Relative Contribution of Fasting and Postprandial Blood Glucose in Overall Glycemic Control: Post Hoc Analysis of a Phase IV Randomized Trial

Diabetes Ther https://doi.org/10.1007/s13300-018-0403-7 ORIGINAL RESEARCH Relative Contribution of Fasting and Postprandial Blood Glucose in Overall Glycemic Control: Post Hoc Analysis of a Phase IV Randomized Trial Qing Su . Jun Liu . Pengfei Li . Lei Qian . Wenying Yang Received: October 26, 2017 Ó The Author(s) 2018 ABSTRACT Introduction: Few prospective clinical trials have investigated the role of fasting blood glucose (FBG) and/or postprandial glucose (PPG) in assessing overall glycemic control by using different insulin regimens. In the present post hoc analysis, we assessed the contribution of FBG and/or PPG in overall glycemic control in Chinese patients under insulin treatment. Enhanced content To view enhanced content for this article go to https://doi.org/10.6084/m9.figshare. 5947834. Q. Su Department of Endocrinology and Metabolism, Xin Hua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China J. Liu Department of Endocrinology and Metabolism, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China P. Li
L. Qian Medical Department, Lilly Suzhou Pharmaceutical Co. Ltd, Shanghai, China Present Address: L. Qian Medical Science Department, Shanghai Haihe Pharmaceutical Co. Ltd, Shanghai, China W. Yang (&) Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China e-mail: Methods: CLASSIFY is a phase IV, randomized, open-label, 26-week, parallel-arm, treat-to-target, multinational, controlled study in patients with type 2 diabetes mellitus to compare the efficacy and safety of insulin lispro mix 25 (LM25) and insulin lispro mix 50 (LM50) as starter insulins. Insulin was titrated with an aim to target pre-meal blood glucose (BG) levels at [ 3.9 and B 6.1 mmol/L before breakfast and dinner. The primary outcome assessed was the change in HbA1c from baseline. Results: Chinese patients contributed 38.7% (N = 156) of the total population. The majority of patients were male (52.6%). The mean (SD) body mass index was 24.54 (3.04) kg/m2 and mean (SD) HbA1c was 8.54 (1.10) % at baseline. At week 26, LM50 showed a significantly greater reduction from baseline in HbA1c (- 2.03% vs - 1.55%, P \ 0.001), average daily BG (- 3.21 vs - 2.34 mmol/L, P \ 0.001), average postmeal BG (- 3.58 vs - 2.39 mmol/L, P \ 0.001), and average prandial BG excursion (- 1.01 vs - 0.22 mmol/L, P = 0.006) than the LM25 group. The reductions in average pre-meal BG (- 2.59 vs - 2.28 mmol/L, P = 0.137) were not significantly different between the groups. The proportion of patients achieving HbA1c targets (\ 7% or B 6.5%) without nocturnal hypoglycemia or weight gain was greater (P \ 0.05) with LM50 compared with LM25. Conclusion: LM50 achieved better overall glycemic control than LM25 as a starter insulin in Diabetes Ther Chinese patients, which may be due to greater improvement in PPG levels. Trial Registration: Clinicaltrials.gov identification number: NCT01773473. Funding: Eli Lilly and Company, Shanghai, China. Keywords: China; Glycosylated hemoglobin; Mixed insulins; Postprandial hyperglycemia; Type 2 diabetes mellitus INTRODUCTION Onset of type 2 diabetes mellitus (T2DM) is noticed in Asian patients at an early age and at a much lower body mass index compared with the Western population because of greater visceral adiposity, fragile beta cell function, and insulin resistance [1–4]. In addition, postprandial glucose (PPG) and blood glucose (BG) excursions are more pronounced in Asian patients because of their carbohydrate-rich diets [5], which are high in glycemic index and glycemic load [6–10]. As a result of these unique genetic, clinical, and dietary characteristics, Asian patients with T2DM need customized treatment strategies. Although the relationship between glycemic control and macroscopic complications is still unclear, there is evidence that both type 1 and type 2 diabetes patients could benefit from tight glycemic control owing to the resulting reduction in microvascular complications [11–16]. Control of plasma glucose is assessed by measurement of glycated hemoglobin (HbA1c), fasting blood glucose (FBG), and PPG. In recent years, glycemic variability has been deemed an emerging and more reliable target to assess BG control [17, 18], especially in patients with acceptable HbA1c levels who are still in need of optimization because of postprandial spikes and hypoglycemic events. However, HbA1c measurement remains the standard and preferred marker in assessing glycemic control and estimating the success of long-term diabetes-related therapies. According to the US Food and Drug Administration [19], the efficacy of glucose-lowering agents should be confirmed by a reduction in HbA1c as the primary endpoint. In the absence of HbA1c estimation, it is controversial whether FBG or PPG serves as a better predictor of glycemic control, although American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) guidelines [20] recommend the use of basal insulin, which mainly targets FBG, as a starter insulin. In China, premixed insulin that targets both FBG and PPG is recommended as a starter insulin besides basal insulin [21]. It is useful to identify the role of FBG and PPG in glycemic control from a clinical perspective. A prospective interventional trial showed that PPG is essential for achieving recommended HbA1c goals [22]. In the DECODE study, an increase in PPG resulted in a significant increase in mortality irrespective of FBG levels [23]. Similar results were shown in a diabetes intervention study [24]. After treatment with oral antihyperglycemic medications (OAMs), most patients eventually need to start on insulin therapy to stop further deterioration of glycemic control caused by beta cell dysfunction. Insulin therapy can be initiated as a basal, basal-bolus, prandial, or premixed regimen [25]. Any insulin with aggressive titration enables patients to reach overall glycemic control. However, different regimens will result in various nonglycemic outcomes like hypoglycemia and weight gain. To evaluate the therapeutic potential of different insulins, treat-to-target trials were introduced to establish the risk–benefit profile of each. These trials evaluate secondary outcomes at similar HbA1c level improvements [26]. Premixed insulins contain both rapid- and intermediate-acting components and are the preferred starter insulins in Asian patients because they are effective on PPG and are more convenient to use [27, 28]. Premixed insulins vary according to the ratio of rapid- and intermediate-acting components. The most commonly used premixed insulins are low mixtures and mid mixtures. Low-mixture insulins are widely used as starter insulin in patients with OAM failure [29, 30], while mid-mixture insulins are used in patients with higher BG excursions or in patients who need a simplified intensive insulin treatment regimen [31, 32]. Recently, a subgroup analysis of a treat-to-tar (...truncated)