Diabetes Ther (2018) 9:987–999 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 / Published online: March 24, 2018 The Author(s) 2018 Methods: CLASSIFY is a phase IV, randomized, ABSTRACT open-label, 26-week, parallel-arm, treat-to-tar- get, multinational, controlled study in patients Introduction: Few prospective clinical trials with type 2 diabetes mellitus to compare the have investigated the role of fasting blood glu- efﬁcacy and safety of insulin lispro mix 25 cose (FBG) and/or postprandial glucose (PPG) in (LM25) and insulin lispro mix 50 (LM50) as assessing overall glycemic control by using dif- starter insulins. Insulin was titrated with an aim ferent insulin regimens. In the present post hoc to target pre-meal blood glucose (BG) levels at analysis, we assessed the contribution of FBG [ 3.9 and B 6.1 mmol/L before breakfast and and/or PPG in overall glycemic control in Chi- dinner. The primary outcome assessed was the nese patients under insulin treatment. change in HbA1c from baseline. Results: Chinese patients contributed 38.7% Enhanced content To view enhanced content for this (N = 156) of the total population. The majority article go to https://doi.org/10.6084/m9.ﬁgshare. of patients were male (52.6%). The mean (SD) body mass index was 24.54 (3.04) kg/m and mean (SD) HbA1c was 8.54 (1.10) % at baseline. Q. Su Department of Endocrinology and Metabolism, Xin At week 26, LM50 showed a signiﬁcantly greater Hua Hospital, Afﬁliated to Shanghai Jiao Tong reduction from baseline in HbA1c (- 2.03% vs University School of Medicine, Shanghai, China - 1.55%, P \ 0.001), average daily BG (- 3.21 J. Liu vs - 2.34 mmol/L, P \ 0.001), average post- Department of Endocrinology and Metabolism, The meal BG (- 3.58 vs - 2.39 mmol/L, P \ 0.001), Fifth People’s Hospital of Shanghai, Fudan and average prandial BG excursion (- 1.01 vs University, Shanghai, China - 0.22 mmol/L, P = 0.006) than the LM25 P. Li L. Qian group. The reductions in average pre-meal BG Medical Department, Lilly Suzhou Pharmaceutical (- 2.59 vs - 2.28 mmol/L, P = 0.137) were not Co. Ltd, Shanghai, China signiﬁcantly different between the groups. The Present Address: proportion of patients achieving HbA1c targets L. Qian (\ 7% or B 6.5%) without nocturnal hypo- Medical Science Department, Shanghai Haihe glycemia or weight gain was greater (P \ 0.05) Pharmaceutical Co. Ltd, Shanghai, China with LM50 compared with LM25. W. Yang (&) Conclusion: LM50 achieved better overall gly- Department of Endocrinology, China-Japan cemic control than LM25 as a starter insulin in Friendship Hospital, Beijing, China e-mail: firstname.lastname@example.org 988 Diabetes Ther (2018) 9:987–999 Chinese patients, which may be due to greater is controversial whether FBG or PPG serves as a improvement in PPG levels. better predictor of glycemic control, although Trial Registration: Clinicaltrials.gov identiﬁca- American Diabetes Association (ADA) and Euro- tion number: NCT01773473. pean Association for the Study of Diabetes (EASD) Funding: Eli Lilly and Company, Shanghai, guidelines  recommend the use of basal insu- China. lin, which mainly targets FBG, as a starter insulin. In China, premixed insulin that targets both FBG and PPG is recommended as a starter insulin Keywords: China; Glycosylated hemoglobin; besides basal insulin . Mixed insulins; Postprandial hyperglycemia; It is useful to identify the role of FBG and Type 2 diabetes mellitus PPG in glycemic control from a clinical per- spective. A prospective interventional trial INTRODUCTION showed that PPG is essential for achieving rec- ommended HbA1c goals . In the DECODE Onset of type 2 diabetes mellitus (T2DM) is study, an increase in PPG resulted in a signiﬁ- cant increase in mortality irrespective of FBG noticed in Asian patients at an early age and at a levels . Similar results were shown in a dia- much lower body mass index compared with the Western population because of greater vis- betes intervention study . After treatment with oral antihyperglycemic ceral adiposity, fragile beta cell function, and insulin resistance [1–4]. In addition, postpran- medications (OAMs), most patients eventually need to start on insulin therapy to stop further dial glucose (PPG) and blood glucose (BG) excursions are more pronounced in Asian deterioration of glycemic control caused by beta cell dysfunction. Insulin therapy can be initiated patients because of their carbohydrate-rich diets , which are high in glycemic index and gly- as a basal, basal-bolus, prandial, or premixed reg- imen . Any insulin with aggressive titration cemic load [6–10]. As a result of these unique genetic, clinical, and dietary characteristics, enables patients to reach overall glycemic control. Asian patients with T2DM need customized However, different regimens will result in various nonglycemic outcomes like hypoglycemia and treatment strategies. Although the relationship between glycemic weight gain. To evaluate the therapeutic potential of different insulins, treat-to-target trials were control and macroscopic complications is still unclear, there is evidence that both type 1 and introduced to establish the risk–beneﬁt proﬁle of each. These trials evaluate secondary outcomes at type 2 diabetes patients could beneﬁt from tight glycemic control owing to the resulting reduction similar HbA1c level improvements . Premixed insulins contain both rapid- and in microvascular complications [11–16]. Control of plasma glucose is assessed by measurement of intermediate-acting components and are the preferred starter insulins in Asian patients glycated hemoglobin (HbA1c), fasting blood glu- because they are effective on PPG and are more cose (FBG), and PPG. In recent years, glycemic convenient to use [27, 28]. Premixed insulins variability has been deemed an emerging and vary according to the ratio of rapid- and inter- more reliable target to assess BG control [17, 18], especially in patients with acceptable HbA1c mediate-acting components. The most com- monly used premixed insulins are low mixtures levels who are still in need of optimization because of postprandial spikes and hypoglycemic and mid mixtures. Low-mixture insulins are widely used as starter insulin in patients with events. However, HbA1c measurement remains the standard and preferred marker in assessing OAM failure [29, 30], while mid-mixture insu- lins are used in patients with higher BG excur- glycemic control and estimating the success of long-term diabetes-related therapies. According sions or in patients who need a simpliﬁed intensive insulin treatment regimen [31, 32]. to the US Food and Drug Administration , the Recently, a subgroup analysis of a treat-to-tar- efﬁcacy of glucose-lowering agents should be conﬁrmed by a reduction in HbA1c as the primary get, phase IV, randomized, open-label, 26-week study  showed that low- and mid-mixture endpoint. In the absence of HbA1c estimation, it Diabetes Ther (2018) 9:987–999 989 insulins were a viable treatment option as star- glucosidase inhibitor, glinide, or dipeptidyl ter insulins in Chinese patients who had inad- peptidase IV inhibitors, or any combination of equate glycemic control with OAMs . The these, during the 8 weeks before screening, or a aim of the present post hoc analysis was to stable dose of thiazolidinedione for 12 weeks assess the signiﬁcance of FBG and/or PPG in prior to screening [33, 34]. achieving overall glycemic control in Chinese Major exclusion criteria included patients patients who were on premixed insulin having type 1 diabetes mellitus, currently tak- treatments. ing insulin or having previous insulin treatment more than 7 days continuously within the 6 months before the screening visit, having METHODS more than one episode of severe hypoglycemia within 6 months prior to the screening visit, Study Design receiving chronic ([ 14 days) systemic gluco- corticoid therapy or receiving such therapy The present results are from a post hoc analysis within 4 weeks prior to the screening visit, of a phase IV, randomized, open-label, 26-week, having an estimated creatinine clearance parallel-arm, multinational, controlled study in (Cockcroft–Gault formula) \ 30 mL/min, as Chinese patients with T2DM comparing insulin determined by a central laboratory at visit 1, or lispro mix 25 (LM25) and insulin lispro mix 50 having any hematologic condition that could (LM50) twice daily for change in HbA1c from interfere with HbA1c measurement [33, 34]. baseline to 26 weeks . The study included a 2- to 4-week screening Treatment and lead-in period, followed by a 26-week treatment period (12-week, weekly intensive, Eligible patients were randomized in a 1:1 ratio to dose-adjustment period and 14-week mainte- receive either LM25 or LM50 twice daily. The nance period). The 26-week treatment duration treatments were injected daily within 15 min was chosen because it allows sufﬁcient time to before breakfast and within 15 min before din- stabilize glycemic control as measured by ner. The dose was chosen to have a target pre- HbA1c and to explore the suitable insulin regi- meal blood glucose level of [ 3.9 and men for patients following initiation of insulin B 6.1 mmol/L ([ 70 and B 110 mg/dL), and was treatment. During the dose-adjustment period, adjusted on the basis of the average pre-breakfast the insulin dose was titrated to bring hyper- BG/pre-dinner BG values from the previous glycemia on target. During the dose-mainte- 3 days, including the day of injection. Details of nance period, the dosage of insulin remained the algorithm followed to choose insulin dose stable. adjustments have been described previously . Study Population Compliance with Ethical Guidelines Major inclusion criteria included male or female All procedures followed were in accordance Chinese patients aged C 18 years with a diag- with the ethical standards of the responsible nosis of T2DM for at least 6 months before the committee on human experimentation (insti- screening visit based on the World Health tutional and national) and with the 1964 Dec- Organization’s diagnostic and classiﬁcation cri- laration of Helsinki, as revised in 2013. teria, with a body mass index of C 18.5 and Informed consent was obtained from all \ 35.0 kg/m , and qualifying HbA1c values of patients for being included in the study. C 7.0% and B 11.0% based on the National Glycohemoglobin Standardization Program at the screening visit. Patients had been taking a stable dose of sulfonylurea, biguanide, a- 990 Diabetes Ther (2018) 9:987–999 Statistical Analyses n = 76), 141 patients (LM25, n = 72; LM50, n = 69) completed the study . The patients’ baseline characteristics have The present analyses were post hoc in nature. been presented previously  and were com- Efﬁcacy and safety analyses were conducted on parable between the treatment groups (Table 1). the full analysis set which included data from A total of 23 (28.8%) patients in the LM25 all randomized subjects receiving at least one treatment group and 19 (25.0%) patients in the dose of the investigational product and was LM50 treatment group did not take any OAMs analyzed according to the treatment the sub- after randomization. jects were assigned, regardless of what study A statistically signiﬁcantly (P \ 0.001) drug was received. Missing data were not greater decrease in HbA1c (%) was noted in the imputed, as all the available post-baseline data LM50 treatment group compared with the were used in the mixed-model repeated mea- LM25 treatment group at the end of the sures analyses. The detailed statistical analyses 26-week treatment period (Fig. 1). A signiﬁ- followed for this study and for the Chinese cantly greater number of patients also achieved subgroup analysis have been presented previ- the HbA1c target of \ 7.0% (72.4% vs 45.0%; ously [33, 34]. At baseline and at the end of the P = 0.001) and B 6.5% (52.6% vs 20.0%; trial, all patients were asked to collect the seven- P \ 0.001) in the LM50 treatment group com- point self-monitored blood glucose (SMBG) pared with the LM25 treatment group . measurements (before and after three meals and A greater proportion of patients achieved the bedtime) on two non-consecutive days. The target FBG and pre-breakfast BG of\ 7.0 mmol/L average of the 2 day’s data was used to deter- (\ 126 mg/dL) and\ 6.1 mmol/L (\ 109.8 mg/ mine the SMBG measurements for baseline and dL), respectively, in the LM25 treatment group week 26, and was used for the analyses. Change compared with the LM50 treatment group; how- in blood glucose was assessed using daily aver- ever, no signiﬁcant differences were noted age BG (average of SMBG readings), average pre- between the treatment groups (Fig. 2). meal BG (average of three pre-meal BG mea- Statistically signiﬁcant decreases in daily surements, i.e., before breakfast [fasting], lunch, average BG LS mean change [95% conﬁdence and dinner), average post-meal BG (average of interval, CI] (LM50, - 3.21 [- 3.55, - 2.86] three post-meal BG measurements, i.e., mmol/L vs LM25, - 2.34 [- 2.67, - 2.01] approximately 2 h after breakfast, lunch, and mmol/L), average post-meal BG average of three dinner), SMBG average excursion (average post- post-meal BG measurements, i.e., approxi- meal BG minus average pre-meal BG), and FBG mately 2 h after breakfast, lunch, and dinner; (evaluated using serum sample). All tests of (LM50, - 3.58 [- 4.06, - 3.11] mmol/L vs treatment effects were conducted at a two-sided LM25, - 2.39 [- 2.84, - 1.93] mmol/L), and alpha level of 0.05. All analyses were performed SMBG average excursion (LM50, - 1.01 [- 1.41, using SAS Version 9.2 (Cary, NC, USA). - 0.61] mmol/L vs LM25, - 0.22 [- 0.62, 0.17] mmol/L) were noted in the LM50 treatment group compared with the LM25 treatment RESULTS group (P \ 0.05). Also, a greater decrease in average pre-meal BG (average of three pre-meal Of 487 patients who entered the study, 403 BG measurements, i.e., before breakfast [fast- patients were randomized to LM25 and LM50 ing], lunch, and dinner) was reported in and 368 patients completed the study. Most of patients treated with LM50 compared with the patients enrolled and randomized were LM25 (LM50, - 2.59 [- 2.89, - 2.29] mmol/L vs from China (n = 156) and Japan (n = 172). The LM25, - 2.28 [- 2.57, - 1.99] mmol/L); how- rest were from Korea (n = 46) and Turkey ever, the difference was not statistically signiﬁ- (n = 29) . Of 156 patients who were ran- cant between the treatment groups. A greater domized from China (LM25, n = 80; LM50, decrease in FBG was reported in the LM25 treatment group compared with the LM50 Diabetes Ther (2018) 9:987–999 991 Table 1 Baseline patient characteristics Characteristics LM25 LM50 N =80 N =76 Gender Female, n (%) 39 (48.80) 35 (46.10) Age, years 56.93 (9.24) 58.61 (9.05) BMI, kg/m 24.41 (2.67) 24.68 (3.40) HbA1c, % 8.60 (1.11) 8.48 (1.10) Duration of T2DM, years 8.68 (5.57) 7.33 (4.65) Baseline FBG, mmol/L 9.61 (2.30) 9.68 (2.27) Baseline 2-h PPG, mmol/L 13.70 (3.41) 13.55 (3.28) Data are presented as mean (SD), except where indicated otherwise BMI body mass index, FBG fasting blood glucose (serum sample), HbA1c glycated hemoglobin, LM25 insulin lispro mix 25, LM50 insulin lispro mix 50, PPG postprandial glucose (capillary blood glucose), SD standard deviation, T2DM type 2 diabetes mellitus Fig. 1 Change from baseline in HbA1c at week 26. HbA1c glycated hemoglobin, LM25 insulin lispro mix 25, LM50 insulin lispro mix 50. Data of 80 patients in LM25 and 76 patients in LM50 were available at week 26 treatment group (LM50, - 2.12 [- 2.53, - 1.72] conditions like nocturnal hypoglycemia or mmol/L vs LM25, - 2.50 [- 2.89, - 2.11] weight gain was signiﬁcantly higher (P \ 0.05) mmol/L); however, the difference was not sta- in the LM50 treatment group compared with tistically signiﬁcant (Table 2). the LM25 treatment group (Table 3). The proportion of patients achieving the targets HbA1c of \ 7.0% and B 6.5% without 992 Diabetes Ther (2018) 9:987–999 Fig. 2 Proportion of patients with target pre-breakfast FBG is fasting reading before the patient eats/drinks. Pre- blood glucose and fasting blood glucose at endpoint breakfast reading is a baseline reading of blood sugar before (\ 7.0 mmol/L [\ 126 mg/dL] and \ 6.1 mmol/L the patient has breakfast at a standard time. Pre-breakfast [\ 109.8 mg/dL], respectively). BG blood glucose, FBG blood glucose is part of SMBG measurement while FBG is fasting blood glucose, LM25 insulin lispro mix 25, LM50 evaluated using serum sample insulin lispro mix 50, SMBG self-monitored blood glucose. without positive outcomes. In recent years, DISCUSSION some studies have shown a positive correlation between HbA1c and FBG [35, 36]. In fact, the The relative contribution of FBG and/or PPG in 4-T Study  demonstrated that mealtime achieving glycemic control has been a subject of insulin was more efﬁcacious than basal insulin interest in the past decade because there is no but required more injections and was associated consensus among clinicians due to conﬂicting with pronounced weight gain and greater reports. Multiple studies have shown contra- hypoglycemia risk. It is now generally accepted dictory conclusions about the positive contri- that antihyperglycemia treatment targeting bution of FBG and/or PPG in overall glycemic PPG is slightly more efﬁcacious than that tar- control [35–39]. geting FBG, although this type of more aggres- The CLASSIFY study  and its subgroup sive approach increases the likelihood of side analysis of Chinese patients  showed that effects like hypoglycemia and weight gain. both LM25 and LM50 improved glycemic con- Considering the lower hypoglycemia rates, trol at the end of 26 weeks of treatment and lower weight gain, and greater simplicity and were well tolerated. In the present post hoc convenience associated with basal insulin , analysis, an attempt was made to determine the the current treatment algorithm of the ADA contribution of FBG and/or PPG in achieving , EASD , and American Association of overall glycemic control in Chinese patients. Clinical Endocrinologists (AACE)  recom- We assessed FBG, pre-meal BG, daily average mends the use of basal insulin as starter insulin BG, post-meal BG, and BG excursions to iden- in patients failing on OAMs and the addition of tify the relative contribution of FBG and/or PPG bolus insulin on further progression. However, in achieving HbA1c targets. the Glycemic Optimization Treatment (GOT) Multiple efforts have been made to target Study, which assessed the glycemic control and HbA1c and FBG in achieving glycemic control Diabetes Ther (2018) 9:987–999 993 Table 2 Change in blood glucose compared with baseline after treatment Variable Baseline, Endpoint, LS mean change from Difference in LS means of change P value mean (SD) mean (SD) baseline (95% CI) from baseline at endpoint (95% CI) Daily average BG (mmol/L) LM25 11.29 (2.78) 8.71 (1.54) - 2.34 (- 2.67, - 2.01) 0.87 (0.40, 1.34) \0.001** (N = 80) LM50 11.02 (2.45) 7.81 (1.17) - 3.21 (- 3.55, - 2.86) (N = 76) Average pre-meal BG (mmol/L) LM25 9.74 (2.63) 7.38 (1.26) - 2.28 (- 2.57, - 1.99) 0.31 (- 0.10, 0.73) 0.137 (N = 80) LM50 9.68 (2.37) 7.06 (1.15) - 2.59 (- 2.89, - 2.29) (N = 76) Average post-meal BG (mmol/L) LM25 12.78 (3.16) 10.07 (2.14) - 2.39 (- 2.84, - 1.93) 1.20 (0.55, 1.85) \0.001** (N = 80) LM50 12.44 (2.82) 8.83 (1.61) - 3.58 (- 4.06, - 3.11) (N = 76) SMBG average excursion (mmol/L) LM25 3.04 (1.80) 2.68 (1.85) - 0.22 (- 0.62, 0.17) 0.78 (0.23, 1.33) 0.006* (N = 80) LM50 2.76 (1.77) 1.77 (1.45) - 1.01 (- 1.41, - 0.61) (N = 76) FBG (mmol/L) LM25 9.61 (2.30) 7.20 (1.64) - 2.50 (- 2.89, - 2.11) - 0.38 (- 0.94, 0.18) 0.179 (N = 80) LM50 9.68 (2.27) 7.60 (1.76) - 2.12 (- 2.53, - 1.72) (N = 76) BG blood glucose, CI conﬁdence interval, FBG fasting blood glucose, LM25 insulin lispro mix 25, LM50 insulin lispro mix 50, LS least squares, SD standard deviation, SMBG self-monitored blood glucose *P B 0.01, **P B 0.001 Average of SMBG readings Average of three pre-meal BG measurements, i.e., before breakfast [fasting], lunch, and dinner Average of three post-meal BG measurements, i.e., approximately 2 h after breakfast, lunch, and dinner SMBG excursion is average post-meal BG minus average pre-meal BG FBG is evaluated using serum sample rate of severe hypoglycemia for ﬁve different higher doses and resulted in a higher rate of dosing algorithms of insulin glargine, showed hypoglycemia; this indicates that 5.56–- that targeting greater FBG reduction required 6.11 mmol/L (100–110 mg/dL) is an ideal target 994 Diabetes Ther (2018) 9:987–999 Table 3 Proportion of patients achieving HbA1c \ 7.0% and B 6.5% targets without hypoglycemia or weight gain Patients achieving target HbA1c < 7.0% HbA1c £ 6.5% HbA1c with LM25 LM50 P value LM25 LM50 P value (N = 80) (N = 76) (N = 80) (N = 76) n (%) n (%) n (%) n (%) No weight gain 15 (18.8) 25 (32.9) 0.0463* 7 (8.8) 18 (23.7) 0.0154* No hypoglycemic episode 16 (20.0) 26 (34.2) 0.0725 8 (10.0) 16 (21.1) 0.0561 No nocturnal hypoglycemic 32 (40.0) 53 (69.7) 0.0002*** 13 (16.3) 38 (50.0) \0.0001*** episode Neither weight gain nor 5 (6.3) 13 (17.1) 0.0446* 2 (2.5) 9 (11.8) 0.0245* hypoglycemic episode Neither weight gain nor 12 (15.0) 24 (31.6) 0.0218* 5 (6.3) 18 (23.7) 0.0028** nocturnal hypoglycemic episode HbA1c glycated hemoglobin, LM25 insulin lispro mix 25, LM50 insulin lispro mix 50, n number of patients who achieved HbA1c goal with the speciﬁed condition *P B 0.05, **P B 0.01, ***P B 0.001 Hypoglycemic episode is deﬁned as a combination of the following: an episode with blood glucose concentration of B 70 mg/dL (B 3.9 mmol/L) with or without symptoms, an episode during which symptoms are indicative of hypo- glycemia but are not accompanied by a blood glucose concentration of B 70 mg/dL (B 3.9 mmol/L), or a severe hypo- glycemic episode (requiring medical assistance as determined by the investigator) Any hypoglycemic event that occurs between bedtime and waking to achieve with insulin glargine treatment, and target value for morning pre-meal BG), and no it is not advisable to aggressively titrate the signiﬁcant difference was reported between the insulin to meet the goal of \ 5.56 mmol/L treatment groups. The insulin dose was com- (\ 100 mg/dL) considering the adverse effects parable between the LM25 and LM50 treatment such as severe hypoglycemia . This ﬁnding groups for the complete duration of the study. This observation suggests that in Chinese reveals that FBG targets should be realistic with insulin glargine treatment rather than patients, LM50 with smaller amounts of basal aggressive. insulin may have a similar effect on pre-meal In most diabetic clinical studies, the impor- BG and FBG levels compared with LM25, which tance and consistence of FBG and SMBG have has relatively more basal insulin. In fact, in a not been fully discussed. Although FBG (mea- Chinese study, Humalog mix 50/50 showed sured by serum sample) was more reliable and signiﬁcantly improved FBG levels compared accurate as the endpoint, SMBG (capillary blood with Humalog mix 75/25 . glucose) was more clinically relevant to evaluate This observation suggests that Asian patients the efﬁcacy of the insulin regimen as the BG may not need much basal insulin to achieve target used in the treatment algorithm was target FBG. In a recently conducted study in based on SMBG rather than FBG. Interestingly, Japanese patients, the maximum mean (SD) in the CLASSIFY substudy , a treat-to-target basal insulin dose needed to achieve signiﬁcant trial, the morning pre-meal BG at endpoint in improvement in HbA1c was 19 (8.5) units both the LM25 and LM50 treatment groups was (U)/day . However, in Caucasians, the total well controlled (\ 126 mg/dL, which is recom- daily basal insulin usually needed to achieve mended by the Chinese Diabetes Society as a target HbA1c was [ 40 U/day . Also, in a Diabetes Ther (2018) 9:987–999 995 recently concluded study in Chinese and Japa- In the present treat-to-target study, a greater nese insulin-naıve patients, once-daily biphasic proportion of patients achieved speciﬁed HbA1c insulin aspart 30 showed similar improvements targets of \ 7.0% and B 6.5% without side in HbA1c and FBG levels compared with insulin effects like weight gain, hypoglycemia, or noc- glargine . These ﬁndings support our turnal hypoglycemic episodes in the LM50 observation of the need for low-dose basal treatment group compared with the LM25 insulin in Asian patients. In a treat-to-target treatment group, indicating LM50 as a better study conducted by Pan et al. , aggressive treatment option. titration of insulin glargine in Chinese patients A recently published pooled analysis in to achieve target FBG levels (6.67 mmol/L insulin-naı¨ve patients who failed on OAMs [120 mg/dL]) did not guarantee achieving target showed that East Asian and Caucasian patients HbA1c levels (\ 7.5%), even when the average have different BG excursions. This may be due insulin dose was titrated to 32 U/day, which is to lower pre-meal BG levels in East Asian relatively high considering the low body mass patients because post-meal BG levels were index of Chinese patients. almost similar in both groups after treatment This ﬁnding suggests that the development with insulin lispro . This result suggests that of beta cell impairment varies in East Asians and ethnicity may play a role in FBG and PPG Caucasians: East Asians may have impaired reductions in insulin treatment. insulin secretion due to beta cell dysfunction after ingestion of a meal, whereas Caucasians Limitations have more impaired insulin secretion during fasting . The present post hoc analysis was a subgroup In the present study, signiﬁcantly greater analysis of the CLASSIFY study in Chinese reduction in HbA1c was noted in patients trea- patients with T2DM. Also, as a result of its open- ted with LM50 compared with LM25; also, a label study design, the present analysis may signiﬁcantly greater number of patients treated have been subject to bias. In the present study, with LM50 achieved target HbA1c levels of randomization was determined by a computer- \ 7% and B 6.5%. At the same time, statisti- generated random sequence using an interac- cally signiﬁcant decreases in daily average BG, tive voice-response system. Additionally, average post-meal BG, and SMBG average because of the post hoc nature of the analysis, excursion were noted in patients treated with the results should be interpreted cautiously. LM50 compared with patients treated with Further analyses should be conducted in order LM25, suggesting that PPG may contribute to to adequately consider the role of ethnicity reaching target HbA1c levels. when concluding the relative contribution of A greater number of patients treated with various BG in glycemic control. LM25 achieved \ 7.0 mmol/L (\ 126 mg/dL) and \ 6.1 mmol/L (\ 109.8 mg/dL) FBG and pre-breakfast BG levels, respectively, compared CONCLUSION with patients treated with LM50; however, the difference was not statistically signiﬁcant In this post hoc analysis, patients in the LM50 between the treatment groups. This result treatment group showed an improvement in shows that the role of FBG may be of limited overall glycemic control, which may be due to clinical signiﬁcance in achieving target HbA1c greater improvements in PPG levels compared levels in Chinese patients in the CLASSIFY study with FBG. The role of PPG in achieving better and that a decrease in PPG may have accounted glycemic control needs to be conﬁrmed in a for a decrease in HbA1c levels compared with prospective, large-scale, randomized clinical FBG levels. Similar results were also shown in trial. patients who were not previously treated with insulin . 996 Diabetes Ther (2018) 9:987–999 Novo Nordisk, received investigator-initiated ACKNOWLEDGEMENTS trial research funds from AstraZeneca, and been a speaker for Novo Nordisk, Bayer, Sanoﬁ Aventis, Merck Sharp & Dohme China, Astra- Funding. This study and article processing Zeneca, Eli Lilly and Company, Boehringer-In- charges were sponsored by Eli Lilly and Com- gelheim, and Servier and has received pany, Shanghai, China. Eli Lilly and Company honorarium and travel support from Merck & was involved in the study design, data collec- Co. as an advisory board member. tion, data analysis, and preparation of the manuscript. Compliance with Ethics Guidelines. All procedures followed were in accordance with Editorial Assistance. The authors would like the ethical standards of the responsible com- to thank Pavan Yenduri, Antonia Baldo, and mittee on human experimentation (institu- Rakesh Ojha (Syneos Health, funded by Eli Lilly tional and national) and with the 1964 and Company) for assistance in drafting, edit- Declaration of Helsinki, as revised in 2013. ing, data integrity review, and proofreading of Informed consent was obtained from all the paper. The authors also thank Fei Li and patients for being included in the study. Wan Qi Zhao (employees of Eli Lilly and Com- pany) for assistance in publication project Data Availability. The datasets generated management; and Jianing Hou and Ying Lou and/or analyzed during the current study are (employees of Eli Lilly and Company) for their available from the corresponding author on support in medical and statistical review of the reasonable request. paper. Open Access. This article is distributed Authorship. All named authors meet the under the terms of the Creative Commons International Committee of Medical Journal Attribution-NonCommercial 4.0 International Editors (ICMJE) criteria for authorship for this License (http://creativecommons.org/licenses/ manuscript, take responsibility for the integrity by-nc/4.0/), which permits any non- of the work as a whole, and have given ﬁnal commercial use, distribution, and reproduction approval for the version to be published. All in any medium, provided you give appropriate authors had full access to all of the data in this credit to the original author(s) and the source, study and take complete responsibility for the provide a link to the Creative Commons license, integrity of the data and accuracy of the data and indicate if changes were made. analysis. Thanking Patients. The authors would like to thank all investigators and participants REFERENCES involved in the study. Disclosures. Qing Su reported no conﬂicts of 1. Huxley R, James WP, Barzi F, et al. Ethnic compar- isons of the cross-sectional relationships between interest outside the submitted work. Jun Liu has measures of body size with diabetes and hyperten- received personal fees for lectures from Eli Lilly sion. Obes Rev. 2008;9(Suppl 1):53–61. and Company, Sanoﬁ, and Novo Nordisk out- side the submitted work. Peng Fei Li is an 2. Chan JC, Malik V, Jia W, et al. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. employee of Eli Lilly and Company. Lei Qian JAMA. 2009;301:2129–40. was at the Medical Department, Lilly Suzhou Pharmaceutical Co. Ltd, Shanghai, China at the 3. Ramachandran A, Snehalatha C, Shetty AS, Nan- time of this study. His current afﬁliation is ditha A. Trends in prevalence of diabetes in Asian countries. World J Diabetes. 2012;3:110–7. Medical Science Department, Shanghai Haihe Pharmaceutical Co. Ltd, Shanghai, China. Wen 4. Ma RC, Chan JC. Type 2 diabetes in East Asians: Ying Yang has attended the advisory board of similarities and differences with populations in Diabetes Ther (2018) 9:987–999 997 Europe and the United States. Ann N Y Acad Sci. 16. Duckworth W, Abraira C, Moritz T, et al. Glucose 2013;1281:64–91. control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39. 5. Kang X, Wang C, Lifang L, et al. Effects of different proportion of carbohydrate in breakfast on post- 17. Tay J, Thompson CH, Brinkworth GD. Glycemic prandial glucose excursion in normal glucose tol- variability: assessing glycemia differently and the erance and impaired glucose regulation subjects. implications for dietary management of diabetes. Diabetes Technol Ther. 2013;15:569–74. Annu Rev Nutr. 2015;35:389–424. 6. Atkinson FS, Foster-Powell K, Brand-Miller JC. 18. Satya Krishna SV, Kota SK, Modi KD. Glycemic International tables of glycemic index and glycemic variability: clinical implications. Indian J Endocri- load values: 2008. Diabetes Care. 2008;31:2281–3. nol Metab. 2013;17:611–9. 7. Gagne´ L. The glycemic index and glycemic load in 19. US Food and Drug Administration. Guidance for clinical practice. Explore (NY). 2008;4:66–9. industry diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention. 8. Livesey G, Taylor R, Livesey H, Liu S. Is there a dose- 2008. http://www.fda.gov/downloads/Drugs/Guida- ncecomplianceregulatoryinformation/Guidances/ response relation of dietary glycemic load to risk of ucm071624.pdf. Accessed 19 May 2017. type 2 diabetes? Meta-analysis of prospective cohort studies. Am J Clin Nutr. 2013;97:584–96. 20. Inzucchi SE, Bergenstal RM, Buse JB, et al. Man- agement of hyperglycaemia in type 2 diabetes, 9. Dong JY, Zhang L, Zhang YH, Qin LQ. Dietary gly- 2015: a patient-centred approach. Update to a caemic index and glycaemic load in relation to the position statement of the American Diabetes Asso- risk of type 2 diabetes: a meta-analysis of prospec- ciation and the European Association for the Study tive cohort studies. Br J Nutr. 2011;106:1649–54. of Diabetes. Diabetologia. 2015;58:429–42. 10. Ludwig DS. The glycemic index: physiological 21. Chinese Diabetes Society. Chinese guidelines for mechanisms relating to obesity, diabetes, and car- the management of type 2 diabetes mellitus (2013 diovascular disease. JAMA. 2002;287:2414–23. edition). Chin J Diabetes Mellitus. 2013;6:447–98. 11. The Diabetes Control and Complications Trial 22. Woerle HJ, Neumann C, Zschau S, et al. Impact of Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the fasting and postprandial glycemia on overall gly- development and progression of long-term com- cemic control in type 2 diabetes—importance of plications in insulin-dependent diabetes mellitus. postprandial glycemia to achieve target HbA1c N Engl J Med. 1993;329:977–86. levels. Diabetes Res Clin Pract. 2007;77:280–5. 12. UK Prospective Diabetes Study (UKPDS) Group. 23. The DECODE study group, for the European Dia- Intensive blood-glucose control with sulphony- betes Epidemiology Group. Glucose tolerance and lureas or insulin compared with conventional mortality: comparison of WHO and American Dia- treatment and risk of complications in patients betes Association diagnostic criteria. Lancet. with type 2 diabetes (UKPDS 33). Lancet. 1999;354:617–21. 1998;352:837–53. 24. Hanefeld M, Fischer S, Julius U, et al. Risk factors for 13. Stratton IM, Adler AI, Neil HA, et al. Association of myocardial infarction and death in newly detected glycaemia with macrovascular and microvascular NIDDM: the Diabetes Intervention Study, 11-year complications of type 2 diabetes (UKPDS 35): follow-up. Diabetologia. 1996;39:1577–83. prospective observational study. BMJ. 2000;321:405–12. 25. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinol- 14. Patel A, MacMahon S, Chalmers J, The ADVANCE ogists and American College of Endocrinology: Collaborative Group, et al. Intensive blood glucose clinical practice guidelines for developing a dia- control and vascular outcomes in patients with type betes mellitus comprehensive care plan—2015. 2 diabetes. N Engl J Med. 2008;358:2560–72. Endocr Pract. 2015;21(Suppl 1):1–87. 15. Gerstein HC, Miller ME, Byington RP, Action to 26. Garber AJ. Treat-to-target trials: uses, interpretation Control Cardiovascular Risk in Diabetes Study and review of concepts. Diabetes Obes Metab. Group, et al. Effects of intensive glucose lowering in 2014;16:193–205. type 2 diabetes. N Engl J Med. 2008;358:2545–59. 27. Mosenzon O, Raz I. Intensiﬁcation of insulin ther- apy for type 2 diabetic patients in primary care: basal-bolus regimen versus premix insulin analogs: 998 Diabetes Ther (2018) 9:987–999 when and for whom? Diabetes Care. 2013;36(Suppl 38. Rosediani M, Azidah AK, Mafauzy M. Correlation 2):S212–8. between fasting plasma glucose, post prandial glu- cose and glycated haemoglobin and fructosamine. 28. Garber AJ, Ligthelm R, Christiansen JS, Liebl A. Med J Malaysia. 2006;61:67–71. Premixed insulin treatment for type 2 diabetes: analogue or human? Diabetes Obes Metab. 39. Swetha NK. Comparison of fasting blood glucose 2007;9:630–9. and post prandial blood glucose with HbA1c in assessing the glycemic control. Int J Healthcare 29. Buse JB, Wolffenbuttel BH, Herman WH, et al. Biomed Res. 2014;2:134–9. DURAbility of basal versus lispro mix 75/25 insulin efﬁcacy (DURABLE) trial 24-week results: safety and 40. Holman RR, Thorne KI, Farmer AJ, et al. Addition of efﬁcacy of insulin lispro mix 75/25 versus insulin biphasic, prandial, or basal insulin to oral therapy glargine added to oral antihyperglycemic drugs in in type 2 diabetes. N Engl J Med. 2007;357:1716–30. patients with type 2 diabetes. Diabetes Care. 2009;32:1007–13. 41. Lavernia F. What options are available when con- sidering starting insulin: premix or basal? Diabetes 30. Su Q, Qian L. Insulin initiation in type 2 diabetes in Technol Ther. 2011;13(Suppl 1):S85–92. China. Shang Med J. 2016;39:176–9. 42. American Diabetes Association. Standards of medi- 31. Tanaka M, Ishii H. Pre-mixed rapid-acting insulin cal care in diabetes—2016. Diabetes Care. 2016;39(Suppl 1):S1–112. 50/50 analogue twice daily is useful not only for controlling post-prandial blood glucose, but also for 43. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Con- stabilizing the diurnal variation of blood glucose sensus statement by the American Association of levels: switching from pre-mixed insulin 70/30 or Clinical Endocrinologists and American College of 75/25 to pre-mixed insulin 50/50. J Int Med Res. Endocrinology on the comprehensive type 2 dia- 2010;38:674–80. betes management algorithm—2016 executive summary. Endocr Pract. 2016;22:84–113. 32. Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H, Martin S. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus 44. Tanenberg R, Zisman A, Stewart J. Glycemia Opti- oral agents: prandial premixed (insulin lispro pro- mization Treatment (GOT): glycemic control and tamine suspension/lispro) versus basal/bolus (glar- rate of severe hypoglycemia for ﬁve different dosing gine/lispro) therapy. Diabetes Care. 2008;31:20–5. algorithms of insulin glargine in patients with type 2 diabetes mellitus [abstract]. American Diabetes 33. Watada H, Su Q, Li PF, Iwamoto N, Qian L, Yang Association (ADA) 2006; 66th Scientiﬁc Ses- WY. Comparison of insulin lispro mix 25 with sions:A567-P. insulin lispro mix 50 as an insulin starter in Asian patients with type 2 diabetes: a phase 4, open-label, 45. Zafar MI, Ai X, Shafqat RA, Gao F. Effectiveness and randomized trial (CLASSIFY study). Diabetes Metab safety of Humalog mix 50/50 versus Humalog mix Res Rev. 2017;33. 75/25 in Chinese patients with type 2 diabetes. Ther Clin Risk Manag. 2014;11:27–32. 34. Su Q, Liu C, Zheng H, et al. Comparison of insulin lispro mix 25 with insulin lispro mix 50 as insulin 46. Furukawa KD, Yamaaki N, Fujimoto A, Ohyama K, starter in Chinese patients with type 2 diabetes Muramoto H. Simple insulin dose adjustment using mellitus (CLASSIFY study): subgroup analysis of a 3-3-1 algorithm in Japanese patients with type 2 phase 4, open-label, randomized trial. J Diabetes. diabetes: start Kanazawa study (self-titration 2017;9:575–85. aggressive algorithm with glargine trial). J Diabetes Mellitus. 2016;6:197–203. 35. Gupta S, Puppalwar PV, Chalak A. Correlation of fasting and post meal plasma glucose level to 47. Rosenstock J, Schwartz SL, Clark CM Jr, Park GD, increased HbA1c levels in type-2 diabetes mellitus. Donley DW, Edwards MB. Basal insulin therapy in Int J Adv Med. 2014;1:127–31. type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 36. Saiedullah M, Hayat S, Kamaluddin SM, Begum S. 2001;24:631–6. Correlation of fasting and post prandial plasma glucose with hemoglobin glycation. Anwer Khan 48. Yang W, Xu X, Liu X, et al. Treat-to-target com- Mod Med Coll J. 2013;4:28–30. parison between once daily biphasic insulin aspart 30 and insulin glargine in Chinese and Japanese insulin-naive subjects with type 2 diabetes. Curr 37. Ketema EB, Kibret KT. Correlation of fasting and Med Res Opin. 2013;29:1599–608. postprandial plasma glucose with HbA1c in assess- ing glycemic control; systematic review and meta- analysis. Arch Public Health. 2015;73:43. Diabetes Ther (2018) 9:987–999 999 49. Pan CY, Sinnassamy P, Chung KD, Kim KW, LEAD glucose and glycated hemoglobin in non-insulin Study Investigators Group. Insulin glargine versus treated type 2 diabetic subjects. Sunsari Techn Coll NPH insulin therapy in Asian type 2 diabetes J. 2012;1:18–21. patients. Diabetes Res Clin Pract. 2007;76:111–8. 52. Yang W, Qian L, Li P. Evaluation of different blood 50. Yabe D, Seino Y, Fukushima M, Seino S. b cell dys- glucose proﬁles between East Asian and Caucasian function versus insulin resistance in the pathogen- insulin-naı¨ve patients with type 2 diabetes mellitus esis of type 2 diabetes in East Asians. Curr Diab Rep. after oral antihyperglycemic medication failure 2015;15:602. [abstract]. Diabetes Metab Res Rev. 2016;32 (S2):42 A415074. 51. Shrestha L, Jha B, Yadav B, Sharma S. Correlation between fasting blood glucose, postprandial blood
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Published: Mar 24, 2018
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