Muharnniad Azhar Mughal ( Department of Pharmacology and Therapeutics, Ziauddin Medical University, Clifton, Karachi. )
Muhammad Jan ( Department of Pharmacology Avub Medical College, Abbottabad. )
Wali Muhammad Maheri ( Department of Physiology, Liaquat Medical College, Jamshoro, Karachi. )
Muhammad Yousuf Memon ( Departments of Biochemistry, Basic Medical Seiences Institute, Jinnah Postgraduate Medical Center, Karachi. )
Mehar Ali ( Departments of Pharmacology and Therapeuties, Basic Medical Seiences Institute, Jinnah Postgraduate Medical Center, Karachi. )
Objective: TO see if Metformin Monotherapy affects glycemic control, serum lipid or lipoprotein levels in the treatnient of type 2 diabetes who were poorly controlled with diet alone or despite maximal closes of (sulfony lurea) oral glucose lowering agents.
Design: A prospective, clinical intervention trial conducted between 1996-1997, Setting: iwo ou L patienL diabetic clinics ol Karachi.
Patients and Methods: A 12-week prospective clinical intervention trial, A total of 30 type 2 diabetic subjects were enrolled of Whom 21 (12 men and 9 women) completed the study period. T heir ages tanged between 35 and 70 years, (mean ± SD 53.3 ± 9.31) years, with a mean duration since diagnosis of diabetes was 4.5 ± 2.3 years, body mass index (mean ± SD) 26.8 ± 3.53 kg/m2 T ‘hey were previousl’ treated with diet alone or had a lreadv been taking maximum closes of sulfonylurea monotherapy with suboptimal glycemic control, i.e., raised lasting blood glucose concentrations of 6-15 mmol/l.. or (108—270 mg/dL) on two occasions, with significant hyperglycemic symptoms. The patients were treated with metlormin monoiherapy with a follow up of 12 weeks. The initial dosage was 500 mg twice dai y and the dosage was increased to two or three tablets depending on the patients nietabol ic changes. By comparing before and after 12 weeks therapy with metform in we assessed the importance of baseline parameters (glvcemk control, serum lipid and lipoprotein concentrations, and measures of change in body weight and hod mass index).
Results: Metformin therapy signficantly decreased fasting blood glucose levels in all patients ± SD) 227.2 ± 37.5 to 168.6 ± 20.5 mg/dl, p<0.001)]. Serum total cholesterol decreased marginallyI(meant SD) 200.3 ± 18.7 to 181 .4 ± 19.4 mg/ dl, p < 0.01)]. Serum total triglycerides concentration also decreased ± SI)) 195.9 ± 31.9 to 174.2 ± 26.6 mg/dl, P< 0.01)]. Low—density lipoproteins declined ± SD) 123.5 ± 16.9 to 105.5 ± 19. I mg/dl, P< 0.01)], and very-low density lipoprotein cholesterol also decreased Rmean ± SD) 39.2 ± 6.4 to 34.8 ±to 5.3 mg/dl, P<0.0I)]. Whereas, high-density lipoprotein c:holesterol tended to increase ± SD) 37.7 ± 5.1 to 39.5 ± 4.9 mg/dl, l’< 0.01)] / while no significant changes occurred in body’ weight antI body mass index.
Conclusion: Met I’ormin treatment was effective, safe. and generally well tolerated (J PMA 50:381, 2000).
Type 2 diabetes mellitus results from impaired insulin secretion and reduced peripheral insulin sensitivity1. It is frequently found to coexist with other conditions, such as obesity. dyslipidem ia, atherosclerotic vascular disease. and hypertension. which contribute to morbidity and mortal ity. The maior clinical objective in the management of type 2 diabetes is to control hyperglycemia; the long-term objective is to Prevent microvascular and macrovascular complications. although hyperglycemia may be adequately controlled. Cardiovascular disease is the major cause of death in type 2 diabetes2. In particular, type 2 diabetes usual lv presents with concomitant elevations in plasma triglyceride (TG ) eve Is3. The Un ited Kingdom Prospective Diabetes Study (UKPDS) report also revealed that cardiovascular disease was the major cause of complications, and the risk flictors included raised LDL-Cholesterol concentrations. Low H DL-Cholesterol concentrations, elevated blood pressure and HbA Ic concentrations, and smoking4. life style changes, dietary and exercise modification, weight loss, and smoking cessation have been shown to have a positive effect on cardiovascular disease risks although glycemic control prevents several of’ the long—term complications of’ diabetes6. Treatment options include diet, oral antihyperglyccmic agents, and insulin 1 Metformin has been used for over 40 years as an effective glucoselowerine agent in type 2 (non-insulin dependent) diabetes mellitus7 Metformin is an oral higuanide, it ameliorates hyperglycemia by improving peripheral sensitivity to insulin, and reducing gastrointestinal glucose absorption and hepatic glucose production I Treatment with metform in patients8.9, Therefore, one could speculate that improvement of glycem ic control could bene ficial lv influence the lipid profiles. However, outcome data potentially beneficial effect of metformin, is not vet available. This study was designed to see if the treatment of type 2 diabetes with nietformin affects glycemic control, serum 1 pid or lipoprotein levels with suboptimal glcemic control with diet alone or sultbnvlurea monotherapy.
Patients and Methods
The study was carried out in the Phanuacologv and Therapeutics. Basic Medical Sciences Institute. J innah Postgraduate Medical Centre, Karachi, during 1996-97. The Patients were selected from two out patient diabetic clinics of Karachi. A total of 21 adult sub ects. 12 males and 9 females. who had sub—optimal gluemic control and were previously treated with diet alone or maximal doses ol’ sulfonylureas alone were included in the study.
The diagnostic criterion was based on clinical history and the finding of a fasting blood glucose concentration higher than 6.0-15.0 mmol/I. or (108—270 mgidL) on two occasions and hyperglycemic symptoms while receiving diet therapy alone or sulfonylure Age was recorded at the beginning of the study for all subjects. Entry criteria was: Ty pe 2 diabetic patients in concomitant dietary follow-up, body mass index (BMI)<35 kg/m2, BMI was calculated as BMl weight (kg)/height (m2)j. Informed consent was obtained from all study participants.
Patients were excluded, if they had severe diabetic complications or any history of significant ketosis, or mypcardial infarction in the previous year. current angina or heart failure, or a severe undercurrent illness likely to limit life or require systemic therapy 10 Those taking medications known to affect lipid or carbohydrate metabolism, and a significant gastrointestinal, cardiovascular or renal disease were also exclided.
All Patients entered a It days run-in period. Study protocol included screening visits to assess patient eligibiIitv. Patients underwent a standardized baseline assessment, in which cardiovascular and relevant risk factors were assessed. All medications were discontinued 10 das before admission to the study. if’ the patients were already on antidiabetic medications. During that period patients were treated with individualized weight maintaining diets (carbohydrate. 60%: fat. <30% protein, 12-20%) with caloric content adjusted to the patient’s age. body weight, and physical activity as reconiniended by the dietitian.
The study period consisted of 2 weeks with weekly follow-up visits. All the patients were prescribed tablets Glucophage (metforniin hydrochloride) as monotherapy taken orally for 12 weeks.
Subjects were requested not to change any habits that could alter blood lipid levels during the studyc including physical activity and diet. Patients were also forbidden to take any other medication during the study. Therapeutic compliance was monitored at each clinic visit by taking “pill count”, eating habits were assessed by three— day dietary records: caloric intake was assessed by dietitian, Detailed analyses of these food records were recorded: body weight assessed with patients’ coats and shoes removed, All patients were followed up for assessment of glycemic control: 12-14 hours thsting blood glucose was measured usually in the morning at baseline and at each weekly visit up to 12 weeks. Lipids and lipoproteins were measured only at baseline and week 12.
Fasting blood glucose was nicasured by using Accutrend Blood Glucose Analyzer (Boehringer Manpheim Mannheim, Germany). Venous blood from an antecuhital vein was drawn from subjects in the seated position. and the plasma was rapidly separated and refrigerated. Serum total cholesterol, high—density lipoprotein cholesterol and serum total triglyceride concentrations were assayed by standard enzymatic colorimctric methods using commercial kits (Spin react, S. A. Spain). Low-density’ lipoprotein cholesterol levels were calculated usiiig a standard formula Very—low density lipoprotein cholesterol was calculated, according to formula proposed by Wilson. cited by Delong et al12.
All data are expressed as means ± SI). Changes in variables have been calculated as values at the end of a 12week, minus values at the baseline; a negative and positive value implies a lowering or increasing of that value. Differences between means of parameters within groups were tested for significance using the Paired Student’s t—test. For all analyses. P values less than 0.05 was considered significant.
Of 30 selected patients 9(30%) having type 2 diabetes discontinued the study. during the first 3 weeks of the treatment period. The reasons for discontinuation were two subjects poor compliance (2). refusal to participate further (4) lost to fol low—up (2) and diarrhea (I). total of 2 1 subjects completed the study, of whom 11 (52.3%) previously used dietary treatment alone. 10 (47.6%) were on maximum dosage of sulfonylureas. Of the sulfonylureas treated patients. 7 received glibenclamide. 5 received 15 mg/d, and 2 were on 2Omg/d of glihenclamide dosage. 3 patients were taking chlorpropamide 500mg/d, all were taking maximum dosages of sulfonylureas previously. Demographic variables of the 2 1 subjects with type 2 diabetes, who received metformin therapy alone in this study are presented in Table 1.
The mean duration of diabetes was 3.5 years, 5.6 years and 5.7 years in patients previously treated with diet alone, glibenclamide and morning and chlorpropaniide respectively. At the end of follow-up, mean body weight did not change significantly: this reflects insignificant reduction in mean body mass index, indicating that all individuals were compliant with the study protocol. The dosage of mctformin was individualized, with the therapeutic response being monitored by blood glucose determinations during the follow up visits. We initiated metformin therapy with a low dose and gradual increased it. Therapy was started with a dosage of 500 mg twice daily administered with the Morning and evening meals). Increase in dose was made weekly (500 mg tablets) as divided doses three timcs daily. and was also adjusted according to patient’s clinical and metabolic response. The metformin dosage was assessed weekly, mean daiIy dose was 1000 mg/day at the start of therapy week- I and mean daily dose was 1333 mg/day at the end of study week-12. The average dose remained throughout the study was 1243 mg/day.
Table 2 shows that fasting blood glucose density lipoprotein cholesteroL LDL-C Low-density lipoprotem cholesterol concentrations progressively decreased in all patients (n=21) 21) mean 12-week difference from baseline was -58.6, (P 0.001). Whereas. glucose concentrations tended to fall in patients previously treated with diet alone (n-11) difference from baseline was -52.4. (P<0.01). Glibenclamide (n- 7) difference from baseline -65.7. (P<0.002) and chlorpropamide (n=3) difference From baseline was -65.7. (N10.002).
As shown in Table 3.
treatment with metformin monotherapy resulted in favorable trend in lipid and lipoprotein profiles in that there was a trend for decreases in serum total cholesterol, serum total triglycerides. LDLcholesterol. and V .DL-cholestrol while high—density lipoprotein cholesterol concentration was significantly increased at the end of 12 week. ‘treatment with metformin was not associated with adverse changes in any of the lipid parameters that were monitored. The effect of the study drug ou all lipid and lipoprotein parameters were statistically signi licant at the end of metform in treatment (P 0.01).
Over 12 weeks, more upper-2astrointestinal (GI) s\\\\:m ptoms were observed with metform in. 4(19%) of patients reported mild, transient gastrointestinal side eflects include diarrhea, nausea, epigastric discom fort and anore ia none of which required cessation ol metiorm in therapy. The majority of the studied subjects II (52.38%) were previous lv treated with diet alone and I 0(47.6 I %) with suifonlureas. No blood glucose values in the hypoglycemic raupe were observed dtiring the study.
In subjects with type 2 diabetes, both defects oF insulin secretion and insulin resistance contribute to the development of hyperglycem ia. The major goals of treatment are to optimize blood glucose control, and normalize the associated lipid disturbances and elevated blood pressure. Pharmacological treatment is often necessary13.
The treatment of type 2 diabetic patients with secondary failure to sulfonylurea is a common problem14 Metformin has been shown to be safe and effective in improving glycemic control in type 2 diabetes when diet or sulfonylureas alone have been inadequate15-17, Metformin alleviates hyperglycemia of type 2 diabetes by inhibiting hepatic glucose production and improving peripheral insulin sensitivity18. Review ol’ literature shows that metformin interferes with several processes linked to hepatic glucose production (gluconeogenesi s, glycogenolysis and their regulatory niechan isms), lowering glucose production and resensitizing the liver to insulin. The hepatic drug effect is largely favored by prevailing glycemia. In peripheral tissttes. metformin potentiates the effects of both hyperglycemia and hyperinsulinemia. Increase in glucose—mediated glucose transport is mainly mediated by an improvement in the glucose transporter’s intrinsic activity. Potentiation of the hormone effect relates to an increase in insulin receptor tyrosine kinase activity’. Both niechan isms (insu lin signaling and glucose transport) result in the activation of glycogen synthase, a limiting enzyme in the causal defects of type 2 diabetes19 In this study we did not directly assess these parameters. hut the resu Its indicating that metform in certainly has positive effect on these physiological mechanisms, as we found significant declined in all the biochemical parameters of the study.
Current studies suggest that controlling hyperglycemia, LDL-cholesterol. and blood pressure are important to protect the diabetic from atherosclerosis. although low—density lipoprotein (LDL) cholesterol is a critically important factor in the development of atherosclcrosis20. Low-density lipoprotein (LDL) oxidation has been suggested to play a key role in the pathogenesis of atherosclerosis, a major complication of diabetes mellitus21 High-density lipoproteins (HDLs) appear to exert the greatest influence independently of other lipoproteins. with low-density lipoproteins (LDls) having a weaker, though still significant. independent relation with coronary heart disease. This correlates negatively with MDL and positively with LDL so probably H DL retards while LDL accelerates the development of’ clinical events22 In addition, reductions in weight, trigly ceride, Ll)L-cholesterol. insulin resistance, and an increase in HDL-cholestrol have also been reported with nietform in treatments23-26. Defranzo and Goodman reported that met form in treatment is associated with reduced plasma lipids in patient with marked hyperglycemia. As expected, fasting blood glucose concentrations were significantly higher in the diet failure and sulfonylureas treated group in the present study: in that groups plasma levels of total cholesterol. L DL-Cholestrol triglycerides and very—low density lipoprotein cholesterol were also sign ificatitly elevated, while ilDl —Cholesterol was decreased at baseline Table 2 and 3.
Although, fasting blood glucose did not reach the acceptable level in this study, hut this might he expected. since the patients have mean fasting blood giticose concentrations ranged between 154.2 and 280 mg/dl at baseline It becomes increasingly more difficult to attain-near normal glycer ie control, this coo Id he related to type 2 diabetes, which is characterized by steady deterioration of glucose control due to progressive b-cell dysfunction27. In this study, we Found significant decrease in serum cholesterol, triglycerides. LDL.-Cholesterol and VLDLCholesterol levels, they still remained higher and were not optimized, and the reason could he higher levels at baseline. The reduction in LDL—Cholesterol associated W ith metformin in this study is of interest because of the strong association between LDI -Cholesterol level and the development of ischemic heart disease. There also apparent change in HDL-cholesterol was observed; mean change 1.8 at 12 week (P 0.01).
Our results are consistent with some previous studies, where an increase in H Dl -Cholesterol has been associated with metformin therapy24,28,29. A significant decrease in serum cholesterol lev els was also found at the end of’ studs.
Only longer—term studies can determine whether metformin will help to prevent eat complications of type 2 diabetes. Although the patients group in otir sttidy was small and not randomized, however, the resu Its need to be conhrmed in future studies.
It may be concluded from the results of this study that metformin improves glveem ic control. irrespective of the patient’s baseline fasting blood glucose concentration, obesity, or previous therapy. It also has beneficial effects on lipid and lipoprotein concentrations. Metformin can be used safely and effectively as first—I inc monotherapy in type 2 diabetes or when diet alone or sul lbnylurea nionotherapy agent fails. It can be particularl suitable when hyperlipidemia especially with respect to plasma lipid profile. H DL cholesterol, L DL , cholesterol and hypoglycemia are clinically important issues. Metformin that provides these effects, when administered to carefu ly selected patients and monitored appropriately, may prove to be valuable in altering its cardiovascular sequelae. Metformin is not associated with weight gain, and does not produce hypoglycenia.
These differential effects may be important in planning therapy when hyperlipidemia accompanies type 2 diabeLes. These data suggest that metformin therapy in subjects with poorly controlled type 2 diabetes offer an advantage in terms of glycemic control and plasma lipid profile.
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