| Background and Objection:With the development of economy continuously,expansion with unhealthy modern life style of high fat, high sugar, high calorie diet and physical activity reduction which cause people daily intake increased significantly and might increase the risk of developing type 2 diabetes.Alarming increases in the prevalence of diabetes,hasing becoming one of the most important chronic non-communicable diseases which can serious hazard to human health. IDF latest statistics showed that globally,the number of people with diabetes is expected to rise from the current estimate of 370 million to 592 million in 2035.An epidemic of T2DM is under way in both developed and developing countries.The Alarming increases in the prevalence of diabetes have occurred in various Chinese populations.The epidemic of diabetes has been fueled by a parallel increase in the prevalence of overweight and obesity.Overweight or obesity not only contributes to the development and worsening of type 2 diabetes, it is also an independent contributor to the cardiovascular risk associated with that disease.A close association between obesity and insulin resistance is seen in all ethnic groups.Obesity leads to insulin resistance,Obesity can be divided central (abdominal) obesity and subcutaneous fat obesity which in accordance with the adipose accumulation parts.Compared to subcutaneous fat obesity, abdominal obesity is more relative to insulin resistance additionally abdominal obesity will increase risk which develepement to diabetes.Analyze the possible reasons,First,abdominal fat is more lipolytically active than subcutaneous fat. In addition, the abdominal adipose store is resistant to the antilipolytic effects of insulin,it lead to decline the number affinity of insulin receptor in fat cells,So that the insulin-induced glucose transport function decline.Finally,the abdominal adipose stores can secret free fatty acids (FFAs),FFAs can inhibit the muscle which can take advantage of glucose.however it decreases in glucose transport have been seen in patients with T2DM which resulting in an increase in intracellular glucose concentrations and decreased glucose uptake.Insulin resistance is the important risk factors occurrence and development which contributes to cardiovascular disease, diabetes and hypertension.Therefore in the process of the treatment of diabetes, weight management should be strengthened.The progressive nature of T2DM, combined with its increasing prevalence and the fact that people are being diagnosed with this disease at a progressively younger Age,means that more people than ever before require insulin to maintain glycaemic control. However, patients and physicians are often reluctant to initiate or intensify insulin in a timely manner, in part due to fear of associated weight gain and hypoglycaemic events.A number of large clinical studies have proved that weight loss remains a more viable approach not only to reducing the risk of developing diabetes but even to disease regression in those individuals who have already been diagnosed. Additionally,it can improve insulin sensitivity and reduce cardiovascular effects.Hence,For diabetes patients with obesity should be strengthened the management, it emphasizes the T2DM with obese patients, Should be effective control of blood glucose,at the same time should also focus on visceral fat, reduce weight, in order to reduce cardiovascular events and mortality risk.Therefore, novel treatment regimens are required to minimize the side effects of insulin,increase patient acceptance of and adherence to therapy, improve health outcomes. There is also a pressing need for therapies that help to reduce weight(especially in obese patients with T2DM) and can reduce cardiovascular risk.Type 2 diabetes has become one of the world’s most important public health problemsLiraglutide is the newest class of T2DM therapy currently available,which improve hperglycemia glucose-dependent stimulation of insulin secretion and suppression inappropriate hyperglucagonemia secretion, recovered the first-phase insulin secretion,slowed gastrointestinal motility (including gastric emptying) and increased satiety through central inhibitory,leading to reduced nutrient intake, additionally, it and has beta cell proliferative,antiapoptotic and differentiation effects.which result in improving glycaemic control,weight loss and protecting the islet cell function.A number of large clinical studies showed that liraglutide to insulin therapy can not only improve glycaemic control,lower risk of hypoglycaemia,but also improve insulin resistance reduce BMI,weight reduction,lower total daily dose of insulin and decrease cardiovascular risk biomarker.however,at present,domestic research about liraglutide as add-on therapy to insulin is less.Hence,the research of Diaz-grim,g.etc. shows that:the liraglutide has improved glycemic control, improved insulin sensitivity and insulin resistance and lower body mass index, and the function of cardiovascular risk markers after the treatment of 14 weeks, the research of Dr Corkin etc. shows that the liraglutide with insulin therapy can obviously reduce blood sugar, total daily insulin dose, weight loss and reduce the risk of hypoglycaemia.the aim of this observational study was to assess the efficay and safety of liraglutide as add-on therapy to insulin in patients with T2DM is overweight or obese patients with poor glycaemic control.The primary endpoint of this study was to evaluate liraglutide as add-on therapy to insulin on body weight, glycemic control, insulin inflammatory biomarkers,total daily insulin dose and hypoglycemia in T2DM patients.Methods1.Study design and participants1.1 Participants:Subjects were selected in our hospital endocrinology clinic T2DM patients in April 2013 to April 2014.Total 62 subjects were erolled in our study which were divided into add on to liraglutide group(the LIRA group) and continuous insulin group(the INS group).The total of subjects in the LIRA group is 30, which:19 are males,11 are females and the average age of 51.57±8.47 years.The total of subjects in the INS group is 30,which:18 are males,14 are females and the average age of 51.57±8.47 years.1.2 Study designIn the LIRA group:starting dose of liraglutide was 0.6 mg once daily, with an increase to 1.2 mg after 1 weeks/with an increase to 1.8 mg after 2 weeks.To avoid hypoglycemia,insulin doses were reduced 30% upon initiation of liraglutide, When there is a gastrointestinal side effects but patients can’t tolerate,the dose of liraglutide was reduced 1.2mg.And adjusting the dose of insulin depending on their blood glucose levels.In the INS group, insulin doses were increased to reach the glycemic targets.The glycemic control target was defined as FBG)≤7mmol/L and 2 hour postprandial blood glucose (2hPG)≤10.0mmol/L.Two groups of patients with oral hypoglycemic drugs remains the same.Telephone follow-up once a week dose was adjusted with -2 to+6 U per injection,in order to glycemic control target,Given the hypoglycemia in the process of study, insulin dose can be reduced.And record adverse reactions during the test.2.Experimental Methods2.1 Specimen CollectionAfter 10h of fasting, all subjects underwent venous blood drawing of the next morning using blood-collection tube. After standing for 30min, they were placed into the centrifuge and centrifuged for 10min at 3000r/min. Separation of serum in sterile EP tube frozen in-80℃ saved for later use.2.2 Experimental MethodsFPG、2hPG、HbAl、weight、BMI、WC、FCP、2hCP、TDID、TC、EDL-C、 LDL-C、TG、TNF-α、IL-6、 APN were measured at baseline and at the end of the trial. Serum TNF-α、IL-6 and APN level was measured by ELISA method. Methods according to kit instructions..Experimental methods according to the kit manual operation. According to the absorbance value of specimens,were calculated for each sample, the corresponding TNF-α、IL-6 and APN levels.2.3 Judging adverse reactionsnausea, diarrhea, vomiting, abdominal pain, constipation and other gastrointestinal symptoms and low blood glucose reaction were recorded in the study.2.4 Statistical MethodsAll statistical analyses were performed according to intention-to-treat, using IBM SPSS version 13.0.p<0.05 was considered significant. Descriptive characteristics are expressed as mean±SD; Independent two-tailed t-tests were performed to assess between-group difference,Paired two-tailed t tests were performed using LIRA group and the INS group.Qualitative data were expressed as number and percentage (%) and WC reduction of value and other indicators of the correlation of inspection analyzed by applying chi-square test.Results1.The characteristics between two groupsA total of 62 patients were enrolled in the study. Of these,60 completed the study,There were 2 patients who did not complete the study in the INS group,The characteristics of the patient between two groups at study entry were not significantly after treatment of 12 weeks, in the LIRA group, there is 1 case subjects who the dose of liraglutide is 0.6 mg/day,1.2 mg/d in 17 cases,1.8 mg/d in 12 cases,No subjects can stop insulin therapy,But there are 24 patients from multiple subcutaneous insulin injections or premixed insulin (2 times/d) instead of a long-acting insulin therapy before sleep.2.Comparison of HbAlc and glucoseFPG、2hP、HbA1c had decreased respectively by (2.5±1.1), (5.5±2.7)mmol/L, (1.8±1.2)%(t=12.73、8.85、8.40,P<0.05)after 12 weeks compared to baseline in the LIRA group;FPG、2hPG、HbAlc had decreased respectively by(2.9±1.6)mmol/L、 (5.6±3.4)mmol/L、(1.7±1.3)%(t=9.78.8.85.7.06.P<0.05) after 12 weeks compared to baseline in the INS group; there is no significant difference between in the LIRA group and in the INS group(t=0.06,0.65,1.16, P>0.05).3.HbAlc compliance rate and the reaching the composite endpointComparison between the two groups of HbAlc of<7% compliance rate and the composite end point(HbAlc≤7% and no hypoglycemia).HbAlc≤7% compliance rate is similarly between two groups(80%/73.3%,P> 0.05);but subjects withHbA1c ≤7%and no hypoglycemia in the LIRA group were better than in the INS group (65.6%/46.8%, P,0.05).4.Comparison of weight、BMI and WCWeight,BMI,WC had decreased by 4.5±0.5kg,1.6±2.1kg/m2,3.3±3.2cm (t=4.07, 4.18,5.65 P< 0.05)after 12 weeks compared to baseline in the LIRA group respectively.On the contrary,weight,BMI,WC had increased respectively (1.0±2.1)kg、 (0.3±0.7)kg/m2、(0.6±1.3)cm (t= 2.51、2.38、2.61,P<0.05)after 12 weeks compared to baseline in the INS group. there is significant between in the LIRA group and in the INS group(t=2.17、2.01、2.63,P<0.05).5.Comparison of blood lipidsTG,TC,HDL-C,LDL-C were no statistical significance after 12 weeks compared to baseline in the LIRA group, TG、TC、HDL-C、LDL-C were also no statistical significance after 12 weeks compared to baseline in the INS group, there is no significant between in the LIRA group and in the INS group(P>0.05).6.Comparison of c peptide and TDIDFCP had increased by 0.83±0.35ng/ml(t=12.83,P<0.01) compared to baseline in the LIRA group,FCP had increased by 0.16±0.08ng/ml(t= 10.74,P<0.01) compared to baseline in the INS group.there is significant between in the LIRA group and in the INS group(t=4.0,P<0.01).2hCP had increased respectively by 0.44±0.34 ng/ml(t=7.08,P<0.05) compared to baseline in the LIRA group,2hCP had increased by 0.22±0.47ng/ml(t=2.63,P<0.05)compared to baseline in the INS group,there is no significant between in the LIRA group and in the INS group(t=0.265, P>0.05).TDID was reduced 25.9±12.7U(t=11.13,P<0.01)compared to baseline in the LIRA group, TDID had increased by 12.1±5.7U(t=11.58, P<0.01) compared to baseline in the INS group,there is significant between in the LIRA group and in the INS group t=13.3,P<0.01)7.Comparison of TNF-α、IL-6 and APNTNF-α had reduced by 1.4±1.2pg/ml(t= 6.18,P<0.01)compared to baseline in the LIRA group,TNF-α had increased by 0.37±1.91pg/ml(t= 1.07,P> 0.05)compared to baseline in the INS group,there is significant between in the LIRA group and in the INS group(t= 3.47,P<0.01).IL-6 had reduced by 0.54±0.86pg/ml(t= 3.47,P<0.01) compared to baseline in the LIRA group,IL-6 had increased by 0.22±0.47pg/ml(t= 1.33,P>0.05)compared to baseline in the INS group,there is significant between in the LIRA group and in the INS group(t=2.2, P<0.05).APN had increased by 1.33±1.84 ng/ml(t= 3.94,P<0.01)compared to baseline in the LIRA group,APN had reduced by 0.24±0.72ng/ml(t=1.81,P>0.05)compared to baseline in the INS group.there is significant between in the LIRA group and in the INS group(t=2.13,P<0.05)8.Correlation analysis WC and other indexsThere was a significant correlation between WC decrease and weight decrease (r=0.38, P<0.01), and BMI decrease (r=0.61,P<0.05) in the LIRA group.9.SaftyThere were no serious adverse reaction exit test between INS group and LIRA group,In the INS group has 6 subjects with hypoglycemia reaction. In the INS group is more subjects with hypoglycemia reaction than in the INS group.However,in the LIRA group is more subjects with gastrointestinal side effects in the INS group.Conclusion1.Insulin were combined with metformin or sulfonylureas for patients with type 2 diabetes with overweight or obese, 1.The effect of lowering FPG,2 HPG, HbAlc were similar between combined with Liraglutide and only insulin dose increased, but compared with Liraglutide the composite end point (HbAlc<7% and no risk of hypoglycaemia) was better than only insulin dose increased,2.Compared with the only insulin dose increased,ccan reduce weight, WC, BMI,and reduce the daily dosage of insulin, and most of the patients can reduce insulin injections3.Compared with the only insulin dose increased, Compared with the only insulin dose increased can reduce TNF-α, IL-6, elevate adiponectin, suggest Liraglutide with anti-inflammatory effect and improve insulin resistance. |
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