Impact Of Baseline BMI On Glycemic Control Of Metformin Monotherapy In Chinese Patients With Type 2 Diabetes

Diabetes mellitus (DM), is a group of metabolic diseases in which there are high blood sugar levels over a prolonged period. The reduction of insulin secretion and (or) insulin resistance may cause disturbance of carbohydrate metabolism combined with fat, protein, water, electrolyte and other metabolic disorders. Serious long-term complications include cardiovascular disease, stroke, kidney failure, foot ulcers and damage to the eyes. Diabetes mellitus is one of the most important non-infectious diseases that threaten people over the world. Based on data of International Diabetes Federation (IDF), in 2011, an estimated 370 million people have diabetes worldwide. The number of people with diabetes is expected to rise to 550 million by 2030 with patients from developing countries making up about 80% of the cases. In 2010, Chinese Center for Disease Control and Prevention (CDC) and Chinese Medical Association had investigated the incidence of diabetes in Chinese population older than 18 years. Base the diagnosis criteria of WHO in 1999, the incidence of diabetes was 9.7% in China; if adding HbAlc≥6.5% as diagnosis criteria the incidence was 11.6%. China may have the largest number of people with diabetes in the world.Type 2 diabetes makes up about 95% of diabetes cases. It is characterized by insulin resistance. Management of type2 diabetes bases on lifestyle interventions which should be insistent throughout the treatment. Medication treatment should begin as soon as monotherapy with lifestyle interventions failed. Anti-diabetic medications are mainly based on two pathophysiology changes of hyperglycemia--insulin receptor defect or insulin secretion reduced. The classes of oral anti-diabetic medications include insulin secretagogues (sulfonylureas, glinides, dipeptidyl peptidase-4 inhibitors), insulin sensitizer (thiazolidinediones) and medication of other mechanisms (alpha glucosidase inhibitors and biguanides).Metformin is the most widespread used oral anti-diabetic medicine It can control glycemic and protect organism in different pathways. The related mechanism includes:(1), Metformin could decrease glyconeogenesis and inhibit the absorption of glucose at intestinal tract. (2) It was proved in rats model that Metformin could reduce the absorption of glucose at intestinal tract to 50%. (3), Metformin can also improve insulin sensitivity. It can develop the activity of tyrosine kinase at hepatocye insulin receptor and improve the ability of insulin binding to insulin receptor in adipocyte of insulin resistant patients. Valensi p, et al reported that Metformin can increase 25%～30% sensitivity of skeletal muscle to insulin. (4) Improve transport, utilization and oxidation of glucose in peripheral tissues. Gunton J E, et al proved that Metformin can improve replacement of glucose transporter-1 to increase the glucose uptake. (5) Decrease cadiovascular complication by lowering the triglyceride and low density lipo protein level (LDL) as well as elevating the high density lipoproteins (HDL) level. Metformin can activate protein kinase through 5-AMP in skeletal muscle and increase activity of untypical protein kinase. By this mechanism, it enhances the glucose uptake and glycolysis, decreases lipid synthesis and increases fatty acid oxidation. As the result, the weight of type 2 diabetes patients significantly decreased by Metformin. (6) It also has effect on arteries to delay cadiovascular complication.Metformin is generally recommended as a first line treatment. A prospective diabetes research in United Kigdom reported that in treatment of obese diabetes patients (defined as>120% ideal body weight), metformin was equivalent to sulfonylureas in Glycemic Control respect; moreover, it had less effect on weight, so use of metformin could delay artery disease development; last but not least, it seldom led to hypoglycemia. These evidences support metformin as the basic medication for overweight or even all weight groups type 2 diabetes patients. In 2006, American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus recommended metformin as the primary treatment and treatment at other stage for type 2 diabetes patients, regardless of the body weight. Moreover, most diabetes management guidelines published recently, such as international diabetes mellitus (IDF) (2005) and National Institute for Health and Clinical Excellence(NICE) (2002),announce similar recommendation. Chinese Type 2 Diabetes Management Guideline (2013) pointed out that metformin is the first choice for type 2 diabetes. And it should be keep in the treatment scheme unless there is a contraindication.However, at Asia-Pacific nation, Western Pacific Region guidelines were a little different from global guideline, that is some recommend metformin as the first line treatment for obese and overweight patients, others also recommend it as the first line treatment for normal weight patients as well. In Chinese, metformin was recommended as the only first choice for obese and overweight patients; but for normal weight patients, metformin was regarded as one of three first line medications included thiazolidinediones, sulfonylureas/glinides and alpha glucosidase inhibitors. The difference between Chinese and global guideline led to only 16% normal weight patients use metformin as first line medication.Moreover, the definitions of normal weight(BMI<24kg/m2), overweight(BMI≥ 24kg/m2 and BMI<28 kg/m2) and obese(BMI≥28kg/m2) are different from global guideline (normal weight BMI≤26 kg/m2, overweight BMI 26-30kg/m2, obese BMI ≥30kg/m2). Based on the definition of Chinese guideline, BMI distribution pattern of Chinese type 2 diabetes patients showed that about 30% patients were normal weight. That is to say, we cannot directly use the result of research in other countries to guide the treatment of type 2 diabetes of different weight. The difference of ethnic and definition of body weight group may lead to difference of the impact of baseline BMI on efficacy of metformin monotherapy.On the other hand, the safety of metformin is also aroused widely concern. There are a large number of reports about the adverse effect of metformin. Among these reports, gastrointestinal adverse reaction is the most common, and the major clinical manifestations of which is loss of appetite, nausea, vomiting, dry mouth, bitter taste, mouth with metallic taste, abdominal distention and diarrhea. It was reported that 0.6% patients taken metformin had to drop out the clinical trial because of diarrhea. Vitamin B deficiency is another main adverse effect of metformin. Lactic acidosis is one of the most serious adverse effects. The elderly or patients with cardiovascular, lung, liver or kidney complication tend to suffering from lactic acidosis. Different from other anti-diabetes medications, metformin monotherapy rarely causes hypoglycemia, unless combines with oral sulfonylureas or insulin. Other adverse reactions of metformin include exfoliative dermatitis, alopecia, peptic ulcer, transaminase elevation, psychosis, ventricular premature beat, renal injury. However, most adverse effect reports in China are case reports, literature analysis and adverse effects occur when combined with other anti-diabetes medication. The reports in clinical trial are rare.So we designed a prospective, three arms, open-label clinical trial to investigate the efficacy and safety of metformin monotherapy in Chinese patients newly diagnosed with type 2 diabetes. The experiment also aim to explory the impact of baseline BMI on the glycemic control and safety of metformin monotherapy in Chinese patients newly diagnosed with type 2 diabetes.Method1. Part one:Patients with newly diagnosed type 2 diabetes were enrolled from July 2010 to December 2013. These patients were divided into three groups according to baseline BMI:normal-weight group (BMI>18.5kg/m2 and BMI<24 kg/m2), overweight group(BMI>24kg/m2 and BMI<28 kg/m2) or obese (BMI>28kg/m2). Extended-release metformin was administered for 16 weeks (500 mg/day, up-titrated weekly to a maximum 2,000 mg/day). The primary efficacy endpoint was the effect of baseline BMI on glycemic control with metformin monotherapy, measured as the change from baseline in glycosylated hemoglobin (HbAlc) at week 16. Other endpoints included comparisons of metformin’s effects on fasting plasma glucose(FPG) and body weight.2. Part two:All the patients included into the Part I research who took at least one dose Metformin and had Security indicators records were included into the safety evaluation research. Adverse events were collected by patient spontaneous reports, directly observation or physician inquires. The incidence rates of adverse events of all patients as well as patients in different BMI groups were described in table. The incidence rates of clinically significant changes from baseline in laboratory tests were also summarized according to baseline BMI.Statistical Analyses was performed using SAS9.2. All interpretations were based on a two-sided 5% significance level.Statistical methodsThe statistical analysis was performed using SAS9.2 statistical software. Qualitative data is described by rate, while quantitative data is described by mean±SD. Qualitative data were carried out by Chi-square test or Fisher test, while quantitative data were carried out by ANOVA,Pearson correlation test was used to test the correlation between waistline, waist/hip ratio, BMI and HbAlc level. All interpretations were based on a two-sided 5% significance level.Result1. Mean HbAlc decreases at week 16, adjusted for baseline values, were-1.82%,1.40% and 1.30% in normal-weight, overweight and obese patients (P>0.05);2. after administered metformin FPG levels decreased significantly in all BMI groups.3. Changes from baseline in TC, LDL-C, HDL-C and TG did not differ significantly among BMI groups at week 16 (P=0.263,0.252,0.597 and 0.257, respectively). BMI decreased 0.13,1.13 and 1.38, respectively(P<0.001).4. Among all the 81 patients,24 patients(29.63%) suffering from adverse event; the incidence of gastrointestinal adverse reaction was 42.86%, which was the most common adverse event in our study; there were no lactic acidosis and hypoglycemia reports in our study.5. Only 3 patients suffering from clinically significant evaluation of alanine aminotransferase, which incidence rate was 3.7%; the incidence rate of clinically significant evaluation of uric acid was the same as that of alanine aminotransferase. No other clinically related laboratory results change was found throughout thisConclusion1. The efficacy of metformin monotherapy was significant for Type 2 diabetes patients of different BMI groups; but the HbAlc of normal weight patients decreased more than overweight and obese patients. Metforin could decrease body weigh significantly; but it had less effect on normal weight patients’body weight.2. gastrointestinal adverse reaction is the most common adverse effect of metformin monotherapy in Chinese type 2 diabetes patients; Most of the adverse effects of metformin monotherapy were moderate, which implies that it is safety for most Chines type 2 diabetes patients.