Commentary on Cardiorenal Protection With the Newer Antidiabetic Agents in Patients With Diabetes and Chronic Kidney Disease

In the Scientific Statement titled Cardiorenal Protection with the Newer Antidiabetic Agents in Patients with Diabetes and Chronic Kidney Disease, five AHA Councils weigh in on the roles of newer antidiabetic agents in cardiorenal protection. Few topics have broader reach into the cardiology, nephrology, endocrinology, and primary care provider and patient communities. Type 2 diabetes mellitus (T2D) is among the most common and consequential of all chronic diseases affecting persons in developed and developing countries. In stark contrast to type 1 diabetes mellitus, wherein excellent glycemic control largely prevents cardiovascular and renal complications, patients with T2D typically experience multiple complications, including accelerated cardiovascular disease, progressive chronic kidney disease (CKD), proliferative retinopathy, and several manifestations of diabetic neuropathy, irrespective of glycemic control. Furthermore, the provision of insulin or oral antidiabetic drugs that augment insulin production fails to prevent these complications. Patients with T2D and CKD experience exceptionally high rates of cardiovascular disease and premature death. Thus, newer approaches to the management of T2D in CKD have the potential to yield major improvements to public health.

The authors of the Scientific Statement focus their attention on evidence supporting the use of sodium glucose co-transporter 2 (SGLT2) inhibitors and the glucagon like peptide receptor-1 agonists (GLP-1 RAs) with emphasis on outcomes in patients with CKD (not on dialysis) with T2D. Both drug classes were developed to better control hyperglycemia, utilizing mechanisms of action distinct from those of insulin or sulfonylurea agents. Ironically, the life-saving potential of these classes of agents might not have been discovered had regulatory agencies not required large randomized clinical trials to demonstrate cardiovascular safety in T2D. In fact, these trials demonstrated substantial cardiovascular benefits that were largely independent of glycemic control. Thereafter, suggestions of kidney benefits in these trials expanded the potential of these drug classes into the realm of delaying CKD progression.

The authors highlight differences across the pivotal SGLT2 inhibitor and GLP-1 RA trials, vis-à-vis trial inclusion criteria for kidney function (described by the estimated glomerular filtration rate (eGFR)) and proteinuria or albuminuria (described by the urine albumin to creatinine ratio (UACR)) and summarize post-hoc trial results stratified by these factors. They highlight the fact that relative effects on death and cardiovascular events were similar among trial participants with and without reduced eGFR or albuminuria; it follows that absolute benefits in patients with CKD would be larger, owing to much higher cardiovascular event rates, and translate into lower numbers needed to treat. Moreover, while the “first round” of trials did not specifically target kidney disease endpoints (e.g., incident CKD or CKD progression in patients with pre-existing CKD), trial results suggested the potential for meaningful benefits.

The CREDENCE (using the SGLT2 inhibitor canagliflozin) and AWARD-7 (using the GLP-1 RA dulaglutide) trials are the two T2D trials published to date that have restricted enrollment to patients with CKD and have demonstrated benefits on kidney disease-related endpoints. In CREDENCE, patients with CKD stages 2 and 3 with albuminuria who were already treated with a maximally tolerated dose of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and randomized to canagliflozin (versus placebo) experienced a 34% reduction in the relative hazard of end-stage kidney disease, doubling of the serum creatinine, or death from kidney disease. In AWARD-7, randomization to dulaglutide (versus insulin glargine) in patients with CKD stages 3 and 4 who were already treated with ACE inhibitors or ARBs experienced a significantly slower rate of decline in eGFR. The DAPA-CKD trial (dapagliflozin versus placebo), conducted in patients with CKD stages 2-4 with and without T2D (eGFR range 25-75 mL/min/1.73m², with restriction to 10% in the proportion of patients with eGFR 60-75 mL/min/1.73m²) was recently terminated following a recommendation by the independent Data Monitoring Committee owing to overwhelming efficacy. The primary composite endpoint in DAPA-CKD was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or renal or cardiovascular death. The ongoing EMPA-KIDNEY (empagliflozin versus placebo) and FLOW (semaglutide versus placebo) trials utilize similar inclusion criteria (eGFR range 25 to 90 mL/min/1.73m²) and primary composite endpoints.

The authors provide physicians, other practice providers, and health system administrators with a roadmap for integrating SGLT2 inhibitors and GLP-1 RAs into clinical practice for patients with T2D and CKD. Relatively low uptake of these agents to date suggest a significant knowledge deficit that can and should be corrected.

Several outstanding questions about these agents remain, including the safety and efficacy of SGLT2 inhibitors and GLP-1 RAs in patients with more advanced CKD (eGFR below 25 mL/min/1.73m²), although clinicians should be reassured knowing that these agents were not discontinued in trial participants who experienced CKD progression (except at the initiation of dialysis or with kidney transplantation) and there was no evidence of heightened risks or an excess of adverse events throughout the trials. Similarly, patients with little or no albuminuria were excluded from the CREDENCE and DAPA-CKD trials; determination of the effects of SGLT2 inhibitors in non-proteinuric CKD would further inform practice. Finally, the completed and ongoing kidney disease-focused trials of SGLT2 inhibitors and GLP-1 RAs were conducted exclusively with patients on maximally tolerated doses of ACE inhibitors or ARBs. While the safety of SGLT2 inhibitors and GLP-1 RAs has been well established in patients with T2D more broadly, many of whom were not treated with inhibitors of the renin-angiotensin-aldosterone system (RAAS), it is unclear whether and to what degree the benefits of SGLT2 inhibitors and GLP-1 RAs depend on co-treatment with RAAS inhibitors.

In summary, the authors of the Scientific Statement have provided an erudite review of the published literature on newer antidiabetic agents in T2D and CKD, a preview of evidence likely to emerge in the coming months and years, and valuable perspectives on next steps in the journey to improve care and reduce the burden of cardiovascular and kidney disease in T2D.