The Kidney as a Treatment Target for Type 2 Diabetes

Address correspondence to Betsy Dokken, NP, PhD, CDE, University of Arizona Department of Medicine, 1656 East Mabel St., Room 412, Tucson, AZ 85724-5218. The Kidney as a Treatment Target for Type 2 Diabetes Betsy Dokken, NP, PhD, CDE Worldwide, more than 220 million people have diabetes.1 In the United States, diabetes is present in 8.3% of the population.2 Type 2 diabetes accounts for 90–95% of all diagnosed cases of adult diabetes.2 The prevalence of type 2 diabetes is projected to increase further, in parallel with obesity,3 a major risk factor for its development.4 Hyperglycemia is the hallmark of diabetes and a key determinant of microvascular complications (e.g., retinopathy, neuropathy, and nephropathy).5 Type 2 diabetes is a major risk factor for the development of cardiovascular disease6 and chronic kidney disease.7 It is also the primary cause of end-stage renal disease, requiring either chronic dialysis or renal transplantation,8 and new cases of blindness among U.S. adults aged 20–74 years.3 Randomized, controlled clinical trials from the 1990s, including the Diabetes Control and Complications Trial (DCCT)9 and the U.K. Prospective Diabetes Study (UKPDS),10,11 found that intensive glycemic control (achieved A1C of ~ 7%) compared to conventional therapy (A1C of ~ 8–9%) can reduce the risk of microvascular complications in patients with type 1 diabetes and in patients with newly diagnosed type 2 diabetes. However, whether intensive glycemic control reduces cardiovascular events is less certain.12 Long-term monitoring of patients from the DCCT13 and UKPDS14 trials found significant reductions in cardiovascular events in patients originally randomized to receive intensive therapy compared to patients who received standard therapy. Type 2 diabetes is a complex and progressive disease that affects 8.3% of the U.S. population. Despite the availability of numerous treatment options for type 2 diabetes, the proportion of patients achieving glycemic goals is unacceptably low; therefore, new pharmacotherapies are needed to promote glycemic control in these patients. The kidney normally reabsorbs 99% of filtered glucose and returns it to the circulation. Glucose reabsorption by the kidney is mediated by sodium-glucose co-transporters (SGLTs), mainly SGLT2. SGLT2 inhibition presents an additional option to promote glycemic control in patients with type 2 diabetes. A number of SGLT2 inhibitors have been synthesized and are in various stages of clinical development for the treatment of type 2 diabetes. Results from clinical trials show that these compounds decrease plasma glucose and body weight in treatment-naive patients and in patients receiving metformin or insulin and insulin sensitizers. Overall, SGLT2 inhibitors appear to be generally well tolerated, but in some studies, signs, symptoms, and other reports of genital and urinary tract infections have been more frequent in drug-treated groups than in placebo groups. Additional clinical trials will determine whether this class of compounds with a unique, insulinindependent mechanism of action becomes a treatment option for reducing hyperglycemia in type 2 diabetes.