Treatment of diabetic kidney disease ‘requires multiple drugs’
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Multiple pathophysiologic abnormalities contribute the development and progression of diabetic kidney disease, and early intervention with triple or even quadruple therapy is needed to prevent complications, according to a speaker.
In addition to maximally tolerated angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker therapy, treatment combining an SGLT2 inhibitor, the nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia, Bayer) and potentially a GLP-1 receptor agonist could serve as an optimal solution for cardiovascular and renal protection in type 2 diabetes, Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center at San Antonio, said during a presentation at the Heart in Diabetes conference.
DeFronzo cautioned that combination therapy in DKD is controversial — currently, there are no randomized controlled trial data 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. “I have taken care of people who are on dialysis and people who are blind ... and we have got to stop the disease. 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.”
DKD is the leading cause of end-stage renal disease in the U.S., and 50% of patients initiating renal replacement therapy have diabetes, DeFronzo said. Additionally, subclinical CVD 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.
“Unlike diabetic retinopathy and some of the macrovascular complications which have been decreasing, there has been no decrease in prevalence of diabetic kidney disease,” DeFronzo said. “Diabetic kidney disease goes hand in hand with CVD. If you have CKD, you are still more likely to die of CVD than from your CKD.”
DeFronzo highlighted the potential benefits of several therapies to treat and prevent complications of DKD:
- Any SGLT2 inhibitor, used early, is beneficial for renal disease. DeFronzo said any FDA-approved SGLT2 inhibitor is a useful agent for correcting multiple components of the so-called “ominous octet” for diabetic nephropathy: renal hypoxia, hypertension, hyperglycemia, deranged tubuloglomerular feedback, albuminuria, the tubular/growth factor hypothesis, genetics and obesity or lipotoxicity, DeFronzo said. He cited data from the CREDENCE trial that showed canagliflozin (Invokana, Janssen) was associated with significant renal benefit even in the setting of an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m2 or lower. “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 does not lower glucose, but can significantly reduce adverse outcomes. As Healio reported in August, data showed finerenone reduced CV event risk by 13% for adults with diabetic kidney disease compared with placebo, primarily driven by a 29% reduction in HF 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. “We now have an additional drug, and there is going to be a lot of controversy about where this drug fits,” DeFronzo said. “This drug does not lower glucose. That does not mean we shouldn’t be using it in our patients. I believe we should be using it very early in combination with the SGLT2 inhibitors.”
- Not all GLP-1 receptor agonists are alike. Data from AMPLITUDE-O, presented at the American Diabetes Association Scientific Sessions in June and reported by Healio, showed an investigational, exendin-4-based GLP-1 receptor agonist, efpeglenatide, reduced CV event risk by 27% and kidney disease progression by 32% compared with placebo for high-risk adults with type 2 diabetes, with or without background SGLT2 inhibitor therapy. Four other GLP-1 receptor agonists with structures based on human GLP-1 have been shown to reduce the risk for CV events among adults with type 2 diabetes, with varying results for renal outcomes. “There is still some question as to where we stand with the GLP-1 receptor agonist in terms of benefit,” DeFronzo said. “Unlike my statement about the SGLT2 inhibitors, where all seem to have similar benefits in terms of renal protection, I am not sure this will turn out to be true for the GLP-1 receptor agonists.”
References:
- Gerstein HC, et al. N Engl J Med. 2021; doi:10.1056/NEJMoa2108269.
- Pitt B, et al. N Engl J Med. 2021; doi:10.1056/NEJMoa2110956.
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DeFronzo RA. Kidney disease in diabetes: Implications for therapy. Presented at: Heart in Diabetes Annual Meeting; Sept. 10-12, 2021 (hybrid meeting).
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