Second-Line Agents for the Treatment of Type 2 Diabetes and Prevention of CKD

• diabetic nephropathy
• Diabetes Mellitus
• Type 2
• Kidney Failure
• Chronic
• Renal Insufficiency
• Chronic

CKD is a common complication of diabetes mellitus and a major public health threat (1,2). Of the 422 million people worldwide who are living with diabetes, most have type 2 diabetes (1), and approximately one third of these patients will develop CKD (3). Patients with type 2 diabetes and comorbid CKD have a 10-year mortality rate of approximately 30%, which is higher than expected on the basis of the excess mortality of each individual condition added together (4). Diabetes is the leading cause of ESRD in the United States and responsible for approximately 45% of incident patients (2). One of the cornerstones for the prevention of CKD and its progression to ESRD in patients with diabetes is tight glycemic control (5,6), with the goal of achieving a hemoglobin A1c target of around 7.0% (6). Clinical practice guidelines recommend that, if lifestyle modifications are not sufficient in achieving glycemic control, metformin should be the initial pharmacologic treatment for most patients with type 2 diabetes (7). Metformin suppresses hepatic gluconeogenesis (8) and is generally well tolerated with low risk for hypoglycemia. However, most patients will eventually need more than one medication to maintain blood glucose control (9), but the optimal regimen for intensifying treatment for these patients is not known.

For patients with type 2 diabetes that is not controlled with metformin, two common treatment modifications are the addition of either a sulfonylurea or insulin (10). Patients are generally reluctant to start insulin due to concerns regarding injections, hypoglycemia, and weight gain (11). However, insulin may have a greater potential to lower hemoglobin A1c compared with other second–line agents, and there remains interest in early intensive insulin therapy as a means to preserve β-cell function (12). The American Diabetes Association (ADA) recommends that insulin should not be delayed in patients with type 2 diabetes who are not meeting their glycemic targets (7). In the last 10–20 years, there has been a trend toward increased insulin prescribing (13) and health care expenditures for insulin (14). However, in a national cohort of veterans with type 2 diabetes, the addition of insulin to metformin was associated with 30% increased risk of acute myocardial infarction, stroke, or death compared with the addition of a sulfonylurea to metformin (15). Although this association requires confirmation, it raises questions regarding the safety of insulin and its effects on other complications associated with diabetes, such as CKD progression, which was not addressed.

In this issue of the Clinical Journal of the American Society of Nephrology, Hung et al. (16) report their findings from a retrospective cohort study of metformin intensification with insulin versus sulfonylureas on CKD progression in a national cohort of veterans with type 2 diabetes. This study leveraged administrative and clinical data from the Veterans Health Administration (VHA), Medicare claims (including Part D), and information on date of death from the National Death index. Patients at the VHA who had no prior history of diabetes treatment and were prescribed metformin for the first time between October of 2001 and September of 2008 were identified as likely to have type 2 diabetes. From this cohort of new metformin users, patients were eligible for this study if they intensified diabetes treatment by adding either a sulfonylurea or insulin to their regimen. Patients were not eligible for this study if they did not have a baseline creatinine, intensified treatment with another class of medications, stopped taking or were not adherent to metformin, or enrolled in hospice care.

This study used propensity score matching for the probability of metformin treatment intensification with insulin to create the final study cohort. Propensity score matching is a statistical technique used in observational studies to balance multiple covariates in an effort to reduce confounding (17). Patients who intensified metformin treatment with insulin were propensity score matched in a 1:4 ratio with patients who intensified metformin treatment with sulfonylureas. The primary outcome was CKD progression defined as either a persistent decline in eGFR by at least 35% from baseline or the development of ESRD. The secondary outcome was a composite of CKD progression and death. Patients were censored for loss of follow-up at the VHA, nonpersistence with metformin, or the prescription of a third class of diabetes medication. Marginal structural models with time-varying covariates were used to estimate the risk of CKD progression and mortality.

Of the 178,341 new metformin users identified during the study period, 72,868 (40.9%) of the patients intensified diabetes therapy, of which 36,405 (50.0%) did so with one of the study regimens. The majority (93.4%) of the eligible patients for this study intensified metformin treatment with the addition of a sulfonylurea, and only 6.6% did so with the addition of insulin. The final matched study cohort consisted of 1989 patients in the metformin and insulin group and 7956 patients in the metformin and sulfonylurea group. Baseline characteristics were well matched between groups. Patients were predominantly men (94%) and white (71%) with median age of 60 years old, baseline creatinine of 1.0 mg/dl, and hemoglobin A1c of 8.1%. Median follow-up time was 1.1 years. There were a total of 426 CKD progression events, most of which were due to eGFR decline (only five patients developed ESRD). There was no difference in the number of patients with CKD progression between groups (31 versus 26 events per 1000 person-years for metformin and insulin versus metformin and sulfonylurea, respectively; adjusted hazard ratio for metformin and insulin, 1.27; 95% confidence interval, 0.99 to 1.63). When considering the composite outcome of CKD progression or death, there were 814 total events (388 deaths). The event rate for CKD progression or death was significantly higher in the metformin and insulin group compared with the metformin and sulfonylurea group (64 versus 49 events per 1000 person-years, respectively; adjusted hazard ratio, 1.33; 95% confidence interval, 1.11 to 1.59).

There are several strengths to this study. Because of the propensity score matching, the two study groups were well balanced in their baseline characteristics. The study findings were robust in several sensitivity analyses, including the intention to treat analysis, in which patients were analyzed on the basis of their initial treatment intensification regimen without regard to subsequent treatment changes. Results were consistent across subgroup analyses by age, race, glycemic control, proteinuria, and baseline eGFR. However, there are several important weaknesses to consider. As the authors acknowledge, residual confounding, exposure misclassification, and generalizability to other populations are concerns. Propensity score matching can only account for observed covariates and cannot address unmeasured confounders, such as duration of diabetes, severity of insulin resistance, physical activity, or depression (18). There were very few ESRD events, and the average follow-up time was relatively short. Effect modification by the type of insulin—long acting, short acting, or premixed—was not examined. Finally, this study only compared metformin intensification with sulfonylureas versus insulin, which represents only two of six classes recommended as second-line agents for diabetes (7). Therefore, the optimal secondary medication after metformin remains to be clarified.

Other than sulfonylureas and insulin, other recommended second–line treatments for diabetes include thiazolidinediones, glucagon–like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide), dipeptidyl peptidase-4 inhibitors (e.g., sitagliptin), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (e.g., empagliflozin). GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are incretin-based therapies, which enhance insulin secretion and suppress glucagon release. In animal models, they can reduce albuminuria, mesangial expansion, and glomerulosclerosis (19). SGLT2 inhibitors decrease renal reabsorption of glucose and reduce intraglomerular pressures and hyperfiltration (20). Overall, each of these second-line agents has comparable effects on glycemic control, with an anticipated reduction in hemoglobin A1c by approximately 1.0%, and current ADA guidelines recommend choosing an agent on the basis of its side effect profile and individual patient preferences (7).

Among these second-line agents for diabetes, there has been recent excitement regarding GLP-1 receptor agonists and SGLT2 inhibitors, which have been shown to reduce cardiovascular events in patients with diabetes and high cardiovascular risk (21,22). Furthermore, both of these medication classes are unique in that they lower BP (23,24), promote weight loss, and seem to be renoprotective (25). In randomized, controlled trials of patients with type 2 diabetes and high cardiovascular risk, liraglutide and empagliflozin were each associated with a reduced risk of nephropathy compared with placebo (21,25). Of note, in each of these trials, over 80% of patients were already on either an angiotensin–converting enzyme inhibitor or an angiotensin II receptor antagonist. The finding that liraglutide or empagliflozin can offer additional renoprotection to traditional renin-angiotensin system blockers is an exciting development that has the potential to change current clinical practices. Additional research is needed to find out if the beneficial cardiovascular and kidney effects are reproducible and specific to the drugs studied (liraglutide and empagliflozin) or represent class effects. In addition, it remains to be determined how each of these second-line agents compares with each other with respect to delaying CKD progression.

Clinicians now have many therapeutic options for patients with type 2 diabetes and initial metformin treatment failure. The study by Hung et al. (16) provides much needed information regarding the comparative effectiveness of two common second–line treatment options but is really just the first step in understanding the implications of different medication choices on renal outcomes.

• Copyright © 2016 by the American Society of Nephrology