, with or without type 2 diabetes. The composite primary outcome is time to first occurrence of kidney disease progression, defined as ESRD, a sustained decline in eGFR to less than 10 mL/min/1.73 m², renal or CV death, or a sustained decline of at least 40% in eGFR from randomization. The estimated completion date is December 2022.

“The important thing about EMPA-KIDNEY is now the enrollment criteria include an eGFR as low as 20 mL/min/1.73 m², and they do not require presence of albuminuria for an eGFR between 20 mL/min/1.73 m² and 45 mL/min/1.73 m²,” Michos said. “This is also for people with or without diabetes. If this trial is also successful, it has implications for a much broader patient population.”

Experts agree data are overwhelming that any SGLT2 inhibitor, used early, is beneficial for kidney disease.

“This is a class of cardiorenal risk-reducing agents that happen to have glucose-lowering as a beneficial side effect,” Bakris said. “That is how you have to think about them.”

DeFronzo said any FDA-approved SGLT2 inhibitor is a useful agent for correcting multiple conditions associated with diabetic nephropathy: renal hypoxia, hypertension, hyperglycemia, deranged tubuloglomerular feedback, albuminuria, and obesity or lipotoxicity.

Katherine R. Tuttle

“Wherever your eGFR is, you benefit,” DeFronzo said. “When you put a patient on this class of drug, they should be on it until the day they walk into the dialysis unit or have their renal transplant.”

Finerenone: Promise of new agent

Clinicians and trialists have long looked for an agent that does not have significant hemodynamic effects, can target inflammation and reduce fibrosis in CKD, Bakris said.

“Spironolactone has been around a long time, but there is hyperkalemia risk,” Bakris said.

Results from the FIDELIO-DKD and FIGARO-DKD trials of finerenone as well as the upcoming FIDELITY-DKD analysis may initiate a new era in treatment of cardiorenal disease, Bakris said.

“We did not want to just do another renal study,” said Bakris, a principal investigator of the finerenone trials. “CREDENCE was out. We wanted to expand on that. We came up with the finerenone program: FIDELIO and then FIGARO, the CV part of it. Together, it is the largest program ever done, with 13,000-plus participants. It also covers the KDIGO ‘heat map’ to a far greater extent than any other drug.”

Data presented at European Society of Cardiology in August showed finerenone reduced CV event risk by 13% for adults with DKD compared with placebo, primarily driven by a 29% reduction in heart failure hospitalizations. In an analysis of the FIGARO-DKD trial — a cohort of patients with less-severe renal disease than those in the companion FIDELIO-DKD trial — researchers also observed a nonsignificant but favorable trend for reduction in severe renal outcomes, including a reduction in the need for renal replacement therapy among participants in the finerenone arm.

“This is a safe drug that allows you further cardiorenal risk reduction. It is the third pillar,” Bakris said. “We, meaning nephrologists, are approaching [heart failure] cardiologists, who have about five drugs to prescribe in [heart failure], using a ‘pillar’ approach. As nephrologists we have had nothing, until now. Now we have SGLT2s and finerenone.”

Combination therapy questions

In addition to maximally tolerated ACE inhibitor or angiotensin receptor blocker therapy, treatment combining an SGLT2 inhibitor, finerenone and potentially a GLP-1 receptor agonist could serve as an optimal solution for CV and renal protection in type 2 diabetes, DeFronzo said.

DeFronzo cautioned that combination therapy in DKD is controversial — currently, there are no randomized controlled trials assessing outcomes with combination therapy.

“Because we have so many abnormalities at the level of the kidney contributing to the pathophysiology, in my opinion, we need to think seriously about combination therapy, and we need to be thinking about combination therapy from the beginning,” DeFronzo said. “Sure, lower the glucose. But if you cannot lower the glucose and the disease has started, then we need to intervene. I would favor using three or all four of the drugs here, even though we do not have the clinical evidence to support that.”

Available data from the FIGARO-DKD trial — which included participants with and without background SGLT2 inhibitor therapy — showed finerenone reduced CV events and slowed CKD progression vs. placebo irrespective of SGLT2 inhibitor use at baseline or at any time during the trial. Sub-analyses conducted to explore the treatment effect of finerenone in patients with and without SGLT2 inhibitor use at baseline also showed additive benefits of SGLT2 inhibition.

In FIDELIO-DKD, researchers observed a 25% reduction in urinary albumin-to-creatinine ratio among participants assigned finerenone and prescribed an SGLT2 inhibitor at baseline, compared with a 32% reduction among those who received finerenone and were not taking an SGLT2 inhibitor at baseline. However, the subgroup of participants prescribed SGLT2 inhibitors was small, making up just 4.6% of the cohort.

“The good news is what we found there were the effects were better in the combination group than not, but at best, it was hypothesis-generating and you could not get a P value,” Bakris said. “But the data are consistent and suggest benefit. Animal studies do show additivity in terms of reduction in albuminuria, reduction in cardiac fibrosis. The short answer to the question of should you be using all three agents? I would argue if you have proteinuric kidney disease, absolutely.”

‘Bite the bullet, start the therapy’

Finerenone, SGLT2 inhibitors and GLP-1 receptor agonists are potent additions to the armamentarium for managing comorbidities associated with type 2 diabetes; however, they fail to address a troublesome root issue.

“We have all these ‘new’ therapies, but they are all coming in during a later stage — to slow progression after you have already developed kidney disease,” DeFronzo said.

“We must go back and remember that diabetes is a disease of glucose. That is not to minimize the risks for heart attack, stroke or ending up on dialysis. But if you keep the HbA1c below 6.5%, you are not going to develop diabetic kidney disease. Good glycemic control should be the foundation of preventing diabetic kidney disease.”

Other fundamentals of disease management, like better use of ACE inhibitors or angiotensin receptor blockers, as well as measuring albumin, are also important, Tuttle said.

“If you look at real-world data, what we know is that ACEs and [angiotensin receptor blockers] are only used in 25% to 40% of typical patients,” Tuttle said. “Before we talk about new therapies, we need to get the house in order, and that brings us back to this issue of albuminuria again. The percentage of albuminuria testing almost exactly mirrors the ACE and [angiotensin receptor blocker] use, about 10% to 40%.”

Michos, who also urged all clinicians to check for albuminuria, said statins, too, remain widely underutilized for people with CKD, with or without diabetes.

Improved communication between specialties could ensure patients receive the therapies they need earlier in their treatment, she said.

“I am excited about trials like EMPA-Kidney, but we do not need more trials,” Michos said. “We already have overwhelming evidence from trials with SGLT2 inhibitors showing benefit. What is lacking now is the implementation piece, getting clinicians to start these therapies and take ownership. It should not be, ‘I recommend their endocrinologist look at this,’ and that appointment is 9 months away. This should be a team-based approach. Whoever is seeing the patient first needs to bite the bullet, start the therapy and then communicate.