Do glucose-lowering medications have different effects on kidney outcomes?

In a recent study published in the JAMA Internal Medicine Journal, researchers evaluated the kidney outcomes in individuals with type 2 diabetes by comparing four classes of medications added to metformin to lower glucose levels.

Study: Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 DiabetesThe GRADE Randomized Clinical Trial. Image Credit: AhmetMisirligul/Shutterstock.comStudy: Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 DiabetesThe GRADE Randomized Clinical Trial. Image Credit: AhmetMisirligul/


The leading cause of kidney failure and chronic kidney disease across the world is diabetes and the timely address of glycemic levels is essential to delay or prevent diabetic kidney disease.

Clinical trials involving patients with type 1 and 2 diabetes have shown that intensive glycemic control decreases the risk of albuminuria and kidney failure and prevents the estimated glomerular filtration rate (eGFR) from decreasing.

Several classes of drugs have exhibited kidney benefits not related to the glycemic effects in type 2 diabetes cases recently.

Drugs belonging to dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagonlike peptide-1 (GLP-1) receptor agonists have been seen to be effective in reducing albuminuria in patients with diabetic kidney disease while both SGLT2 and GLP-1 inhibitors have improved the eGFR over time.

However, whether treatment with glucose-lowering medications that are non-SGLT2 inhibitors is directly beneficial to type 2 diabetes patients without diabetic kidney disease remains unclear.

About the study

In the present study, the researchers evaluated the detailed kidney outcomes after the administration of the interventions included in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study.

The four classes of medications added to metformin and commonly used to lower glucose levels include sitagliptin, which is a DPP-4 inhibitor; liraglutide, GLP-1 receptor agonist; the sulfonylurea glimepiride; and glargine, the basal insulin.

The trial included participants who had been diagnosed with type 2 diabetes at the age of 30 years or above, had diabetes for less than 10 years and a hemoglobin A1c (HbA1c) of 6.8–8.5%, and were being treated with metformin.

Individuals with recent cardiovascular events and heart failure were not included in the study. Furthermore, men and women with creatinine levels above 1.5 mg/dL and 1.4 mg/dL, respectively, were excluded from the study, but subsequently, the threshold parameter of creatinine levels was replaced by eGFR.

Participants were assigned randomly to interventions consisting of sitagliptin, liraglutide, glimepiride, and glargine along with metformin. Glycemic control was initially monitored through HbA1c values and later through basal and prandial levels of insulin.

The measured outcomes included body weight, seated blood pressure, and albumin and creatinine assays to determine kidney function. The change in eGFR between year one and the follow-up was one of the primary measured outcomes, as the eGFR slope is a proxy for the progression of kidney disease among populations with low risk.

The second primary outcome was the increase in albuminuria, which is an indicator of kidney disease progression, leading to dialysis, transplant, or death.


The findings indicated that the four classes of glucose-lowering medications — DPP-4 inhibitor, GLP-1 receptor, sulfonylurea, and basal insulin — along with metformin did not seem to make any significant difference to kidney function over the five-year follow-up.

The eGFR slope or the progression of albuminuria did not exhibit any change during the follow-up period.

The cumulative incidence of composite outcomes of kidney disease progression, largely represented by the progression of albuminuria was 11.5% at the end of the five-year follow-up.

However, this figure was lower than the five-year incidence of diabetic kidney disease observed in a prospective cohort consisting of patients with newly diagnosed diabetes in the United Kingdom, which reported increased albuminuria of 17.3%.

Subgroup analyses examining the heterogeneity based on factors such as ethnicity, sex, age, body mass index, HbA1c levels, and hypertension also reported null results.

Although the results were not statistically significant, the protocol sensitivity analyses reported more favorable hazard ratios for liraglutide and sitagliptin, and additional time might bring about benefits.

As seen in the case of type 1 diabetes, intensive management of glucose levels might result in changes in kidney parameters.


To summarize, the researchers investigated whether the addition of glucose management drugs with metformin for intensive glycemic management in the early stages of type 2 diabetes brings about improvements in kidney outcomes.

Overall, the results reported that none of the four classes of glycemic management medications exhibited an advantage in preventing the progression of diabetic kidney disease among type 2 diabetes patients.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.


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