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How Should We Individualize Management for Patients With Type 2 Diabetes and CKD?

Vivian A. Fonseca, MD, FRCP

Tullis-Tulane Alumni Chair in Diabetes
Professor of Medicine
Chief,
Section of Endocrinology
Tulane University School of Medicine
New Orleans, Louisiana


Vivian Fonseca, MD, FRCP: research support (paid to institution): Fractyl, Jaguar Gene Therapy; constultant/speaker: Abbott, Asahi Astra-Zeneca, Novo Nordisk, Sanofi; stock/stock options: Abbott, Amgen, BRAVO4Health, Mellitus Health; patent: BRAVO Risk Engine for Predicting Diabetes Complications.


View ClinicalThoughts from this Author

Released: September 14, 2022

Key Takeaways

  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors are good choices for patients who have less severe CKD and need improvements in their glycemic control.
  • Finerenone is approved to reduce the risk of sustained estimated GFR decline, end stage kidney disease, cardiovascular death, and prevent hospitalization for heart failure or nonfatal myocardial infarction in adults with CKD associated with type 2 diabetes (T2D). It may be a good choice for patients with more advanced CKD.
  • SGLT2 inhibitors and finerenone have not been studied in combination for CKD and T2D, but are theoretically safe to use together and may provide additive benefits

Individualizing Management With Type 2 Diabetes and Chronic Kidney Disease
As clinicians caring for patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), our primary aim is to prevent CKD progression and cardiovascular (CV) disease events in high-risk patients. The baseline for care should be similar for all patients with T2D: blood pressure control, especially in CKD, and glycemic control are essential to prevent the progression of the other complications of T2D. We should also be monitoring for signs of progression such as a decrease in estimated GFR, worsening proteinuria, and medication side effects such as electrolyte disturbances.

RAAS Blockade
The RAAS blockade remains a key cornerstone of therapy. Many of the clinical trials of the newer agents we now use for treatment of CKD in T2D were done with the background of RAAS blockers including angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) titrated to the maximum tolerated dose. It is important to emphasize that we should not only use RAAS blockade but should titrate to the maximum tolerated dose of the agents if we want to see the same benefits in our patients that were observed in clinical trials. Some clinicians are hesitant to use RAAS blockers as CKD advances, but these agents should be continued as patients with more advanced stages of CKD can tolerate and benefit from further RAAS blockade, except in situations when hyperkalemia is present.

Treatment Options
With the RAAS blockade as our backbone of therapy, we can choose to add the newer agents for CKD treatment, including SGLT2 inhibitors and a novel nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone. Finerenone was approved by the FDA in 2021 to reduce the risk of sustained estimated GFR decline, end stage kidney disease, and CV death, and prevent hospitalization for heart failure (HF) or nonfatal myocardial infarction in adults with CKD associated with T2D. The choice of using finerenone vs an SGLT2 inhibitor and whether to use them in combination depends on the condition of the patient, including the stage of their CKD and other risk factors such as glycemic control.

If glycemic control can be improved, using an SGLT2 inhibitor early to improve glycemic control and slow the progression of CKD would be a good choice. However, as the GFR falls and the CKD gets more advanced, the beneficial effect of SGLT2 inhibitors on glucose lowering declines. Consequently, the SGLT2 inhibitors are not effective for glycemic control if the GFR drops below 30-45 mL/min/1.73 m2. But they can be used to slow the progression of CKD or HF. The SGLT2 inhibitors can also prevent hospitalization for patients with HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). The use of SGLT2 inhibitors with lower GFR values has been less well studied in clinical trials, but we do have some data on patients with lower eGFR values from the recent EMPA‑KIDNEY trial results.

For many years, patients with more advanced CKD and eGFRs well below 30 mL/min/1.73 m2 were using MRAs, such as spironolactone. A concern for these patients is the risk of hyperkalemia conferred by use of MRAs, which increases as the disease progresses and can lead to further complications, including cardiac arrhythmias, etc. The new MRA, finerenone, is less likely to cause hyperkalemia than spironolactone, but monitoring patients is still necessary.

The approval of finerenone was primarily supported by 2 extensive and complementary phase III outcome trials studying finerenone as an add-on to background ACE inhibitor or ARB therapy in patients with T2D and CKD. The FIDELIO-DKD trial study showed finerenone can reduce CKD progression without causing significant hyperkalemia.

The FIGARO-DKD trial also showed the cardiac advantages of MRAs; specifically, CV events were reduced, including hospitalization for HF. When given a choice between finerenone and an SGLT2 inhibitor, an SGLT2 inhibitor is recommended for patients who need improved glycemic control and have less advanced CKD. For those with more advanced CKD, finerenone and SGLT2 inhibitors are probably equally beneficial.

Combination Therapy
There are not sufficient studies on SGLT2 inhibitors used in combination with MRAs. However, there is no evidence to suggest that using these drugs in combination is irrational, as SGLT2 inhibitors have been used in combination with spironolactone for many years. There are small studies of combination therapy with empagliflozin and finerenone that have been presented but no results from large clinical trials, though there are trials that are ongoing.

Advanced Disease
For patients with advanced CKD as well as coronary artery disease and HF, more advanced treatment is essential with 3-4 drugs that make up the pillars of therapy, including SGLT2 inhibitors, a beta blocker, a neprilysin inhibitor, and an MRA. The order the therapies are used likely depends on the severity of the disease and predominant feature including CKD or HF.  These 4 pillars of therapy are widely accepted in clinical practice for patients with advanced diseases. There are also ongoing trials looking at the benefits of glucagon-like peptide‑1 receptor agonists for use in these patients. We know that they are beneficial for patients with ASCVD, but whether they will have significant benefits in CKD and HF remains to be seen.

Conclusion
In conclusion, there is a large body of literature to support a new framework for CKD management as the disease advances, and we now have multiple options for treatment. The decision on whether to add an SGLT2 inhibitor or MRA to RAAS blockade or to use the agents in combination depends on individual patient factors including comorbidities and severity of CKD.

Your Thoughts?
What are your thoughts and questions on managing your patients With Type 2 Diabetes and CKD? Please answer the polling question and join the conversation by posting a comment in the discussion section below.

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This activity is supported by independent educational grants from
Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company
Bayer HealthCare Pharmaceuticals Inc.

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