Effect of dipeptidyl-peptidase IV inhibitors on glycemic variability in patients with type 2 diabetes : a systematic review of clinical trials and meta-analysis

다국어 초록 (Multilingual Abstract)

Background and Aim: Glycemic variability (GV) can induce oxidative stress and interfere with the endothelial function, which can cause the development of diabetic complications. Recently, management of GV is emerging as the one of the targets to prevent the diabetic complications in diabetic patients and dipeptidyl-peptidase IV (DPP-IV) inhibitors have been expected to have favorable effect on reduction of GV in type 2 diabetic patients. However, no previous studies have systematically evaluated the effect of DPP-IV inhibitors on GV. To evaluate the effect of DPP-IV inhibitors on GV compared with other oral anti-hyperglycemic drugs, we performed a systematic review and meta-analysis of currently available randomized controlled trials (RCTs) that assessed the effect of DPP-IV inhibitors on mean amplitude of glycemic excursions (MAGE) using a continuous glucose monitoring system (CGMS) in patients with type 2 diabetes.
Methods and Results: From inception to March 2018, relevant 102 articles were retrieved and 7 RCTs met the inclusion/exclusion criteria. DPP-IV inhibitors showed a significant reduction of MAGE in comparison with other oral anti-hyperglycemic drugs (-14.35mg/dL; 95% confidence interval (CI): -20.84, -7.86; p<0.0001). But, DPP-IV inhibitors did not significantly reduce HbA1c compared with other oral anti-hyperglycemic drugs (-0.06%; 95% CI: -0.26, 0.15; p=0.59).

Conclusions: This systematic review and meta-analysis found that DPP-IV inhibitors significantly reduced GV compared with other oral anti-hyperglycemic drugs in type 2 diabetic patients while exhibiting similar blood glucose-lowering effect. However, further studies utilizing a larger number of patients and a long-term follow-up duration are needed to investigate the effect of DPP-IV inhibitors on GV and diabetic complications.

국문 초록 (Abstract)

연구 배경 및 목적: 혈당 변동성(Glycemic variability, GV)은 산화 스트레스를 유발하고 내피세포 기능을 방해하여 당뇨병성 합병증을 야기할 수 있다. 최근 혈당 변동성을 조절하는 것은 당뇨병 환자에서 당뇨병성 합병증을 예방하기 위한 치료 목표 중 하나로 떠오르고 있고, 제 2 형 당뇨병 환자에서 DPP-IV(Dipeptidyl-peptidase IV) 억제제는 혈당 변동성 감소에 긍정적인 효과를 줄 것으로 기대되고 있다. 그러나, 지금까지 혈당 변동성에 대한 DPP-IV 억제제의 효과를 체계적으로 평가한 연구는 없었다. 다른 경구용 혈당 강하제와 비교하여 혈당 변동성에 대한 DPP-IV 억제제의 효과를 평가하고자, 제 2 형 당뇨병 환자에서 연속 혈당 모니터링 시스템(Continuous glucose monitoring system, CGMS)을 사용하여 DPP-IV 억제제의 혈당 변동폭(Mean amplitude of glycemic excursions, MAGE) 효과를 평가한 무작위 대조 연구들(Randomized controlled trials, RCTs)에 대해 체계적인 문헌 고찰과 메타 분석을 수행하였다.

연구방법 및 결과: 총 102개의 연구 중에서 7개의 연구가 포함되었다. 다른 경구용 혈당 강하제군에 비해 DPP-IV 억제제군에서 MAGE가 유의하게 감소한 것으로 나타났다 (MAGE: -14.35mg/dL, 95% 신뢰구간: -20.84, -7.86; p<0.0001). 반면 DPP-IV 억제제군과 다른 경구용 혈당 강하제군의 혈당 강하 효과에 대한 유의한 차이는 없었다 (Glycated hemoglobin(HbA1c): -0.06%; 95% 신뢰구간: -0.26, 0.15; p=0.59).

결론: 본 연구를 통해, DPP-IV 억제제가 제 2형 당뇨병 환자에서 다른 경구용 혈당 강하제와 유사한 혈당 강하 효과를 나타내면서, 혈당 변동성을 유의하게 개선시키는 것을 확인하였다. 그러나, 혈당 변동성 및 당뇨병성 합병증에 대한 DPP-IV 억제제의 효과를 조사하는 대규모의 장기간 추적 관찰 연구들이 추가적으로 진행될 필요가 있다.

목차 (Table of Contents)

• 1 Introduction 1
• 1.1 Background 1
• 1.2 Objective 5
• 2 Materials and methods 6
• 2.1 Data sources and search strategy 6
• 2.2 Clinical trial selection criteria 7
• 2.2.1 Inclusion criteria 7
• 2.2.2 Exclusion criteria 9
• 2.3 Data extraction 10
• 2.4 Assessment of risk of bias 11
• 2.5 Endpoint 12
• 2.6 Statistical analysis 13
• 3 Results 16
• 3.1 Study characteristics 16
• 3.2 Risk of bias 21
• 3.3 Effect of DPP-IV inhibitors on MAGE 23
• 3.3.1 DPP-IV inhibitors vs. other oral anti-hyperglycemic drugs 23
• 3.3.2 DPP-IV inhibitors vs. Sulfonylureas 24
• 3.4 Subgroup analyses 27
• 3.4.1 Patients with type 2 diabetes with BMI≥25kg/m2 at baseline 27
• 3.4.2 Patients with type 2 diabetes subdivided into groups with HbA1c≥7.5% and HbA1c <7.5% at baseline 28
• 3.4.3 Patients with type 2 diabetes receiving metformin monotherapy and patients with newly diagnosed type 2 diabetes at baseline 29
• 3.4.4 Type of DPP-IV inhibitors subdivided into sitagliptin and vildagliptin 30
• 3.5 Meta-regression of the reduction of MAGE by DPP-IV inhibitors in relation to baseline characteristics 35
• 3.6 Effect of DPP-IV inhibitors on HbA1c 39
• 4 Discussion 41
• 5 Conclusion 47
• References 48
• Appendix 53
• 국문초록 54