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Is extreme management of diabetes hurting or helping the kidneys?

Type 2 diabetes occurrence is increasing rapidly worldwide. It has affected about 285 million patients in 2010 and is expected to reach 439 million by 2030. The globalization of the diabetes epidemic, given its micro- and macrovascular problems, imposes enormous economic burden on patients and healthcare systems in both developed and developing economics. Among the diabetic microvascular diseases, chronic kidney disease (CKD) presents unique challenges. Diabetes is the leading cause of end stage renal disease (ESRD). Chronic kidney disease contributes to the development of cardiovascular disease and therefore increases the risk of death and cardiovascular events. Approximately 40 % of patients with type 2 diabetes have higher urinary albumin excretion consistent with underlying renal disease and 17% of patients with diabetes have CKD. Intensive glycemic control may play a vital role to halt or slow down the advancement of diabetic kidney disease. Anti-hyperglycemic agents in these patients are inadequate due to safety and tolerability concerns. Metformin, sulfonylureas and thiazolidione are connected with an increased incidence of hypoglycemia, weight gain and lactic acidosis in patients with type 2 diabetes and CKD. Patients with type 2 diabetes and CKD do not achieve or maintain adequate glycemic control. The use of metformin in CKD patients is controversial, and is even on FDA black box warnings as causing lactic acidosis, which is rare but potentially fatal. A previous study (ADVANCE) proved that intensive glucose control in type 2 diabetes patients drastically decreased the risk of renal outcomes, including new or worsening nephropathy and ESKD.

The purpose of this study was to find out if long-term intensive glycemic control can lead to ESKD. ADVANCE-surviving patients were recruited for ADVANCE–ON, a post-trial study. HbA1c fasting blood glucose, blood pressure, weight, and serum creatinine of patients were assessed at their first post-trial and then annually. The cause of death for patients who died was recorded. Telephone or home visits are offered to patients who cannot do a follow-up. The study outcome was ESKD, stroke, cardiovascular death, myocardial infarction and hypoglycemia. Cumulative incidence survival curves and Cox proportional hazards models were some of the statistical methods used. The patients end points of the date of death, date of last visit, and date of vital status were noted.

Of the 8,494 patients, 4,283 of them did intensive glycemic treatment while 4,211 underwent the standard glucose control. Of these, 5,131 of them completed their visit. The post-trial follow-up of 5.4 years, gliclazide modified release, metformin, insulin, glitazones and glucosidase inhibitors are used in both intensive and standard glucose with an HbA1c of (0.67%, 95% CI 0.64, 0.70 P<0.001) was observed at the end of randomized therapy. 2.9 years later, the post-trial visit had (0.08% 95% CI -0.07, 0.22 P =0.29). There was a rise in HbA1c in the intensive control group versus the standard group. The HbA1c levels of the two groups converged at the post-trial visit (7.3% vs 7.3%, P=0.29). 27 patients recorded ESKD during in-trial events and 37 of the patients died due to renal causes. 55 patients recorded ESKD during post-trial and 64 died due to renal causes. There was a drastic decrease in the risk of ESKD witnessed in intensive glucose control in trial period. (7 vs 20 events, HR 0.35 95%CI 0.15, 0.83 P=0.02). These values persisted after 9.9 years of follow-up (29 vs 53, HR 0.54 95% CI 0.34, 0.85 P< 0.01). Over the 9.9 years, 194 patients needed to be treated with intensive glucose control to prevent one ESKD event. Also, the number needed to be treated by CKD stage was 109 for CKD stages 1 and 2 and 393 for CKD stage 3 or more.

In conclusion, it was clear that intensive glucose control had no effect on overall cardiovascular death, all-cause mortality, myocardial infarction, or stroke. Also, baseline CKD status had no effect on intensive glucose control on these outcomes. However, control continues to protect against the development of ESKD in type 2 diabetes patients, but the patients with most benefit are those with preserved kidney function. The weakness of this study includes the non-adjudicated renal end points and lack of complete biochemical data for all patients during the post-trial follow-up.

Practice Pearls:

CKD is the leading cause of end stage renal disease worldwide and contributes to the development of cardiovascular diseases, thus increasing the risk of death and cardiovascular events.

Intensive glycemic control in type 2 diabetes decreased drastically the primary composite outcome of microvascular events mainly as consequence of a reduction in nephropathy.

Type 2 diabetes patients who benefit the most are those with preserved kidney function. Intermediate effects in in the group were those with CKD stage 1 and 2 and a lesser effects in CKD stage 3 or greater at baseline.

References:

Kuo, Chin-Chi et al. “Prevalence of Metformin Use and the Associated Risk of Metabolic Acidosis in US Diabetic Adults with CKD: A National Cross-Sectional Study.” Ed. Jinxian Xu. Medicine 94.51 (2015): e2175. PMC. Web. 22 June 2016.

Sagara, Masaaki et al. “Impact of Teneligliptin on Oxidative Stress and Endothelial Function in Type 2 Diabetes Patients with Chronic Kidney Disease: A Case–control Study.” Cardiovascular Diabetology 15 (2016): 76. PMC. Web. 22 June 2016.

Perkovic V, Heerspink HL, Chalmers J, et al.: ADVANCE collaborative Group. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney outcomes in patients with type 2 diabetes. Kidney Int 2013; 83:517-523