New Innovative Treatments Are On The Horizon for Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of mortality for patients with type 2 diabetes (T2D), with almost half of those with renal failure having DKD and most having T2D, according to Melissa Leroux, BS, from the University of Colorado Anschutz Medical Campus.

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In a session at the American Diabetes Association 84th Scientific Sessions, Michael Christensen, PhD; Krishna Adeshara, PhD; and Emily Kobayashi, BS, discussed various innovative approaches in diabetes-induced kidney disease.

Leroux said that pediatric patients who are in kidney failure have a lower life expectancy than adults with the same diagnosis. Youth onset has a more aggressive phenotype than adults, resulting in worse glycemic control and insulin resistance with a higher risk of progressive DKD.

In 2016, the Renal HEIR Study (NCT03584217) was conducted. Results of the study showed that adolescents with diabetes exhibited relative glycemia hyperoxia when compared to healthy controls. In 2020, a follow-up study (Renal HEIRitage) was conducted, in which patients underwent computed tomography scans followed by positron emission tomography scans. There were 11 healthy controls and 30 patients with T2D and obesity enrolled in the study.

The results showed that cortical perfusion decreased in the T2D and obesity group, and cortical oxidation rate increased. Furthermore, there was a positive correlation with cortical oxidative rate and higher urine albumin-creatinine ratio (UACR), according to Leroux.

“In addition to seeing the reduced cortical oxidative rate, we also saw improved insulin sensitivity,” Leroux said. “[It] is super important when you consider that adolescents with [T2D] have higher insulin resistance.”

In another study covered by Christensen, investigators used mouse models to compare monotherapy semaglutide with semaglutide in combination with lisinopril for obesity and hyperglycemia.

In the mouse models, investigators found that semaglutide improved obesity and hyperglycemia both as a monotherapy and with lisinopril combination therapy, with the combination having less significant reductions. Further, semaglutide monotherapy reduced blood glucose, hemoglobin A1c, and diastolic and systolic blood pressure. For blood pressure, even further reductions were found with the combination therapy.

For urinary biomarkers, there were reductions in UACR and even greater reductions when lisinopril was added to the therapy. There were also reduced KIM-1/creatinine ratios for both the monotherapy and combination, but even further reduction with the monotherapy. Lastly, monotherapy and combination reduced glomerulosclerosis, but greater reductions were seen with the combination.

Adeshara discussed glyoxalase I (GLO1), which is a key enzyme in the glyoxalase system that plays a role in protecting cells from toxic byproducts of glycolysis. The study she presented aimed to show a potential link between GLO1 expression and DKD in type 1 diabetes (T1D).

“There are studies showing that individuals with [T1D] have reduced glyoxalase I enzymatic activity in the blood, [and] they found that there was a reduced expression of glyoxalase I in those individuals with [T1D] and chronic disease,” Adeshara said.

The investigators found that there was no causal association between GlO1 expression in kidney specific-tissues or in whole blood and phenotypes of DKD. Further, higher GLO1 protein expression in the blood was associated with chronic kidney disease (CKD), CKD with presence of DKD, and CKD with estimated glomerular filtration rate (eGFR) of less than 15. Additionally, there was higher glyoxalase I expression, particularly in skin and salivary glands, which was associated with the reduced risk of CKD.

Adeshara said that the study supports causality between GLO1 expression and CKD, particularly for the skin and salivary glands, suggesting that GLO1 expression could be involved in altered DKD susceptibility for individuals with T1D.

In the final part of the presentation, Kobayashi presented a study which identified data-driven subgroups of adults at risk for T2D in relation with metabolic trajectories over time with clinical outcomes.

The investigators found that there were 8 metabolic trajectory clusters that were driven by distinct clinical phenotypes, including UACR and insulin. There were also no differences in the 8 clusters in sex, race, or treatment. The phenotypes examined included fasting glucose, fasting insulin, total cholesterol, systolic blood pressure, diastolic blood pressure, waist circumference, A1c, high-density lipoprotein, low-density lipoprotein, eGFR, UACR, and body mass index.

The first 2 groups were considered healthy but had low insulin levels, according to Kobayashi. Then there were 3 insulin groups and 3 groups with high weights for eGFR or urine elements, or both. The clusters showed various data, with some showing lowering fasting and others with UACR elements; however, Kobayashi said the most interesting group had neither increased insulin nor UACR.

“Renal dysfunction biomarkers of fasting insulin and urine outlook differ between clusters and did not necessarily correlate with eGFR instance rates,” Kobayashi said.

There is a need for new biomarkers to distinguish the clusters, which included individuals who were at high risk but did not present with insulin and UACR biomarkers. Kobayashi emphasized that there should be a focus on this patient population.

Reference

LerouxM, Christensen M, Adeshara K, Kobayashi E. Oral Presentations - Metabolic Pathways to Protection—Innovative Approaches in Diabetes-Induced Kidney Disease. Presented At: ADA 84th Scientific Sessions; June 21-June 24, 2024; Orlando, Florida.