Background :
The efficacy and safety of insulin glargine in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) is well established. It provides an effective basal insulin supply with once daily dosing and has a lower propensity to cause hypoglycemia as compared to neutral protamine Hagedorn (NPH) with similar efficacy in glycemic control.  However, there is paucity of data on its usage in subjects with diabetes and chronic kidney disease (CKD) owing to lack of pharmacokinetic-pharmacodynamics studies in patients with varying magnitude of renal insufficiency.

Aim :
To assess the safety and efficacy of insulin glargine in T2DM patients with established CKD (stage 3 and beyond).

Methodology: 
Dual-centered, retrospective, real world observational study from the hospital registry for patients attending the outpatient department of endocrinology and/or nephrology. Participants were screened for eligibility based on eGFR values. Patients with CKD stage 3, 4 or 5 were included in the present study. Patients who were not optimally controlled or experienced frequent hypoglycemia on Oral anti-diabetic drugs (OADs) or NPH insulin received insulin glargine at bedtime. All patients were taking insulin glargine for a period of at least 24 weeks.  Patients not optimally controlled were defined as either having one or more of the following: fasting plasma glucose > 150 mg/dL, post prandial plasma glucose > 200 mg/dL, HbA1c > 8.5% despite patients receiving optimal dose of two or three OADs. All patients’ demographic records with respect to age, gender, height, body weight, body mass index (BMI), blood pressure (BP), and duration of diabetes were collected from author’s clinic database. Blood samples were investigated for glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), post prandial plasma glucose (PPPG), blood urea nitrogen (BUN), serum creatinine (Scr), estimated glomerular filtration rate (eGFR), urine albumin creatinine ratio (UACR), sodium (Na), potassium (K), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C). Subgroup analyses were done to see events of hypoglycemia in different stages of CKD. Data of only those patients were considered for final evaluation having both baseline and post-treatment values of the study parameters. 

Results :
A total of 71 patients (46 male and 25 female) with CKD stage 3 & CKD stage 4 (mean GFR 40.17 ± 9.13 ml/min) were included in the study. The mean age of the patients and the mean duration of disease were 62.3 ± 1.34 and 15.98 ± 0.96 years, respectively. At the end of 24 weeks study period, significant reductions were observed for FPG, PPPG and HbA1c, p<0.001 for all parameters. In addition, a non-significant but modest increase in eGFR levels of 8 mL/min/1.73 m2 (p=0.076) was also demonstrated. A significant mean reduction of 305 mg/g in the urine ACR levels, p=0.006 was also achieved. However no significant changes were observed in BUN, Scr, sodium and potassium levels. No significant changes were noted in any of the anthropometric parameters namely body weight, BMI, SBP, DBP or in the lipid parameters (LDL-C, TG, TC) except HDL-C level, which was found to be significantly decreased at the end of study period. The rate of hypoglycemia (set at <70 mg/dl) was found as 0.19 events per patient year. Asymptomatic hypoglycemia (1.27 events versus 0.20 events per patient year, p<0.001), mild hypoglycemia (0.91 events versus 0.27 events per patient year, p=0.020) and severe hypoglycemia (0.55 events versus 0.10 events per patient year, p=0.013), but not nocturnal hypoglycemia (0.26 events versus 0.14 events per patient year, p=0.236) was found to be higher in stage 4 CKD than stage 3 CKD.

Discussion:
Insulin glargine is effective in achieving good glycemic control without causing any significant weight gain and hypoglycemia. The mean duration of diabetes in present study is 16 years which connotes an insulinopenic state similar to T1DM. Accordingly, rate of hypoglycemia (0.19 events per person year) was similar to that of the landmark DCCT trial in T1DM subjects without renal dysfunction (0.17 events per person year). However, it is much lower than previous reports of hypoglycemia in T2DM patients with CKD (1.29 events per person year). Furthermore, significant reduction in ACR was observed which implies an additional benefit of lowering CVD risk in this subgroup of patients. The renal endpoint was also favorable with a modest increase in eGFR levels post-treatment.

Conclusion:
Insulin glargine improved HbA1c in this short-term study and proved to be safe and well tolerated in patients with type 2 diabetes and diabetic kidney disease (Stage 3 and beyond).

Study of real life safety and efficacy of insulin glargine in T2DM patients with established chronic kidney disease