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Commentary: Renal Disease in Type 2 Diabetes, November 2022

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Ronald M. Goldenberg, MD, FRCPC, FACE

Agents proven to reduce major kidney issues in type 2 diabetes include renin-angiotensin system blockers, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid inhibitors, but there are few data on the renal effects of the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. In a post-hoc analysis of the SURPASS-4 trial, Heerspink and colleagues reported that tirzepatide slowed the rate of estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (ACR) compared with insulin glargine U100. There was also a reduction (≥ 40% decline) in the composite kidney outcome of eGFR, end-stage kidney disease (ESKD), death due to kidney failure, and new-onset macroalbuminuria, and this was driven by the reduction in new-onset macroalbuminuria. Although this was a post-hoc, exploratory analysis, the benefit of tirzepatide on kidney effects suggests that this agent should be studied in type 2 diabetes patients at high risk for kidney disease progression to determine whether indeed there will be a kidney protective effect.

Diabetes is the leading cause of ESKD, and recognizing patients at high risk for progression to ESKD is paramount. Abnormal glycolipid metabolism contributes to the development and progression of diabetic kidney disease (DKD). Bile acids, by regulating glycolipid metabolism, may indirectly provide renoprotective effects. Xiao and colleagues have published a retrospective cohort study of 184 Chinese patients with type 2 diabetes and biopsy-proven DKD. They found that low levels of bile acids (≤2.8 mmol/L) were associated with an over fivefold risk for ESKD after adjusting for known factors associated with ESKD. This is the first study suggesting a link between low bile acid levels and adverse kidney outcomes in DKD, and it provides a rationale for studying bile acid analogs as therapeutic agents for the treatment of DKD.

SGLT2 inhibitors and GLP-1 receptor agonists have proven cardiorenal benefits in type 2 diabetes, and each is recommended in guidelines for patients at higher risk for cardiorenal complications. There are no head-to-head randomized trials of SGLT2 inhibitors vs GLP-1 receptor agonists, and studies suggesting an increased risk for lower-extremity amputation with SGLT2 inhibitors have shown inconsistent results. Lee and colleagues conducted a retrospective cohort study in Taiwan, and, after propensity score-matching patients with type 2 diabetes treated with SGLT inhibitors or GLP-1 receptor agonists, they found no significant difference in major adverse limb events between the two groups. Although limited by retrospective design, short follow-up, and a low number of events, this study suggests that SGLT2 inhibitors and GLP-1 receptor agonists should continue to be used as indicated and according to diabetes guidelines, with no difference in amputation rates between these two classes of antihyperglycemic agents.

Gastrointestinal adverse events are the most common side effects related to metformin use. Many clinicians choose an extended-release metformin preparation over immediate-release, believing that there may be better tolerability, but studies have shown inconsistent results. In a systematic review, meta-analysis, and meta-regression of randomized controlled trials, Nabrdalik and colleagues demonstrated an increased risk for abdominal pain, nausea, and diarrhea with metformin compared with other antidiabetic drugs or placebo, as well as a reduced risk for bloating and diarrhea with extended-release metformin compared with immediate-release formulations. These findings reinforce the practice for considering metformin extended-release over immediate-release formulations to reduce the chance of gastrointestinal side effects.

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