New Weapons Against Cardiorenal Syndrome

Gregory A. Nichols, PhD


June 24, 2019

At the American Diabetes Association (ADA) Annual Scientific Sessions, there is always heavy emphasis on the microvascular and macrovascular complications of diabetes, particularly chronic kidney disease (CKD) and cardiovascular disease (CVD). The recently concluded 79th meeting was no exception.

Although CKD has long been recognized as a risk factor for CVD, these complications of diabetes have historically been treated as separate problems. Several presentations, however, recognized the "cardiorenal syndrome" (CRS), in which dysfunction in one organ (the heart or the kidney) induces dysfunction in the other.[1] This is not a new concept; a 2008 consensus conference described and defined five subtypes of CRS.[2] The renewed interest in CRS may be attributable to cardiovascular outcomes trials that show beneficial effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on both cardiovascular and renal outcomes (more on this below).

New Analyses From CREDENCE and CARMELINA

At ADA, we learned of new data from two previously reported clinical trials that should add to the therapeutic arsenal for addressing CRS. The CREDENCE trial evaluated the renal and cardiovascular effects of the SGLT2i canagliflozin in patients with diabetes and CKD, defined as an estimated glomerular filtration rate (eGFR) between 30 and 89 mL/min/1.73 m2 and a urine albumin-to-creatinine ratio between 300 and 5000 mg/g. The main results reported in April showed a 30% reduction in the primary composite outcome of end-stage kidney disease, a doubling of serum creatinine, or death from renal or cardiovascular causes.[3] The new results reported at the ADA meeting stratified the results by presence of CVD.

Reductions in CV death or hospitalization for heart failure were 26% in the primary prevention group (those without CVD at baseline) and 34% in the secondary prevention group, whereas risk for CV death, myocardial infarction, or stroke was 32% and 15% lower in the primary and secondary prevention groups, respectively. This is the first time that a diabetes medication has shown a CV benefit in patients without preexisting CVD. Renal outcomes were nearly identical in both groups.

The second half of the session presented new data from the CARMELINA trial on linagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor. Like other DPP-4s, linagliptin had previously shown no benefit but also no risk in its CV outcomes trial in patients with diabetes and high CV and renal risk.[4] It did not affect the risk for heart failure hospitalization in patients with or without preexisting heart failure or by level of CKD.[5] The new results presented were subanalyses of renal outcomes. In general, these outcomes did not differ between the linagliptin and placebo groups, but those on linagliptin had a 14% reduced risk for progression of albuminuria, a finding that was consistent across categories of eGFR. Time to reduction in albuminuria greater than 50% and a sustained reduction of 50% also favored the linagliptin group.

Clinical and Cost Implications

The clinical implications of the new data presented for both CREDENCE and CARMELINA are worth noting. Nearly 10% of the US adult population has diabetes, and up to 40% of those individuals have some form of kidney disease.[6] Until recently, the main treatment of diabetic kidney disease was with renin-angiotensin-aldosterone system (RAAS) inhibitors, and CVD risk was mitigated primarily with statins. CV outcomes trials of SGLT2i have consistently demonstrated CV risk reduction in the context of statin therapy as well as slowing of kidney disease progression in the context of RAAS blockade therapy. The results of DPP-4 trials have not shown CV benefit, but the CARMELINA results suggest possible reversal of kidney damage, also on a background of RAAS blockade.

These new weapons to combat CRS are expensive, but worsening kidney damage and declining kidney function substantially increase all types of medical care costs.[7,8] No formal cost-benefit analysis of any of these drugs has been performed; it’s possible that they would pay for themselves through fewer CV and renal events in the long term.


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