DIABETES TECHNOLOGY & THERAPEUTICS Volume 17, Number 2, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.0190
ORIGINAL ARTICLE
Efficacy and Safety of Metformin for Patients with Type 1 Diabetes Mellitus: A Meta-Analysis Cong Liu, MD,1 Dan Wu, MM,2 Xuan Zheng, MM,3 Ping Li, MD,1 and Ling Li, MD1
Abstract
Background: Insulin is an essential therapy for patients with type 1 diabetes mellitus (T1DM). With the progression of the disease, many patients with T1DM may have an increased prevalence of insulin resistance; thus the common standard insulin therapy requires a high insulin dosage (>1 unit/kg/day) and is usually associated with many side effects. Studies have shown that metformin may benefit those insulin-resistant individuals with T1DM. This meta-analysis was performed to provide the evidence of clinical efficacy and safety of metformin in T1DM. Materials and Methods: We conducted a search on Medline, EMBASE, and the Cochrane Library for relevant studies published before May 2014 based on ‘‘metformin’’ and ‘‘diabetes mellitus, type 1.’’ The following outcomes were evaluated: hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), lipid metabolism, weight, insulin dosage, hypoglycemia, diabetic ketoacidosis, or gastrointestinal adverse events (AEs). The meta-analysis was performed using Review Manager version 5.2 software (The Nordic Cochrane Centre, Copenhagen, Denmark). Results: In total, eight randomized controlled trials were included. Metformin was associated with a reduction in daily insulin dosage, body weight, total cholesterol level, low-density lipoprotein level, and high-density lipoprotein level but an increase in risk of gastrointestinal AEs compared with placebo treatment in T1DM patients. No significant difference was found between the metformin group and the placebo group in HbA1c level, FPG level, or triglycerides level. No significant difference was found between the metformin group and the placebo group in the risk of severe hypoglycemia or diabetic ketoacidosis. Conclusions: Metformin may decrease the daily insulin dosage, body weight, and lipid levels in T1DM. However, metformin does not increase the incidence of hypoglycemia and ketoacidosis. High-quality, largesample, and long-term follow-up clinical trials are needed to confirm these conclusions. maintaining such a target by the common standard insulin therapy strategy required high daily insulin dosage (>1 unit/ kg/day).3 The literature revealed that a high insulin dosage was often associated with increased risk of hypoglycemia, weight gain, and, in some cases, the aggravation of cardiovascular risk factors, including dyslipidemia.4 Metformin is the first-line oral hypoglycemic agent commonly used in the treatment of type 2 diabetes mellitus (T2DM).5 It decreases the glucose level primarily by suppressing hepatic glucose production (hepatic gluconeogenesis). Metformin improve glycemic control with modest weight loss, which could be beneficial to the reduction of diabetes-related complications.6–8 Based on the positive effects of metformin from the studies in T2DM, we therefore propose that metformin may benefit those insulin-resistant
Introduction
T
ype 1 diabetes mellitus (T1DM) is an autoimmunemediated disease resulting from the selective and progressive destruction of insulin-producing b-cells in pancreatic islets. Insulin administration is essential for patients with T1DM, yet keeping euglycemia is highly challenging in clinical practice. The Diabetes Control and Complications Trial1 and its follow-up observations2 have shown that intensive glucose control was associated with significant long-term reduction in both microvascular and macrovascular complications in T1DM patients. However, many patients could not reach the recommended target in hemoglobin A1c (HbA1c) levels during the insulin therapy. The reason was that achieving and
1 NO.2 Department of Endocrinology, 2NO.2 Department of Rheumatology, and 3Department of Hospice, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China.
1
2
43.5 – 13.1
Jacobsen et al.11 (2009)
46.1 – 11.6
39.9 – 12.9 46 – 8
17.2 – 1.7
Lund et al.14 (2009)
Meyer et al.15 (2002) Pitocco et al.16 (2012)
Sa¨rnblad et al.17 (2003) 16.9 – 1.4
41.1 – 9.8 41 – 10
44.9 – 10.8
44.9 – 10.8
48 – 12
37.3 – 9.6
15.9 – 1.7
PL
F, female; M, male; MET, metformin; PL, placebo.
46.1 – 11.6
Lund et al.13 (2008)
48 – 12
15.7 – 1.9
Hamilton et al.3 (2003)
Khan et al.12 (2006)
MET
Reference (year of study)
Age (years)
5/11
20/11 9/12
33/16
33/16
8/7
14/10
6/8
MET
4/10
17/14 9/12
31/20
31/20
8/7
7/6
PL
Sex (M/F)
9.1 – 5.0
No data 9.2 – 0.7
30 (5–51)
30 (5–51)
19 – 10
17.8 – 10.3
9.7 – 4.4
MET
7.1 – 3.0
No data 8.8 – 0.8
26 (6–56)
26 (6–56)
19 – 10
20.3 – 10.2
6.9 – 3.8
PL
Duration of diabetes MET dose Starting dose was 500 mg/day, and the dose was increased by 500 mg/day each week to a maximum of 1,000 mg/day (500 mg twice) for those weighing < 50 kg, 1,500 mg/day (one 1,000-mg and one 500-mg dose) for those weighing 50–75 kg, or 2,000 mg/day (1,000 mg twice) for those weighing > 75 kg. Starting dose was 500 mg twice daily for 2 weeks, followed by 1,000 mg twice daily for the rest of the study period. Starting dose was 850 mg/day, and the dose was increased by 850 mg/day each week to a maximum of 850 mg three times daily. The starting dose was 500 mg once daily, and the dose was increased to maximum (1,000 mg twice daily) after 3 weeks. The starting dose was 500 mg once daily, and the dose was increased to maximum (1,000 mg twice daily) after 3 weeks. 850 mg twice daily The starting dose was 850 mg/day, and the dose was increased by 850 mg/day each week to a maximum of 850 mg three times daily. Starting dose was 500 mg daily in the morning for 1 week, followed by 500 mg twice daily for 3 weeks and then 1,000 mg twice daily for the rest of the study period.
Table 1. Basic Characteristics of Included Studies
3 months
6 months 6 months
12 months
12 months
16 weeks
24 weeks
3 months
Study duration
30
62 42
100
100
15
24
27
Study size
3
3 3
3
3
5
3
5
Jadad score
META-ANALYSIS OF METFORMIN IN T1DM
3
T1DM patients whose daily insulin requirement was more than 1 unit/kg of body weight.3 We also propose that metformin may produce a better control of glucose and lipids with less weight gain and a reduced daily insulin dosage. To investigate and provide an up-to-date and comprehensive picture of the clinical efficacy and safety of metformin in T1DM, we conducted this meta-analysis to provide the evidence that metformin might be prescribed for some patients with T1DM. Materials and Methods
We captured all relevant studies published before May 2014 in Medline, EMBASE, and the Cochrane Library based on the following search terms as medical subject headings: (1) ‘‘metformin’’ and (2) ‘‘diabetes mellitus, type 1’’ or ‘‘type 1 diabetes’’ or ‘‘insulin dependent diabetes.’’ We included the studies in this meta-analysis if (1) they were randomized controlled trials, (2) the duration of treatment was ‡12 weeks, (3) they used a parallel design or crossover design of metformin versus placebo treatment, and (4) they reported data on HbA1c change, fasting plasma glucose (FPG) change, lipid metabolism, weight change, insulin dosage, hypoglycemia, or diabetic ketoacidosis, or gastrointestinal adverse events (AEs) were investigated. Abstracts of cited articles were reviewed by two independent investigators (X.Z. and P.L.) to determine the relevance. Disagreements were resolved through discussion and consensus or, as needed, with a third investigator (L.L.) and confirmed by consensus. When there were multiple articles from the same trial, the most complete and recently reported data were used. The quality of included articles was further assessed using the criteria of Jadad et al.9 The score range was from 0 to 5 (a high score indicating high quality). The statistical analysis was performed with Review Manager version 5.2 (The Nordic Cochrane Centre, Copenhagen, Denmark) from the Cochrane Collaboration (2013). Continuous variables were analyzed using the weighted mean differences (MD) under general circumstances but standardized MD for different units of measurement, whereas categorical dichotomous variables were assessed using relative risks (RR). A P value of < 0.05 was considered to be statically significant, and 95% confidence intervals (CI) were reported. Homogeneity was tested by the Q statistic (significance level at P < 0.10) and the I2 statistic (significance level at I2 > 50%).10 A random-effects model was used if the Q or I2 statistic was significant. Otherwise, a fixed-effects model was used.
FIG. 1. Flowchart demonstrating process of study selection. Results
The initial literature search retrieved 340 relevant articles. Two hundred and one articles were excluded after the titles were scanned. One hundred and twenty-one articles were excluded after the abstracts were carefully read. Then, 10 articles were excluded for various reasons (duplicate, review, case report, no required data), and finally eight randomized controlled trials were retained for meta-analysis (Fig. 1).3,11–17 Pooled analysis included 300 patients. Overall, included studies were of adequate methodologic quality (mean Jadad score of 3.5 for included studies; all of the eight studies had a score of ‡ 3). Included studies, basic characteristics of enrolled patients, and details on drug therapy are presented in Table 1. The results of meta-analysis showed that metformin was associated with a reduction in daily insulin dosage (in units/ day) (MD = - 1.36; 95% CI, - 2.28 to - 0.45; P = 0.004) (Fig. 2), lower body weight (in kg) (MD = - 2.41; 95% CI, - 4.17 to - 0.65; P = 0.007) (Fig. 3), lower total cholesterol level (in mmol/L) (MD = - 0.25; 95% CI, - 0.46 to - 0.05; P = 0.02) (Fig. 4), lower low-density lipoprotein level (in mmol/L) (MD = - 0.24; 95% CI, - 0.41 to - 0.07; P = 0.005)
FIG. 2. Meta-analysis of insulin dosage of metformin for type 1 diabetes.3,11–13,15 CI, confidence interval; IV, inverse variance.
4
LIU ET AL.
FIG. 3. Meta-analysis of body weight change of metformin for type 1 diabetes.11–13,17 CI, confidence interval; IV, inverse variance.
FIG. 4. Meta-analysis of total cholesterol change of metformin for type 1 diabetes.11,12,14 CI, confidence interval; IV, inverse variance. (Fig. 5), and lower high-density lipoprotein level (mmol/L) (MD = - 0.05; 95% CI, - 0.08 to - 0.03; P < 0.00001) (Fig. 6) but an increase in the risk of gastrointestinal AEs (RR = 1.38; 95% CI, 1.10–1.74; P = 0.005) (Fig. 7) compared with placebo treatment in T1DM patients. No significant difference was found between the metformin group and the placebo group for the HbA1c level (%) (MD = - 0.20; 95% CI, - 0.45 to - 0.05; P = 0.11) (Fig. 8), FPG level (in mmol/ L) (MD = - 1.17; 95% CI, - 4.70 to 2.35; P = 0.51) (Fig. 9), and triglycerides level (in mmol/L) (MD = 0.10; 95% CI, - 0.05 to 0.25; P = 0.18) (Fig. 10). No significant difference was found between the metformin group and the placebo group in the risk of severe hypoglycemia (RR = 1.28; 95% CI, 0.71–2.30; P = 0.41) (Fig. 7) or diabetic ketoacidosis (RR = 0.21; 95% CI, 0.01–4.23; P = 0.31) (Fig. 7). Discussion
We found only eight randomized studies of metformin therapy in T1DM, which were small samples. Nonetheless,
the meta-analysis results showed that metformin produced greater reduction in daily insulin dosage, body weight, total cholesterol, and low-density lipoprotein than placebo. However, metformin showed lower high-density lipoprotein and higher risk of gastrointestinal AEs compared with placebo. No significant difference was found between metformin and placebo for HbA1c, FPG, and triglycerides levels or the risk of severe hypoglycemia and diabetic ketoacidosis. Another meta-analysis has obtained similar results.18 Metformin was thought to improve the reduced insulin sensitivity in overweight subjects,19 prediabetes,20 patients with T2DM,21 and patients with T1DM.22 In our metaanalysis, metformin administration significantly decreased the daily insulin dose requirement, indicating that metformin might improve the insulin sensitivity in T1DM. There was no significant effect on HbA1c and FPG, which might be expected as patients would tend to adjust their insulin dosage toward their usual HbA1c and FPG levels. Although several potential benefits on glycemic control have been reported in
FIG. 5. Meta-analysis of low-density lipoprotein level change of metformin for type 1 diabetes.11,12,14 CI, confidence interval; IV, inverse variance.
META-ANALYSIS OF METFORMIN IN T1DM
5
FIG. 6. Meta-analysis of high-density lipoprotein level change of metformin for type 1 diabetes.11,12,14 CI, confidence interval; IV, inverse variance. different studies,10,12,17,23 there is little evidence that metformin has any significant effect on HbA1c or FPG in T1DM. Patients with T1DM and T2DM showed a significant prior risk of cardiovascular disease compared with the group without diabetes.24 In the group without diabetes as well as in
patients with diabetes, dyslipidemia is an important cardiovascular disease risk factor.25 In our meta-analysis, we found metformin has been associated with a reduction in total cholesterol and low-density lipoprotein levels, and we speculate that metformin may reduce the risk of cardiovascular
FIG. 7. Meta-analysis of safety of metformin for type 1 diabetes.3,11–13,15–17 AEs, adverse events; CI, confidence interval; GI, gastrointestinal; MH, Mantel–Haenszel.
6
LIU ET AL.
FIG. 8. Meta-analysis of hemoglobin A1c level change of metformin for type 1 diabetes.3,11–13,15,17 CI, confidence interval; IV, inverse variance.
FIG. 9. Meta-analysis of fasting plasma glucose level change of metformin for type 1 diabetes.3,12,13 CI, confidence interval; IV, inverse variance. disease. Only one17 of our included studies reported cardiovascular AEs: two patients with two events in the metformin group versus four patients with five events in the placebo group (not a significant difference). Metformin has been definitively found to reduce cardiovascular events in T2DM,26,27 whereas in T1DM, metformin has been proposed to have beneficial effects on cardiovascular risks, but this needs to be further proven.28 Another double-blind, randomized, placebo-controlled trial will provide important information on a potential intervention of metformin to improve cardiovascular morbidity and mortality in children with T1DM at high risk from cardiovascular disease.29 In order to reduce gastrointestinal AEs, medication (metformin or placebo) in all studies was taken during or at the end of meals. Although a higher gastrointestinal AE risk was shown in the metformin treatment group in patients with T1DM, only four patients in the metformin group in all eight studies were withdrawn because of digestive symptoms.3,15
We therefore concluded that the gastrointestinal AEs of metformin can be tolerated in most patients with T1DM. The differences were not statistically significant in severe hypoglycemia and diabetic ketoacidosis. Based on the results in our analysis, we concluded that metformin administration was safe in combination with insulin therapy in patients with T1DM. Eight included studies met the inclusion criteria, with a mean Jadad score of 3.5. Therefore the conclusions of this systematic analysis are reliable. In summary, metformin, which may possibly decrease the risk of cardiovascular events, was safe and effective in patients with T1DM. It could be a credible alternative for T1DM patients who are on high daily insulin dosage and with a high risk of hypoglycemia, obvious body weight gain, and possibly high risk of cardiovascular exposure during the monoinsulin therapy. More high-quality, large-sample, further long-term follow-up, randomized, multicenter clinical trials are needed to confirm our results.
FIG. 10. Meta-analysis of triglycerides level change of metformin for type 1 diabetes.11,12,14 CI, confidence interval; IV, inverse variance.
META-ANALYSIS OF METFORMIN IN T1DM
7
Author Disclosure Statement
No competing financial interests exist.
18.
References
1. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–986. 2. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653. 3. Hamilton J, Cummings E, Zdravkovic V, et al.: Metformin as an adjunct therapy in adolescents with type 1 diabetes and insulin resistance: a randomized controlled trial. Diabetes Care 2003;26:138–143. 4. Timar R, Timar B, Degeratu D, et al.: Metabolic syndrome, adiponectin and proinflammatory status in patients with type 1 diabetes mellitus. J Int Med Res 2014;42:1131–1138. 5. Bailey CJ, Turner RC: Metformin. N Engl J Med 1996; 334:574–579. 6. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865. 7. Gerich JE: Oral hypoglycemic agents. N Engl J Med 1989; 321:1231–1245. 8. Bailey CJ: Biguanides and NIDDM. Diabetes Care 1992; 15:755–772. 9. Jadad AR, Moore RA, Carroll D, et al.: Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. 10. Higgins JP, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–1558. 11. Jacobsen IB, Henriksen JE, Beck-Nielsen H: The effect of metformin in overweight patients with type 1 diabetes and poor metabolic control. Basic Clin Pharmacol Toxicol 2009; 105:145–149. 12. Khan AS, McLouqhney CR, Ahmed AB: The effect of metformin on blood glucose control in overweight patients with Type 1 diabetes. Diabet Med 2006;23:1079–1084. 13. Lund SS, Tarnow L, Astrup AS, et al.: Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. PLoS One 2008;3:e3363. 14. Lund SS, Tarnow L, Astrup AS, et al.: Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes. Diabetes Obes Metab 2009;11:966–977. 15. Meyer L, Bohme P, Delbachian I, et al. The benefits of metformin therapy during continuous subcutaneous insulin infusion treatment of type 1 diabetic patients. Diabetes Care 2002;25:2153–2158. 16. Pitocco D, Zaccardi F, Tarzia P, et al.: Metformin improves endothelial function in type 1 diabetic subjects: a pilot, placebo-controlled randomized study. Diabetes Obes Metab 2013;15:427–431. 17. Sa¨rnblad S, Kroon M, Aman J: Metformin as additional therapy in adolescents with poorly controlled type 1 dia-
19.
20.
21.
22.
23. 24.
25.
26. 27.
28.
29.
betes: randomised placebo-controlled trial with aspects on insulin sensitivity. Eur J Endocrinol 2003;149:323–329. Vella S, Buetow L, Royle P, et al.: The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 2010;53:809–820. Tamura Y, Watada H, Sato F, et al.: Effects of metformin on peripheral insulin sensitivity and intracellular lipid contents in muscle and liver of overweight Japanese subjects. Diabetes Obes Metab 2008;10:733–738. Malin SK, Gerber R, Chipkin SR, et al.: Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care 2012;35:131–136. Gonza´lez-Ortiz M, Martı´nez-Abundis E, Robles-Cervantes JA, et al.: Effect of metformin glycinate on glycated hemoglobin A1C concentration and insulin sensitivity in drug-naive adult patients with type 2 diabetes mellitus. Diabetes Technol Ther 2012;14:1140–1144. Moon RJ, Bascombe LA, Holt RI: The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being. Diabetes Obes Metab 2007;9:143–145. Urakami T, Morimoto S, Owada M, et al.: Usefulness of the addition of metformin to insulin in pediatric patients with type 1 diabetes mellitus. Pediatr Int 2005;47:430–433. Schramm TK, Gislason GH, Køber L, et al.: Diabetes patients requiring glucose-lowering therapy and non-diabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 2008;117:1945–1954. Ryde´n L, Standl E, Bartnik M, et al.: Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007;28:88–136. Holman RR, Paul SK, Bethel MA, et al.: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–1589. Kooy A, de Jager J, Lehert P, et al.: Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009;169:616–625. Saunders SA, Wallymhamed M, Macfarlane IA: Improvements in glycaemic control and cardiovascular risk factors in a cohort of patients with type 1 diabetes over a 5-year period. QJM 2009;102:29–34. Anderson J, Pen˜a AS, Sullivan T, et al.: Does metformin improve vascular heath in children with type 1 diabetes? Protocol for a one year, double blind, randomised, placebo controlled trial. BMC Pediatr 2013;13:108.
Address correspondence to: Cong Liu, MD NO.2 Department of Endocrinology Shengjing Hospital of China Medical University NO.39, Huaxiang Road Tiexi District Shenyang 110022, Liaoning, People’s Republic of China E-mail: [email protected]
ORIGINAL ARTICLE
Efficacy and Safety of Metformin for Patients with Type 1 Diabetes Mellitus: A Meta-Analysis Cong Liu, MD,1 Dan Wu, MM,2 Xuan Zheng, MM,3 Ping Li, MD,1 and Ling Li, MD1
Abstract
Background: Insulin is an essential therapy for patients with type 1 diabetes mellitus (T1DM). With the progression of the disease, many patients with T1DM may have an increased prevalence of insulin resistance; thus the common standard insulin therapy requires a high insulin dosage (>1 unit/kg/day) and is usually associated with many side effects. Studies have shown that metformin may benefit those insulin-resistant individuals with T1DM. This meta-analysis was performed to provide the evidence of clinical efficacy and safety of metformin in T1DM. Materials and Methods: We conducted a search on Medline, EMBASE, and the Cochrane Library for relevant studies published before May 2014 based on ‘‘metformin’’ and ‘‘diabetes mellitus, type 1.’’ The following outcomes were evaluated: hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), lipid metabolism, weight, insulin dosage, hypoglycemia, diabetic ketoacidosis, or gastrointestinal adverse events (AEs). The meta-analysis was performed using Review Manager version 5.2 software (The Nordic Cochrane Centre, Copenhagen, Denmark). Results: In total, eight randomized controlled trials were included. Metformin was associated with a reduction in daily insulin dosage, body weight, total cholesterol level, low-density lipoprotein level, and high-density lipoprotein level but an increase in risk of gastrointestinal AEs compared with placebo treatment in T1DM patients. No significant difference was found between the metformin group and the placebo group in HbA1c level, FPG level, or triglycerides level. No significant difference was found between the metformin group and the placebo group in the risk of severe hypoglycemia or diabetic ketoacidosis. Conclusions: Metformin may decrease the daily insulin dosage, body weight, and lipid levels in T1DM. However, metformin does not increase the incidence of hypoglycemia and ketoacidosis. High-quality, largesample, and long-term follow-up clinical trials are needed to confirm these conclusions. maintaining such a target by the common standard insulin therapy strategy required high daily insulin dosage (>1 unit/ kg/day).3 The literature revealed that a high insulin dosage was often associated with increased risk of hypoglycemia, weight gain, and, in some cases, the aggravation of cardiovascular risk factors, including dyslipidemia.4 Metformin is the first-line oral hypoglycemic agent commonly used in the treatment of type 2 diabetes mellitus (T2DM).5 It decreases the glucose level primarily by suppressing hepatic glucose production (hepatic gluconeogenesis). Metformin improve glycemic control with modest weight loss, which could be beneficial to the reduction of diabetes-related complications.6–8 Based on the positive effects of metformin from the studies in T2DM, we therefore propose that metformin may benefit those insulin-resistant
Introduction
T
ype 1 diabetes mellitus (T1DM) is an autoimmunemediated disease resulting from the selective and progressive destruction of insulin-producing b-cells in pancreatic islets. Insulin administration is essential for patients with T1DM, yet keeping euglycemia is highly challenging in clinical practice. The Diabetes Control and Complications Trial1 and its follow-up observations2 have shown that intensive glucose control was associated with significant long-term reduction in both microvascular and macrovascular complications in T1DM patients. However, many patients could not reach the recommended target in hemoglobin A1c (HbA1c) levels during the insulin therapy. The reason was that achieving and
1 NO.2 Department of Endocrinology, 2NO.2 Department of Rheumatology, and 3Department of Hospice, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China.
1
2
43.5 – 13.1
Jacobsen et al.11 (2009)
46.1 – 11.6
39.9 – 12.9 46 – 8
17.2 – 1.7
Lund et al.14 (2009)
Meyer et al.15 (2002) Pitocco et al.16 (2012)
Sa¨rnblad et al.17 (2003) 16.9 – 1.4
41.1 – 9.8 41 – 10
44.9 – 10.8
44.9 – 10.8
48 – 12
37.3 – 9.6
15.9 – 1.7
PL
F, female; M, male; MET, metformin; PL, placebo.
46.1 – 11.6
Lund et al.13 (2008)
48 – 12
15.7 – 1.9
Hamilton et al.3 (2003)
Khan et al.12 (2006)
MET
Reference (year of study)
Age (years)
5/11
20/11 9/12
33/16
33/16
8/7
14/10
6/8
MET
4/10
17/14 9/12
31/20
31/20
8/7
7/6
PL
Sex (M/F)
9.1 – 5.0
No data 9.2 – 0.7
30 (5–51)
30 (5–51)
19 – 10
17.8 – 10.3
9.7 – 4.4
MET
7.1 – 3.0
No data 8.8 – 0.8
26 (6–56)
26 (6–56)
19 – 10
20.3 – 10.2
6.9 – 3.8
PL
Duration of diabetes MET dose Starting dose was 500 mg/day, and the dose was increased by 500 mg/day each week to a maximum of 1,000 mg/day (500 mg twice) for those weighing < 50 kg, 1,500 mg/day (one 1,000-mg and one 500-mg dose) for those weighing 50–75 kg, or 2,000 mg/day (1,000 mg twice) for those weighing > 75 kg. Starting dose was 500 mg twice daily for 2 weeks, followed by 1,000 mg twice daily for the rest of the study period. Starting dose was 850 mg/day, and the dose was increased by 850 mg/day each week to a maximum of 850 mg three times daily. The starting dose was 500 mg once daily, and the dose was increased to maximum (1,000 mg twice daily) after 3 weeks. The starting dose was 500 mg once daily, and the dose was increased to maximum (1,000 mg twice daily) after 3 weeks. 850 mg twice daily The starting dose was 850 mg/day, and the dose was increased by 850 mg/day each week to a maximum of 850 mg three times daily. Starting dose was 500 mg daily in the morning for 1 week, followed by 500 mg twice daily for 3 weeks and then 1,000 mg twice daily for the rest of the study period.
Table 1. Basic Characteristics of Included Studies
3 months
6 months 6 months
12 months
12 months
16 weeks
24 weeks
3 months
Study duration
30
62 42
100
100
15
24
27
Study size
3
3 3
3
3
5
3
5
Jadad score
META-ANALYSIS OF METFORMIN IN T1DM
3
T1DM patients whose daily insulin requirement was more than 1 unit/kg of body weight.3 We also propose that metformin may produce a better control of glucose and lipids with less weight gain and a reduced daily insulin dosage. To investigate and provide an up-to-date and comprehensive picture of the clinical efficacy and safety of metformin in T1DM, we conducted this meta-analysis to provide the evidence that metformin might be prescribed for some patients with T1DM. Materials and Methods
We captured all relevant studies published before May 2014 in Medline, EMBASE, and the Cochrane Library based on the following search terms as medical subject headings: (1) ‘‘metformin’’ and (2) ‘‘diabetes mellitus, type 1’’ or ‘‘type 1 diabetes’’ or ‘‘insulin dependent diabetes.’’ We included the studies in this meta-analysis if (1) they were randomized controlled trials, (2) the duration of treatment was ‡12 weeks, (3) they used a parallel design or crossover design of metformin versus placebo treatment, and (4) they reported data on HbA1c change, fasting plasma glucose (FPG) change, lipid metabolism, weight change, insulin dosage, hypoglycemia, or diabetic ketoacidosis, or gastrointestinal adverse events (AEs) were investigated. Abstracts of cited articles were reviewed by two independent investigators (X.Z. and P.L.) to determine the relevance. Disagreements were resolved through discussion and consensus or, as needed, with a third investigator (L.L.) and confirmed by consensus. When there were multiple articles from the same trial, the most complete and recently reported data were used. The quality of included articles was further assessed using the criteria of Jadad et al.9 The score range was from 0 to 5 (a high score indicating high quality). The statistical analysis was performed with Review Manager version 5.2 (The Nordic Cochrane Centre, Copenhagen, Denmark) from the Cochrane Collaboration (2013). Continuous variables were analyzed using the weighted mean differences (MD) under general circumstances but standardized MD for different units of measurement, whereas categorical dichotomous variables were assessed using relative risks (RR). A P value of < 0.05 was considered to be statically significant, and 95% confidence intervals (CI) were reported. Homogeneity was tested by the Q statistic (significance level at P < 0.10) and the I2 statistic (significance level at I2 > 50%).10 A random-effects model was used if the Q or I2 statistic was significant. Otherwise, a fixed-effects model was used.
FIG. 1. Flowchart demonstrating process of study selection. Results
The initial literature search retrieved 340 relevant articles. Two hundred and one articles were excluded after the titles were scanned. One hundred and twenty-one articles were excluded after the abstracts were carefully read. Then, 10 articles were excluded for various reasons (duplicate, review, case report, no required data), and finally eight randomized controlled trials were retained for meta-analysis (Fig. 1).3,11–17 Pooled analysis included 300 patients. Overall, included studies were of adequate methodologic quality (mean Jadad score of 3.5 for included studies; all of the eight studies had a score of ‡ 3). Included studies, basic characteristics of enrolled patients, and details on drug therapy are presented in Table 1. The results of meta-analysis showed that metformin was associated with a reduction in daily insulin dosage (in units/ day) (MD = - 1.36; 95% CI, - 2.28 to - 0.45; P = 0.004) (Fig. 2), lower body weight (in kg) (MD = - 2.41; 95% CI, - 4.17 to - 0.65; P = 0.007) (Fig. 3), lower total cholesterol level (in mmol/L) (MD = - 0.25; 95% CI, - 0.46 to - 0.05; P = 0.02) (Fig. 4), lower low-density lipoprotein level (in mmol/L) (MD = - 0.24; 95% CI, - 0.41 to - 0.07; P = 0.005)
FIG. 2. Meta-analysis of insulin dosage of metformin for type 1 diabetes.3,11–13,15 CI, confidence interval; IV, inverse variance.
4
LIU ET AL.
FIG. 3. Meta-analysis of body weight change of metformin for type 1 diabetes.11–13,17 CI, confidence interval; IV, inverse variance.
FIG. 4. Meta-analysis of total cholesterol change of metformin for type 1 diabetes.11,12,14 CI, confidence interval; IV, inverse variance. (Fig. 5), and lower high-density lipoprotein level (mmol/L) (MD = - 0.05; 95% CI, - 0.08 to - 0.03; P < 0.00001) (Fig. 6) but an increase in the risk of gastrointestinal AEs (RR = 1.38; 95% CI, 1.10–1.74; P = 0.005) (Fig. 7) compared with placebo treatment in T1DM patients. No significant difference was found between the metformin group and the placebo group for the HbA1c level (%) (MD = - 0.20; 95% CI, - 0.45 to - 0.05; P = 0.11) (Fig. 8), FPG level (in mmol/ L) (MD = - 1.17; 95% CI, - 4.70 to 2.35; P = 0.51) (Fig. 9), and triglycerides level (in mmol/L) (MD = 0.10; 95% CI, - 0.05 to 0.25; P = 0.18) (Fig. 10). No significant difference was found between the metformin group and the placebo group in the risk of severe hypoglycemia (RR = 1.28; 95% CI, 0.71–2.30; P = 0.41) (Fig. 7) or diabetic ketoacidosis (RR = 0.21; 95% CI, 0.01–4.23; P = 0.31) (Fig. 7). Discussion
We found only eight randomized studies of metformin therapy in T1DM, which were small samples. Nonetheless,
the meta-analysis results showed that metformin produced greater reduction in daily insulin dosage, body weight, total cholesterol, and low-density lipoprotein than placebo. However, metformin showed lower high-density lipoprotein and higher risk of gastrointestinal AEs compared with placebo. No significant difference was found between metformin and placebo for HbA1c, FPG, and triglycerides levels or the risk of severe hypoglycemia and diabetic ketoacidosis. Another meta-analysis has obtained similar results.18 Metformin was thought to improve the reduced insulin sensitivity in overweight subjects,19 prediabetes,20 patients with T2DM,21 and patients with T1DM.22 In our metaanalysis, metformin administration significantly decreased the daily insulin dose requirement, indicating that metformin might improve the insulin sensitivity in T1DM. There was no significant effect on HbA1c and FPG, which might be expected as patients would tend to adjust their insulin dosage toward their usual HbA1c and FPG levels. Although several potential benefits on glycemic control have been reported in
FIG. 5. Meta-analysis of low-density lipoprotein level change of metformin for type 1 diabetes.11,12,14 CI, confidence interval; IV, inverse variance.
META-ANALYSIS OF METFORMIN IN T1DM
5
FIG. 6. Meta-analysis of high-density lipoprotein level change of metformin for type 1 diabetes.11,12,14 CI, confidence interval; IV, inverse variance. different studies,10,12,17,23 there is little evidence that metformin has any significant effect on HbA1c or FPG in T1DM. Patients with T1DM and T2DM showed a significant prior risk of cardiovascular disease compared with the group without diabetes.24 In the group without diabetes as well as in
patients with diabetes, dyslipidemia is an important cardiovascular disease risk factor.25 In our meta-analysis, we found metformin has been associated with a reduction in total cholesterol and low-density lipoprotein levels, and we speculate that metformin may reduce the risk of cardiovascular
FIG. 7. Meta-analysis of safety of metformin for type 1 diabetes.3,11–13,15–17 AEs, adverse events; CI, confidence interval; GI, gastrointestinal; MH, Mantel–Haenszel.
6
LIU ET AL.
FIG. 8. Meta-analysis of hemoglobin A1c level change of metformin for type 1 diabetes.3,11–13,15,17 CI, confidence interval; IV, inverse variance.
FIG. 9. Meta-analysis of fasting plasma glucose level change of metformin for type 1 diabetes.3,12,13 CI, confidence interval; IV, inverse variance. disease. Only one17 of our included studies reported cardiovascular AEs: two patients with two events in the metformin group versus four patients with five events in the placebo group (not a significant difference). Metformin has been definitively found to reduce cardiovascular events in T2DM,26,27 whereas in T1DM, metformin has been proposed to have beneficial effects on cardiovascular risks, but this needs to be further proven.28 Another double-blind, randomized, placebo-controlled trial will provide important information on a potential intervention of metformin to improve cardiovascular morbidity and mortality in children with T1DM at high risk from cardiovascular disease.29 In order to reduce gastrointestinal AEs, medication (metformin or placebo) in all studies was taken during or at the end of meals. Although a higher gastrointestinal AE risk was shown in the metformin treatment group in patients with T1DM, only four patients in the metformin group in all eight studies were withdrawn because of digestive symptoms.3,15
We therefore concluded that the gastrointestinal AEs of metformin can be tolerated in most patients with T1DM. The differences were not statistically significant in severe hypoglycemia and diabetic ketoacidosis. Based on the results in our analysis, we concluded that metformin administration was safe in combination with insulin therapy in patients with T1DM. Eight included studies met the inclusion criteria, with a mean Jadad score of 3.5. Therefore the conclusions of this systematic analysis are reliable. In summary, metformin, which may possibly decrease the risk of cardiovascular events, was safe and effective in patients with T1DM. It could be a credible alternative for T1DM patients who are on high daily insulin dosage and with a high risk of hypoglycemia, obvious body weight gain, and possibly high risk of cardiovascular exposure during the monoinsulin therapy. More high-quality, large-sample, further long-term follow-up, randomized, multicenter clinical trials are needed to confirm our results.
FIG. 10. Meta-analysis of triglycerides level change of metformin for type 1 diabetes.11,12,14 CI, confidence interval; IV, inverse variance.
META-ANALYSIS OF METFORMIN IN T1DM
7
Author Disclosure Statement
No competing financial interests exist.
18.
References
1. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–986. 2. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653. 3. Hamilton J, Cummings E, Zdravkovic V, et al.: Metformin as an adjunct therapy in adolescents with type 1 diabetes and insulin resistance: a randomized controlled trial. Diabetes Care 2003;26:138–143. 4. Timar R, Timar B, Degeratu D, et al.: Metabolic syndrome, adiponectin and proinflammatory status in patients with type 1 diabetes mellitus. J Int Med Res 2014;42:1131–1138. 5. Bailey CJ, Turner RC: Metformin. N Engl J Med 1996; 334:574–579. 6. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865. 7. Gerich JE: Oral hypoglycemic agents. N Engl J Med 1989; 321:1231–1245. 8. Bailey CJ: Biguanides and NIDDM. Diabetes Care 1992; 15:755–772. 9. Jadad AR, Moore RA, Carroll D, et al.: Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. 10. Higgins JP, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–1558. 11. Jacobsen IB, Henriksen JE, Beck-Nielsen H: The effect of metformin in overweight patients with type 1 diabetes and poor metabolic control. Basic Clin Pharmacol Toxicol 2009; 105:145–149. 12. Khan AS, McLouqhney CR, Ahmed AB: The effect of metformin on blood glucose control in overweight patients with Type 1 diabetes. Diabet Med 2006;23:1079–1084. 13. Lund SS, Tarnow L, Astrup AS, et al.: Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. PLoS One 2008;3:e3363. 14. Lund SS, Tarnow L, Astrup AS, et al.: Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes. Diabetes Obes Metab 2009;11:966–977. 15. Meyer L, Bohme P, Delbachian I, et al. The benefits of metformin therapy during continuous subcutaneous insulin infusion treatment of type 1 diabetic patients. Diabetes Care 2002;25:2153–2158. 16. Pitocco D, Zaccardi F, Tarzia P, et al.: Metformin improves endothelial function in type 1 diabetic subjects: a pilot, placebo-controlled randomized study. Diabetes Obes Metab 2013;15:427–431. 17. Sa¨rnblad S, Kroon M, Aman J: Metformin as additional therapy in adolescents with poorly controlled type 1 dia-
19.
20.
21.
22.
23. 24.
25.
26. 27.
28.
29.
betes: randomised placebo-controlled trial with aspects on insulin sensitivity. Eur J Endocrinol 2003;149:323–329. Vella S, Buetow L, Royle P, et al.: The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 2010;53:809–820. Tamura Y, Watada H, Sato F, et al.: Effects of metformin on peripheral insulin sensitivity and intracellular lipid contents in muscle and liver of overweight Japanese subjects. Diabetes Obes Metab 2008;10:733–738. Malin SK, Gerber R, Chipkin SR, et al.: Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care 2012;35:131–136. Gonza´lez-Ortiz M, Martı´nez-Abundis E, Robles-Cervantes JA, et al.: Effect of metformin glycinate on glycated hemoglobin A1C concentration and insulin sensitivity in drug-naive adult patients with type 2 diabetes mellitus. Diabetes Technol Ther 2012;14:1140–1144. Moon RJ, Bascombe LA, Holt RI: The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being. Diabetes Obes Metab 2007;9:143–145. Urakami T, Morimoto S, Owada M, et al.: Usefulness of the addition of metformin to insulin in pediatric patients with type 1 diabetes mellitus. Pediatr Int 2005;47:430–433. Schramm TK, Gislason GH, Køber L, et al.: Diabetes patients requiring glucose-lowering therapy and non-diabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 2008;117:1945–1954. Ryde´n L, Standl E, Bartnik M, et al.: Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007;28:88–136. Holman RR, Paul SK, Bethel MA, et al.: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–1589. Kooy A, de Jager J, Lehert P, et al.: Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009;169:616–625. Saunders SA, Wallymhamed M, Macfarlane IA: Improvements in glycaemic control and cardiovascular risk factors in a cohort of patients with type 1 diabetes over a 5-year period. QJM 2009;102:29–34. Anderson J, Pen˜a AS, Sullivan T, et al.: Does metformin improve vascular heath in children with type 1 diabetes? Protocol for a one year, double blind, randomised, placebo controlled trial. BMC Pediatr 2013;13:108.
Address correspondence to: Cong Liu, MD NO.2 Department of Endocrinology Shengjing Hospital of China Medical University NO.39, Huaxiang Road Tiexi District Shenyang 110022, Liaoning, People’s Republic of China E-mail: [email protected]
