Drug combinations may help slow the progression of diabetic kidney disease

A mouse study conducted by Washington University School of Medicine in St. Louis suggests that combining SGLT2 inhibitors – a new class of diabetes drugs that lower blood sugar – with older diabetes drugs may help slow the progression of diabetic kidney disease. Commonly prescribed SGLT2 inhibitors include dapagliflozin (Farxiga), empagliflozin (Jardiance), and canagliflozin (Invokana).

Diabetes is the main driver of kidney disease, a life-threatening disease that affects 37 million Americans, many of whom are unaware that their kidneys are diseased. There is no cure, and current treatments for end-stage disease are mostly limited to dialysis and kidney transplantation.

In search of improved drug therapies to protect the kidneys of patients with diabetes, a mouse study conducted by Washington University School of Medicine in St. Louis suggests that the combination of SGLT2 inhibitors – a new class of diabetes drugs that lower blood sugar – along with older diabetes drugs may help slow the progression of diabetic kidney disease.

Commonly prescribed SGLT2 inhibitors include dapagliflozin (Farxiga), empagliflozin (Jardiance), and canagliflozin (Invokana). The latter is manufactured by Janssen Pharmaceuticals, whose scientists collaborated in this study.

SGLT2 inhibitors have had remarkably positive effects on diabetic kidney disease, the best effects we’ve seen in decades, but scientists haven’t understood precisely how and why these drugs work so well. By studying mice, we found that these drugs may be even more effective at protecting the kidneys when combined with other diabetes drugs, and with this approach we should be able to achieve better results. in patients because the drugs act synergistically on the kidneys. , at least at the cellular level.”


Benjamin D. Humphreys, MD, PhD, Senior Author, Director, Division of Nephrology, University of Washington

The results are published June 15 in Cell Metabolism.

Diabetic nephropathy occurs in about 40% of patients with type 2 diabetes, leading to kidney failure, cardiovascular disease and premature death. Blacks, Native Americans, and Hispanics develop diabetes, kidney disease, and kidney failure at higher rates than Caucasians.

Diabetes damages the kidneys by preventing the organs from efficiently filtering waste and excess fluid from the body. Because symptoms such as nausea, vomiting, trouble sleeping, and swollen limbs are common and not specific to kidney disease, most people don’t realize they have it until irreparable organ damage sets in. produce.

SGLT2 inhibitors – officially known as sodium-glucose-2 cotransporter inhibitors – induce the kidneys to remove excess sugar from the blood, and this sugar is eliminated from the body through the urine. “Additionally, this class of drugs is also highly protective against heart disease,” said Humphreys, who is also the Joseph Friedman Professor of Kidney Disease in Medicine.

Most patients with type 2 diabetes are only prescribed one drug, but study results suggest that combination therapies may be more effective because different drug classes target different cell types in the kidney. .

Studying mice that had developed diabetic kidney disease, the researchers analyzed how mouse kidneys respond to five diabetes treatment regimens prescribed to patients. The team examined the responses using single-cell RNA sequencing, which allowed them to identify changes in the kidneys at the cellular and molecular level to the different treatments. Understanding these interworkings can help researchers target specific cells to improve drug therapies.

They studied the effects of individual drug classes and drug combinations, focusing on three drug classes: SGLT2 inhibitors; angiotensin converting enzyme inhibitors (ACE inhibitors), such as Lisinopril; and thiazolidinediones (TZDs, also known as insulin sensitizers). Rosiglitazone is a common TZD.

“We designed our study to try to understand how combination therapies affect the kidney differently than single therapies,” said study first author Haojia Wu, PhD, assistant professor in the Division of Nephrology. “We found that each of the different drug classes targeted different cell types, providing cellular rationale for combination therapies to better slow the progression of diabetic kidney disease.”

The study found that the combination of SGLT2 inhibitors with lisinopril had better protective effects on the kidney than either treatment alone.

The researchers also noted that SGLT2 inhibitors seemed to prompt the kidney to activate a starvation response, similar to how the body slows down its metabolism when fasting for prolonged periods. “This may reduce overall energy consumption in the kidney, allowing it to function more efficiently and placing less of a long-term load on it, possibly explaining why this class of drugs is so effective,” Humphreys said.

“We live in very exciting times for diabetic nephropathy treatments,” he added. “Our study adds to growing evidence that combination therapies provide strong patient benefits. We believe that such approaches should be adopted in routine clinical practice.”

Humphreys said future observational studies in people taking combination therapies should provide further evidence.

Source:

Journal reference:

Wu, H. et al. (2022) Single-cell transcriptomic response mapping of murine diabetic kidney disease in therapies. Cellular metabolism. doi.org/10.1016/j.cmet.2022.05.010.

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