Background

Accumulating evidence suggests that the modulation of incretin signaling is beneficial in both glycemic control, as well as nephroprotection. Metformin has been reported to inhibit DPP-4 and increase GLP-1-receptors  expression. Thereby, DPP-4 inhibitor vildagliptin in combination with metformin could additively improve glycemic control and metabolic status in type 2 diabetes (DM 2) with attractive therapeutic option in regard to diabetic nephropathy (DN). 
Aim

A randomized comparative clinical study assessed the effect of the combination of vildagliptin in daily dose 50 mg and metformin in daily dose 1500 mg added-on insulin therapy on renal function in type 2 diabetic patients.
Method

We investigated the dynamics of metabolic parameters, estimated GFR using creatinine (eGFRcr) and cystatin C (eGFRcys), urinary albumin-to-creatinine ratio (UACR) in first morning urine sample, and excretion of liver-type fatty acid binding protein (L-FABP) in 43 insulin-treated near-compensated patients with normal/mildly impaired renal function (CKD C1-2,A 1-2) randomizing in 1:1 ratio  either to continue insulin therapy (IG group, n=21), or to receive 6-month combined vildagliptin and metformin treatment added to insulin (VMIG group, n=22). Main non-inclusion criteria were contraindications   to metformin or vildagliptin treatment, severe micro- and macrovascular complications of DM 2, non-diabetic renal disease, nephrotoxic drugs usage, uncontrolled hypertension and dyslipidemia, inflammatory and oncological conditions, hepatic impairment or ALT/AST elevation beyond x2 upper normal limit, pregnancy and lactation. Safety and participants’ adherence were provided by consulting visits and telephone interaction at least once a month. All patient received the recommendations not to change water, meat, and protein intake, and to avoid strenuous physical exercise 3 days prior to the analyses collecting. The primary aim was a significant improvement in UACR and GFR using the CKD-EPI equation. Secondly, the effect on urinary L-FABP-to-creatinine ratio was assessed. Thirdly, the effect of metformin and vildagliptin combination addition on such risk factors of renal dysfunction progression as fasting and postprandial glycemia, HbA1c, systolic and diastolic BP, BMI, serum cholesterol and triglycerides, and  the value of insulin resistance were evaluated.    
Results

The mean age of patients in IG group was 60.1 ± 6.13 years, in VMIG group - 63.7 ± 4.21 years, р=0.032, and majority were women (about 60 %). Duration of DM type 2 was approximately 10 years. Albuminuric stage of DN was present in 42.9 % of participants in IG group and in 54.6% in VMIG group ,p=0.048. eGFR, UACR level, and main assessed parameters were comparable in both groups. After 6 months, there were no significant changes in main assessed parameters in IG group. VMIG group showed significant decrease in HbA1c (-5.5 %, from 7.2 ± 0.5% до 6.8 ± 0.7 %, p=0.0003), fasting plasma glucose (-12.9 %, from 6.9 ± 1.5 to 6.0 ± 1.22 mmol/l, p=0.014), and blood triglycerides (-21.4 %, from 2.2 ± 1.4 to 1.76±0.75 mmol/l, p=0.016) compared to IG group. Whiles eGFRcr and eGFRcys in VMIG group did not significantly change (eGFRcr +1.2 % from 76.4 ± 13.1 ml/min/1.73 m2), UACR and urinary L-FABP decreased significantly (-11.8 % (from 33.7 [17.5;84.0] to 27.4 [16.5;63.9] mg/g, p=0.019) and -7.3% (p=0.028), respectively. Multivariate regression analysis revealed glucose- and metabolic-independent pattern of UACR changes. However, the dynamic of L-FABP in VMIG was correlated with the dynamic of fasting blood glucose (r = - 0.58, р=0.004) and triglycerides (r=0.66, р=0.001).
Discussion

The study showed that 6-month combined vildagliptin and metformin treatment added on insulin therapy in near-compensated type 2 diabetic patients demonstrated nephroprotection regarding albuminuria and urinary excretion of tubular injury marker L-FABP. Moreover, UACR beyond decrease in UACR was unrelated to normalization of DM2 compensation parameters.  Concomitant treatment with  the DPP4 inhibitor vildagliptin and metformin may offer an attractive glycemic reduction and metabolic status improvement  with synergistic action while exerting additional nephroprotective benefits.

Prospects of nephroprotection in type 2 diabetic patients using the combination of vildagliptin and metformin