| Objective:Type 2 diabetes mellitus (T2DM) is fast-growing among population across the world. A latest cross-sectional survey on a sample of 98,658 Chinese adults in China showed that the prevalence of diabetes reached 11.6%, and the prevalence of pre-diabetes is as high as 50.1%, prompt the prevalence of diabetes in China will continue to rise in the future. The characteristics of T2DM are beta cell dysfunction and insulin resistance. The function of beta cell in newly Diagnosed T2DM patients only remind 50%, and with the progression will eventually lead to beta cell function failure. We would like to see that through early intervention can finally achieve metabolic memory effect, so that patients achieve long-term benefit. Newly Diagnosed T2DM patients compliance are good, and the potential of alpha/beta cell function improvement is larger. Therefore, in order to protect the beta cell function and delay the beta cell function failure, newly Diagnosed T2DM patients should take active interventions. Aim to the pathophysiology of T2DM, Professor DeFronzo put forward a new triple therapy as thiazolidinedione (TZD)+ metformin+glucagon-like peptide-1 (GLP-1) analogues or dipeptidyl peptidase-IV (DPP-4) inhibitors. Triple therapy almost full range according to the pathophysiology of T2DM, thereby has an important effect on lasting glycemic control and beta cell protection. A large number of studies have demonstrated that a short period of intensive insulin therapy can improve beta-cell function and control glucose well, so patients with newly diagnosed T2DM using insulin intensive treatment in the clinical applications have gradually extensive. Triple therapy model offers a new way for the treatment of T2DM, but the model should be verification in clinical application, and now a lot of clinical research are focused on the effect of glycemic control, and less further explore its effect on the alpha/beta cell function and adipokines. Few clinical studies about triple therapy model in China. Therefore, we hope that through the comparison with insulin intensive treatment, (1) to explore the comparative glycaemic efficacy and impact on α/β-cell function of triple combination therapy and intensive insulin therapy for newly diagnosed T2DM;(2) to investigate the influence of adipokines and body weight of triple combination therapy and intensive insulin therapy for newly diagnosed T2DM.Methods:Drug naive, newly diagnosed T2DM subjects were randomized in an open fashion design in a single center study to Saxagliptin/Metformin/Rosiglitazone (Triple Therapy) (n=23) or insulin 70 30 mix group (Intensive Insulin Therapy) (n=21) for 24 weeks. The mean age of Triple Therapy subjects was 49.4±12.8 years. Initial treatment dose for Saxagliptin (5mg/day)+metformin (0.5g, twice/day)+ rosiglitazone (4mg/day), metformin maximum can be adjusted to 2.0 g/d according to the level of blood glucose. Intensive Insulin Therapy group were included 21 cases (including 13 cases of male/8 cases of female), the mean age was 51.9 ±14.5 years, initial treatment dose for Insulin Aspart 30 Injection (initial total dose of 0.4-0.5 IU/kg,50% before breakfast,50% amount of insulin before dinner), with fasting glucose< 6.1 mmol/L and postprandial blood glucose 2 h<8.0 mmol/L as the goal. Two groups of subjects were treated for 24 weeks, every 4 weeks, with a telephone follow-up to ask patients self-monitoring of blood glucose level and the occurrence of adverse events. Every 8 weeks for an outpatient follow-up, weight, waist circumference, blood pressure testing, FBG, FINs, c-peptide, HbAlc test, and collected 3.0 ml venous blood on an empty stomach, separation of serum, natural coagulation after 10 to 20 min, centrifugal 20 minutes (2000 to 3000 r/min). After separation of serum in vitro, serial number, sealing at-80℃ low temperature refrigerator, finally used for target detection. In before and after 24 weeks treatment, fasting 12 hours for the fasting blood glucose (FBG), glycosylated hemoglobin (HbAlc), insulin (FINs) and c-peptideF, the GC test, and the total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), blood urea nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT), aspertate aminotransferase (AST) levels were detected. (1) to observe BG, FINs, c-peptide, HbAlc, record adverse events (nausea, anorexia, asymptomatic hypoglycemia, severe symptomatic hypoglycemia, low blood sugar) of two treatments in the evaluation of the safety of the treatments, by using the Homeostatic model assessment 2 insulin resistance index (HOMA2-IR) and Homeostatic model assessment 2 insulin secretion index (HOMA2-% beta) evaluation of beta cell function (FBG and fasting c-peptide were input the software to calculating HOMA2-IR, FBG and fasting c-peptide were input the software to computing HOMA2-β%, fasting c-peptide units for ng/mL, FBG unit as mmol/L), used Glucagon (GC) level to evaluate function of alpha cells.(2) before treatment, treatment for 8 weeks,16 weeks and 24 weeks detected and compared two groups with serum adiponectin (ADP), leptin (Leptin), tumor necrosis factor-alpha (TNF-alpha), resistance element (Resistin) and free fatty acid (FFA), and record the change of the two groups with body mass index (BMI). Use ELISA kits to detected the level of GC, leptin, ADP, resistin, FFA and TNF-alpha, and all the testing operations are accordance with the specifications.All the data for the statistical analysis by SPSS 18.0 software. To accord with normal distribution measurement data to x±s, HOMA2-IR and HOMA2-β% were taken the natural logarithm of normal again after statistical analysis for the skew distribution. Comparison between groups by using two independent sample t test. Non-normal distribution measurement data using the median and interquartile spacing, group comparison using the Mann-Whitney U test. Expressed count data using percentage, comparison between groups by chi-square test and trend analysis. The comparison of before and after treatment, accord with normal distribution and variance, with matching t test. Comparison between the two groups with group t test. Correlation analysis used Pearson correlation analysis. With P< 0.05 for the difference was statistically significant.Results:After 24 weeks treatment, the treatment dose respectively at the termination of the two treatments:Triple Therapy Group for Saxagliptin (5mg/day)+ metformin (0.5g, triple/day)+rosiglitazone (4mg/day). Intensive Insulin Therapy group at the end of the average insulin dosage for 21 IU/d. (1) After 24 weeks treatment, FBG, HbAlc, LnHOMA 2-IR and GC level were significantly decreased, and LnHOMA 2- %β increased significantly (P<0.05) in Triple Therapy Group, while FBG, HbAlc levels were significantly decreased, and LnHOMA 2-IR and LnHOMA 2- %β level were significantly increased (P<0.05) in Intensive Insulin Group. Blood biochemical results showed that TC, LDL-C before and after treatment were significantly reduced, and the difference was statistically significant (P< 0.05), ALT, AST, Cr, BUN, TG, HDL-C differences had no statistical significance (P> 0.05) in Intensive Insulin Group. Before and after treatment of BUN, TC, LDL, HDL-C-C were significantly reduced, and the difference is statistically significant (P< 0.05); ALT, AST, TG Cr, no statistical differences (P> 0.05) in Triple Therapy Group. It had no significant difference in changing the magnitude of FBG, HbAlc and LnHOMA 2- %beta (P>0.05), but Triple Therapy Group in decreasing LnHOMA 2-IR and GC were significant higher than Intensive Insulin Group (P< 0.05). After 24 weeks treatment of Triple Therapy, four patients in the treatment occurred nausea,3 patients occurred poor appetite, but all subjects can endure. One patient in symptomatic hypoglycemia occurred after strenuous exercise. After 24 weeks, Intensive Insulin Group were not present symptoms of nausea, and 2 patients occurred in asymptomatic hypoglycemia, five patients with symptomatic hypoglycemia. Two groups of patients under treatment were not severe hypoglycemia. Two methods of treatment had no significant effect on hepatic and renal function.(2) 24 weeks after treatment,Triple Therapy Group significantly increased level of ADP, leptin, TNF alpha, resistin, FFA and BMI levels were significantly lower (P < 0.05). A significant rise in Intensive Insulin Group of ADP and BMI level, leptin and FFA levels were significantly lower (P<0.05), TNF alpha and resistin level has no obvious difference (P>0.05). Further analysis found that change of ADP between two groups has no significant difference (P>0.05). Leptin [(-4.5±5.9) vs (-1.6±2.7)μg/L, P<0.05], resistin [(-5.3±5.8) vs (-1.7±4.8)μg/L, P<0.05], FFA [(-284.2±153.4) vs (-151.3±167.7)μmol/L, P<0.01) and BMI [(-2.1±1.6) vs (0.8±1.7) kg/m2, P<0.01) decreased significantly higher of Triple Therapy Group than that of Intensive Insulin Group, comparison between the two groups found that adiponectin level change amplitude of no significant difference (P> 0.05). Pearson correlation analysis showed a negative relationship between ADP and HOMA2-IR.Conclusion:For newly diagnosed T2DM patients, (1) triple combination therapy using Saxagliptin/Metformin/Rosiglitazone and the use of Intensive Insulin treatment can be fully effectively glycemic control, at the same time, to a certain extent to improve β-cell function and reduce insulin resistance. And compared with Intensive Insulin treatment, the effect of triple combination therapy in reducing insulin resistance is stronger, and has significant inhibition of GC level, so triple combination therapy has effectively glycemic control and significantly improve alpha/beta-cells function. (2) triple combination therapy compared with Intensive Insulin treatment, can adjust the level of Adipokines significantly, elevated adiponectin concentration and lower leptin, TNF alpha, resistin and FFAs concentration effectively, relieved inflammation, lipotoxicity and the insulin resistance. (3) triple combination therapy not only has effective glycemic control, but also can reduce the occurrence of hypoglycemia events and body weight. So for the newly diagnosed of T2DM patients, especially when complicating with overweight or obese, using the triple combination therapy not only can effectively control the glucose and bidirectional regulation function of islet cells, but also can regulate Adipokines imbalance, reduce hypoglycemic events and slightly reduce body weight, bring more benefit for such patients. But as a result of the sample size of this study is less, so we need to enlarge sample size in the future and multicenter randomized controlled trials, to further explore the curative effect of triple therapy for alpha/beta cell function and the influence of Adipokines. |
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