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Published in: Drugs 10/2015

Open Access 01-07-2015 | Review Article

Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention

Authors: Ulrike Hostalek, Mike Gwilt, Steven Hildemann

Published in: Drugs | Issue 10/2015

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Abstract

People with elevated, non-diabetic, levels of blood glucose are at risk of progressing to clinical type 2 diabetes and are commonly termed ‘prediabetic’. The term prediabetes usually refers to high–normal fasting plasma glucose (impaired fasting glucose) and/or plasma glucose 2 h following a 75 g oral glucose tolerance test (impaired glucose tolerance). Current US guidelines consider high–normal HbA1c to also represent a prediabetic state. Individuals with prediabetic levels of dysglycaemia are already at elevated risk of damage to the microvasculature and macrovasculature, resembling the long-term complications of diabetes. Halting or reversing the progressive decline in insulin sensitivity and β-cell function holds the key to achieving prevention of type 2 diabetes in at-risk subjects. Lifestyle interventions aimed at inducing weight loss, pharmacologic treatments (metformin, thiazolidinediones, acarbose, basal insulin and drugs for weight loss) and bariatric surgery have all been shown to reduce the risk of progression to type 2 diabetes in prediabetic subjects. However, lifestyle interventions are difficult for patients to maintain and the weight loss achieved tends to be regained over time. Metformin enhances the action of insulin in liver and skeletal muscle, and its efficacy for delaying or preventing the onset of diabetes has been proven in large, well-designed, randomised trials, such as the Diabetes Prevention Program and other studies. Decades of clinical use have demonstrated that metformin is generally well-tolerated and safe. We have reviewed in detail the evidence base supporting the therapeutic use of metformin for diabetes prevention.
Literature
1.
2.
American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36:1033–46.PubMedCentral
3.
4.
American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2015;38(Suppl 1):S31–3.
5.
Merlotti C, Morabito A, Pontiroli AE. Prevention of type 2 diabetes: a systematic review and meta-analysis of different intervention strategies. Diabetes Obes Metab. 2014;16:719–27.PubMed
6.
DeFronzo RA, Bonnadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care. 1992;15:318–68.PubMed
7.
DeFronzo RA. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis. Neth J Med. 1997;50:191–7.PubMed
8.
Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007;30:753–9.PubMed
9.
Buysschaert M, Bergman M. Definition of prediabetes. Med Clin North Am. 2011;95:289–97.PubMed
10.
Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34:3035–87.PubMed
11.
Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160–7.PubMed
12.
World Health Organization: Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO Consultation. Part 1: diagnosis and classification of diabetes mellitus. Geneva: World Health Organization; 1999.
13.
Mann DM, Carson AP, Shimbo D, Fonseca V, Fox CS, Muntner P. Impact of A1C screening criterion on the diagnosis of pre-diabetes among U.S. adults. Diabetes Care. 2010;33:2190–5.PubMedCentralPubMed
14.
Cohen RM, Haggerty S, Herman H. HbA1c for the diagnosis of diabetes and prediabetes: is it time for a mid-course correction? J Clin Endocrinol Metab. 2010;95:5203–6.PubMedCentralPubMed
15.
DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(Suppl 2):S127–38.PubMedCentralPubMed
16.
Rhee MK, Herrick K, Ziemer DC, Vaccarino V, Weintraub WS, Narayan KM, et al. Many Americans have prediabetes and should be considered for metformin therapy. Diabetes Care. 2010;33:49–54.PubMedCentralPubMed
17.
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care. 2008;31:464–9.PubMed
18.
19.
Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.PubMedCentral
20.
Ramachandran A, Arun N, Shetty AS, Snehalatha C. Efficacy of primary prevention interventions when fasting and postglucose dysglycemia coexist: analysis of the Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2). Diabetes Care. 2010;33:2164–8.PubMedCentralPubMed
21.
Cheng YJ, Gregg EW, Geiss LS, Imperatore G, Williams DE, Zhang X, et al. Association of A1c and fasting plasma glucose levels with diabetic retinopathy prevalence in the US population: implication for diabetes diagnostic thresholds. Diabetes Care. 2009;32:2027–77.PubMedCentralPubMed
22.
Nguyen TT, Wang JJ, Wong TY. Retinal vascular changes in prediabetes and pre- hypertension: new findings and their research and clinical implications. Diabetes Care. 2007;30:2708–15.PubMed
23.
Barr EL, Zimmet PZ, Welborn TA, Jolley D, Magliano DJ, Dunstan DW, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 2007;116:151–7.PubMed
24.
Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22:233–40.PubMed
25.
DECODE Study Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001;161:397–405.
26.
Tyrberg M, Melander A, Lovestam-Adrian M, Lindblad U. Retinopathy in subjects with impaired fasting glucose: the NANSY-Eye baseline report. Diabetes Obes Metab. 2008;10:646–51.PubMed
27.
Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 2007;24:137–44.PubMedCentral
28.
DeFronzo RA, Abdul-Ghani M. Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol. 2011;108(3 Suppl):3B–24B.PubMed
29.
Rydén L, Mellbin L. Glucose perturbations and cardiovascular risk: challenges and opportunities. Diabetes Vasc Dis Res. 2012;9:170–6.
30.
Ferrannini E, Gastaldelli A, Iozzo P. Pathophysiology of prediabetes. Med Clin North Am. 2011;95:327–39.PubMed
31.
Hopper I, Billah B, Skiba M, Krum H. Prevention of diabetes and reduction in major cardiovascular events in studies of subjects with prediabetes: meta-analysis of randomised controlled clinical trials. Eur J Cardiovasc Prev Rehabil. 2011;18:813–23.PubMed
32.
Bingisser R, Cairns C, Christ M, Hausfater P, Lindahl B, Mair J, et al. Cardiac troponin: a critical review of the case for point-of-care testing in the ED. Am J Emerg Med. 2012;30:1639–49.PubMed
33.
Selvin E, Lazo M, Chen Y, Shen L, Rubin J, McEvoy JW, et al. Diabetes mellitus, prediabetes, and incidence of subclinical myocardial damage. Circulation. 2014;130:1374–82.PubMed
34.
Paulweber B, Valensi P, Lindström J, Lalic NM, Greaves CJ, McKee M, et al. A European evidence-based guideline for the prevention of type 2 diabetes. Horm Metab Res. 2010;42(Suppl 1):S3–36.PubMed
35.
Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia. 2006;49:434–41.PubMed
36.
Johnson AB, Webster JM, Sum CF, Argyraki M, Cooper BG, et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metabolism. 1993;42:1217–22.PubMed
37.
Wright AD, Cull CA, Macleod KM, Holman RR. Hypoglycemia in type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complicat. 2006;20:395–401.PubMed
38.
Bailey CJ, Mynett KJ, Page T. Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol. 1994;112:671–5.PubMedCentralPubMed
39.
Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol. 1992;105:1009–13.PubMedCentralPubMed
40.
Wu T, Thazhath SS, Bound MJ, Jones KL, Horowitz M, Rayner CK. Mechanism of increase in plasma intact GLP-1 by metformin in type 2 diabetes: stimulation of GLP-1 secretion or reduction in plasma DPP-4 activity? Diabetes Res Clin Pract. 2014;106:e3–6.PubMed
41.
Thondam SK, Cross A, Cuthbertson DJ, Wilding JP, Daousi C. Effects of chronic treatment with metformin on dipeptidyl peptidase-4 activity, glucagon-like peptide 1 and ghrelin in obese patients with type 2 diabetes mellitus. Diabet Med. 2012;29:e205–10.PubMed
42.
Cuthbertson J, Patterson S, O’Harte FP, Bell PM. Addition of metformin to exogenous glucagon-like peptide-1 results in increased serum glucagon-like peptide-1 concentrations and greater glucose lowering in type 2 diabetes mellitus. Metabolism. 2011;60:52–6.PubMed
43.
Liu Y, Hong T. Combination therapy of dipeptidyl peptidase-4 inhibitors and metformin in type 2 diabetes: rationale and evidence. Diabetes Obes Metab. 2014;16:111–7.PubMed
44.
Napolitano A, Miller S, Nicholls AW, Baker D, Van Horn S, Thomas E, et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014;9:e100778.PubMedCentralPubMed
45.
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122:253–70.
46.
Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494:256–60.PubMedCentralPubMed
47.
Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001;24:489–94.PubMed
48.
Green BD, Irwin N, Duffy NA, Gault VA, O’harte FP, Flatt PR. Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1. Eur J Pharmacol. 2006;547:192–9.PubMed
49.
Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302:510–5.PubMed
50.
Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genomics. 2010;20:38–44.PubMed
51.
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;352:854–65.
52.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.PubMed
53.
Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, 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;169:616–25.PubMed
54.
55.
de Jager J, Kooy A, Schalkwijk C, van der Kolk J, Lehert P, Bets D, et al. Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. J Intern Med. 2014;275:59–70.PubMed
56.
Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P, editors. Metformin, the gold standard: a scientific handbook. Chichester: Wiley, 2007. p. 135–152.
57.
Scarpello JHB. Optimal dosing strategies for maximising the clinical response to metformin in type 2 diabetes. Br J Diabetes Vasc Dis. 2001;1:28–36.
58.
Feher MD, Al-Mrayat M, Brake J, Leong KS. Tolerability of prolonged-release metformin (Glucophage) in individuals intolerant to standard metformin: results from four UK centres. Br J Diabetes Vasc Dis. 2007;7:225–8.
59.
Cryer DR, Nicholas SP, Henry DH, Mills DJ, Stadel BV. Comparative outcomes study of metformin intervention versus conventional approach. The COSMIC Approach Study. Diabetes Care. 2005;28:539–43.PubMed
60.
Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P, editors. Metformin, the gold standard: a scientific handbook. Chichester: Wiley; 2007. p. 173–192.
61.
Singh AK, Kumar A, Karmakar D, Jha RK. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. J Postgrad Med. 2013;59:253–7.PubMed
62.
de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, et al. Long-term treatment with metformin in patients with type 2 diabetes treated with insulin and risk of vitamin B12 deficiency: a randomised, placebo-controlled trial. BMJ. 2010;340:c2181.PubMedCentralPubMed
63.
Niafar M, Hai F, Porhomayon J, Nader ND. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med. 2015;10:93–102.PubMed
64.
Zinman B, Harris SB, Neuman J, Gerstein HC, Retnakaran RR, Raboud J, et al. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet. 2010;376:103–11.PubMed
65.
Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006;49:289–97.PubMed
66.
Li CL, Pan CY, Lu JM, Zhu Y, Wang JH, Deng XX, et al. Effect of metformin on patients with impaired glucose tolerance. Diabet Med. 1999;16:477–81.PubMed
67.
Iqbal Hydrie MZ, Basit A, Shera AS, Hussain A. Effect of intervention in subjects with high risk of diabetes mellitus in Pakistan. J Nutr Metab. 2012;2012:867604.PubMedCentralPubMed
68.
Wenying Y, Lixiang L, Jinwu Q, Guangwei L, Zhiqing Y, Xiaoren P. The preventive effect of acarbose and metformin on the IGT population from becoming diabetes mellitus: a 3-year multicentral prospective study. Chin J Endocrinol Metab. 2001;17:131–4.
69.
Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677–86.PubMed
70.
Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–50.PubMed
71.
Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537–44.PubMed
72.
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072–7.PubMed
73.
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486–94.PubMed
74.
Torgerson JS, Hauptman J, Boldrin MN, Sjöstrom L. XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study. Diabetes Care. 2004;27:155–61.PubMed
75.
Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368:1096–105.PubMed
76.
DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551–62.
77.
Ramachandran A, Snehalatha C, Mary S, Selvam S, Kumar CK, Seeli AC, et al. Pioglitazone does not enhance the effectiveness of lifestyle modification in preventing conversion of impaired glucose tolerance to diabetes in Asian Indians: results of the Indian Diabetes Prevention Programme-2 (IDPP-2). Diabetologia. 2009;52:1019–26.PubMed
78.
Carlsson LM, Peltonen M, Ahlin S, Anveden Å, Bouchard C, Carlsson B, et al. Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N Engl J Med. 2012;367:695–704.PubMed
79.
Diabetes Prevention Program Research Group. The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care. 1999;22:623–34.
80.
Fujimoto WY. Background and recruitment data for the U.S. Diabetes Prevention Program. Diabetes Care. 2000;23(Suppl 2):B11–3.PubMedCentralPubMed
81.
Herman WH, Hoerger TJ, Brandle M, Hicks K, Sorensen S, Zhang P, et al. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med. 2005;142:323–32.PubMedCentralPubMed
82.
Perreault L, Kahn SE, Christophi CA, Knowler WC, Hamman RF. Regression from pre-diabetes to normal glucose regulation in the diabetes prevention program. Diabetes Care. 2009;32:1583–8.PubMedCentralPubMed
83.
Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the Diabetes Prevention Program. Diabetes Care. 2003;26:977–80.
84.
85.
Hamman RF, Horton E, Barrett-Connor E, Bray GA, Christophi C, Crandall J, et al. Factors affecting the decline in incidence of diabetes in the Diabetes Prevention Program Outcome Study (DPPOS). Diabetes. 2015;64:989–98.PubMed
86.
Perreault L, Pan Q, Mather KJ, Watson KE, Hamman RF, Kahn SE. Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study. Lancet. 2012;379:2243–51.PubMedCentralPubMed
87.
Rubin RR, Ma Y, Peyrot M, Marrero DG, Price DW, Barrett-Connor E, et al. Antidepressant medicine use and risk of developing diabetes during the diabetes prevention program and diabetes prevention program outcomes study. Diabetes Care. 2010;33:2549–51.PubMedCentralPubMed
88.
Orchard TJ, Temprosa M, Barrett-Connor E, Fowler SE, Goldberg RB, et al. Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabet Med. 2013;30:46–55.PubMedCentralPubMed
89.
Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35:731–7.
90.
Lachin JM, Christophi CA, Edelstein SL, Ehrmann DA, Hamman RF, Kahn SE, et al. Factors associated with diabetes onset during metformin versus placebo therapy in the diabetes prevention program. Diabetes. 2007;56:1153–9.PubMedCentralPubMed
91.
Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE, Haffner SM, et al. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes. 2005;54:2404–14.PubMed
92.
Fujimoto WY, Jablonski KA, Bray GA, Kriska A, Barrett-Connor E, Haffner S, et al. Body size and shape changes and the risk of diabetes in the diabetes prevention program. Diabetes. 2007;56:1680–5.PubMedCentralPubMed
93.
Diabetes Prevention Program Research Group. Relationship of body size and shape to the development of diabetes in the diabetes prevention program. Obesity (Silver Spring). 2006;14:2107–17.
94.
Bray GA, Jablonski KA, Fujimoto WY, Barrett-Connor E, Haffner S, Hanson RL, et al. Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program. Am J Clin Nutr. 2008;87:1212–8.PubMedCentralPubMed
95.
West DS, Elaine Prewitt T, Bursac Z, Felix HC. Weight loss of black, white, and Hispanic men and women in the Diabetes Prevention Program. Obesity (Silver Spring). 2008;16:1413–20.
96.
Perreault L, Ma Y, Dagogo-Jack S, Horton E, Marrero D, Crandall J, et al. Sex differences in diabetes risk and the effect of intensive lifestyle modification in the Diabetes Prevention Program. Diabetes Care. 2008;31:1416–21.PubMedCentralPubMed
97.
Walker EA, Molitch M, Kramer MK, Kahn S, Ma Y, Edelstein S, et al. Adherence to preventive medications: predictors and outcomes in the Diabetes Prevention Program. Diabetes Care. 2006;29:1997–2002.PubMedCentralPubMed
98.
Ratner RE, Christophi CA, Metzger BE, Dabelea D, Bennett PH, Pi-Sunyer X, et al. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab. 2008;93:4774–9.PubMedCentralPubMed
99.
Florez H, Pan Q, Ackermann RT, Marrero DG, Barrett-Connor E, Delahanty L, et al. Impact of lifestyle intervention and metformin on health-related quality of life: the diabetes prevention program randomized trial. J Gen Intern Med. 2012;27:1594–601.PubMedCentralPubMed
100.
Marrero D, Pan Q, Barrett-Connor E, de Groot M, Zhang P, Percy C, et al. Impact of diagnosis of diabetes on health-related quality of life among high risk individuals: the Diabetes Prevention Program outcomes study. Qual Life Res. 2014;23:75–88.PubMedCentralPubMed
101.
Mather KJ, Funahashi T, Matsuzawa Y, Edelstein S, Bray GA, Kahn SE, et al. Adiponectin, change in adiponectin, and progression to diabetes in the Diabetes Prevention Program. Diabetes. 2008;57:980–6.PubMedCentralPubMed
102.
Rubin RR, Knowler WC, Ma Y, Marrero DG, Edelstein SL, Walker EA, et al. Depression symptoms and antidepressant medicine use in Diabetes Prevention Program participants. Diabetes Care. 2005;28:830–7.PubMed
103.
Rubin RR, Ma Y, Marrero DG, Peyrot M, Barrett-Connor EL, Kahn SE, et al. Elevated depression symptoms, antidepressant medicine use, and risk of developing diabetes during the diabetes prevention program. Diabetes Care. 2008;31:420–6.PubMedCentralPubMed
104.
Crandall JP, Polsky S, Howard AA, Perreault L, Bray GA, Barrett-Connor E, et al. Alcohol consumption and diabetes risk in the Diabetes Prevention Program. Am J Clin Nutr. 2009;90:595–601.PubMedCentralPubMed
105.
Ratner R, Goldberg R, Haffner S, Marcovina S, Orchard T, Fowler S, et al. Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes Care. 2005;28:888–94.PubMed
106.
Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005;142:611–9.PubMedCentralPubMed
107.
Goldberg RB, Temprosa M, Haffner S, Orchard TJ, Ratner RE, Fowler SE, et al. Effect of progression from impaired glucose tolerance to diabetes on cardiovascular risk factors and its amelioration by lifestyle and metformin intervention: the Diabetes Prevention Program randomized trial by the Diabetes Prevention Program Research Group. Diabetes Care. 2009;32:726–32.PubMedCentralPubMed
108.
Diabetes Prevention Program Research Group. Changes in albumin excretion in the diabetes prevention program. Diabetes Care. 2009;32:720–5.PubMedCentral
109.
Friedman AN, Marrero D, Ma Y, Ackermann R, Narayan KM, Barrett-Connor E, et al. Value of urinary albumin-to-creatinine ratio as a predictor of type 2 diabetes in pre-diabetic individuals. Diabetes Care. 2008;31:2344–8.PubMedCentralPubMed
110.
Krakoff J, Clark JM, Crandall JP, Wilson C, Molitch ME, Brancati FL, et al. Effects of metformin and weight loss on serum alanine aminotransferase activity in the diabetes prevention program. Obesity (Silver Spring). 2010;18:1762–7.PubMedCentralPubMed
111.
Haffner S, Temprosa M, Crandall J, Fowler S, Goldberg R, Horton E, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes. 2005;54:1566–72.PubMed
112.
Pollin TI, Isakova T, Jablonski KA, de Bakker PI, Taylor A, McAteer J, et al. Genetic modulation of lipid profiles following lifestyle modification or metformin treatment: the Diabetes Prevention Program. PLoS Genet. 2012;8:e1002895.PubMedCentralPubMed
113.
Hivert MF, Jablonski KA, Perreault L, Saxena R, McAteer JB, Franks PW, et al. Updated genetic score based on 34 confirmed type 2 diabetes Loci is associated with diabetes incidence and regression to normoglycemia in the diabetes prevention program. Diabetes. 2011;60:1340–8.PubMedCentralPubMed
114.
Jablonski KA, McAteer JB, de Bakker PI, Franks PW, Pollin TI, Hanson RL, et al. Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes. 2010;59:2672–81.PubMedCentralPubMed
115.
Delahanty LM, Pan Q, Jablonski KA, Watson KE, McCaffery JM, Shuldiner A, et al. Genetic predictors of weight loss and weight regain after intensive lifestyle modification, metformin treatment, or standard care in the Diabetes Prevention Program. Diabetes Care. 2012;35:363–6.PubMedCentralPubMed
116.
Florez JC, Jablonski KA, McAteer J, Sandhu MS, Wareham NJ, Barroso I, et al. Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program. Diabetologia. 2008;51:451–7.PubMedCentralPubMed
117.
Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, Shuldiner AR, et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006;355:241–50.PubMedCentralPubMed
118.
Florez JC, Jablonski KA, McAteer JB, Franks PW, Mason CC, Mather K, et al. Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. PLoS One. 2012;7:e44424.PubMedCentralPubMed
119.
Florez JC, Jablonski KA, Taylor A, Mather K, Horton E, White NH, et al. The C allele of ATM rs11212617 does not associate with metformin response in the Diabetes Prevention Program. Diabetes Care. 2012;35:1864–7.PubMedCentralPubMed
120.
Snehalatha C, Mary S, Joshi VV, Ramachandran A. Beneficial effects of strategies for primary prevention of diabetes on cardiovascular risk factors: results of the Indian Diabetes Prevention Programme. Diab Vasc Dis Res. 2008;5:25–9.PubMed
121.
Ramachandran A, Snehalatha C, Samith Shetty A, Nanditha A. Predictive value of HbA1c for incident diabetes among subjects with impaired glucose tolerance: analysis of the Indian Diabetes Prevention Programmes. Diabet Med. 2012;29:94–8.PubMed
122.
Snehalatha C, Mary S, Selvam S, Sathish Kumar CK, Shetty SB, Nanditha A, et al. Changes in insulin secretion and insulin sensitivity in relation to the glycemic outcomes in subjects with impaired glucose tolerance in the Indian Diabetes Prevention Programme-1 (IDPP-1). Diabetes Care. 2009;32:1796–801.PubMedCentralPubMed
123.
Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V. Metabolic syndrome does not increase the risk of conversion of impaired glucose tolerance to diabetes in Asian Indians: result of Indian Diabetes Prevention Programme. Diabetes Res Clin Pract. 2007;76:215–8.PubMed
124.
Retnakaran R, Qi Y, Harris SB, Hanley AJ, Zinman B. Changes over time in glycemic control, insulin sensitivity, and beta-cell function in response to low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance. Diabetes Care. 2011;34:1601–4.PubMedCentralPubMed
125.
126.
Armato J, DeFronzo RA, Abdul-Ghani M, Ruby R. Successful treatment of prediabetes in clinical practice: targeting insulin resistance and β-cell dysfunction. Endocr Pract. 2012;18:342–50.PubMed
127.
Lily M, Godwin M. Treating prediabetes with metformin: systematic review and meta-analysis. Can Fam Physician. 2009;55:363–9.PubMed
128.
Yuen A, Sugeng Y, Weiland TJ, Jelinek GA. Lifestyle and medication interventions for the prevention or delay of type 2 diabetes mellitus in prediabetes: a systematic review of randomised controlled trials. Aust N Z J Public Health. 2010;34:172–8.PubMed
129.
Andreadis EA, Katsanou PM, Georgiopoulos DX, Tsourous GI, Yfanti GK, Gouveri ET, et al. The effect of metformin on the incidence of type 2 diabetes mellitus and cardiovascular disease risk factors in overweight and obese subjects–the Carmos study. Exp Clin Endocrinol Diabetes. 2009;117:175–80.PubMed
130.
Malin SK, Gerber R, Chipkin SR, Braun B. Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care. 2012;35:131–6.PubMedCentralPubMed
131.
Numbenjapon N, Nakavachara P, Santiprabhob J, Kiattisakthavee P, Wongarn R, Likitmaskul S. Successful strategy to improve glucose tolerance in Thai obese youth. J Med Assoc Thai. 2010;93(Suppl 6):S131–8.PubMed
132.
Fontbonne A, Diouf I, Baccara-Dinet M, Eschwege E, Charles MA. Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper–body obese subjects with mild glucose anomalies: a post-hoc analysis of the BIGPRO1 trial. Diabetes Metab. 2009;35:385–91.PubMed
133.
Lehtovirta M, Forsén B, Gullström M, Häggblom M, Eriksson JG, Taskinen MR, et al. Metabolic effects of metformin in patients with impaired glucose tolerance. Diabet Med. 2001;18:578–83.PubMed
134.
Garnett SP, Baur LA, Noakes M, Steinbeck K, Woodhead HJ, Burrell S, et al. Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers—RESIST. A randomised control trial investigating the effects of two different diets on insulin sensitivity in young people with insulin resistance and/or pre-diabetes. BMC Public Health. 2010;10:575.PubMedCentralPubMed
135.
Srinivasan S, Ambler GR, Baur LA, Garnett SP, Tepsa M, et al. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab. 2006;91:2074–80.PubMed
136.
Freemark M, Bursey D. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics. 2001;107:E55.PubMed
137.
Kay JP, Alemzadeh R, Langley G, D’Angelo L, Smith P, Holshouser S. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism. 2001;50:1457–61.PubMed
138.
Kendall D, Vail A, Amin R, Barrett T, Dimitri P, Ivison F, et al. Metformin in obese children and adolescents: the MOCA trial. J Clin Endocrinol Metab. 2013;98:322–9.PubMed
139.
Gómez-Díaz RA, Talavera JO, Pool EC, Ortiz-Navarrete FV, Solórzano-Santos F, Mondragón-González R, et al. Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial. Metabolism. 2012;61:1247–55.PubMed
140.
Fu JF, Liang L, Zou CC, Hong F, Wang CL, Wang XM, et al. Prevalence of the metabolic syndrome in Zhejiang Chinese obese children and adolescents and the effect of metformin combined with lifestyle intervention. Int J Obes (Lond). 2007;31:15–22.
141.
Quinn SM, Baur LA, Garnett SP, Cowell CT. Treatment of clinical insulin resistance in children: a systematic review. Obes Rev. 2010;11:722–30.PubMed
142.
Manu P, Correll CU, van Winkel R, Wampers M, De Hert M. Prediabetes in patients treated with antipsychotic drugs. J Clin Psychiatry. 2012;73:460–6.PubMed
143.
Wu RR, Jin H, Gao K, Twamley EW, Ou JJ, Shao P, et al. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo–controlled study. Am J Psychiatry. 2012;169:813–21.PubMed
144.
Wang M, Tong JH, Zhu G, Liang GM, Yan HF, Wang XZ. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophr Res. 2012;138:54–7.PubMed
145.
Hoffmann VP, Case M, Jacobson JG. Assessment of treatment algorithms including amantadine, metformin, and zonisamide for the prevention of weight gain with olanzapine: a randomized controlled open-label study. J Clin Psychiatry. 2012;73:216–23.PubMed
146.
Carrizo E, Fernández V, Connell L, Sandia I, Prieto D, Mogollón J, et al. Extended release metformin for metabolic control assistance during prolonged clozapine administration: a 14 week, double–blind, parallel group, placebo-controlled study. Schizophr Res. 2009;113:19–26.PubMed
147.
Wu RR, Zhao JP, Jin H, Shao P, Fang MS, Guo XF, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA. 2008;299:185–93.PubMed
148.
Chen CH, Chiu CC, Huang MC, Wu TH, Liu HC, Lu ML. Metformin for metabolic dysregulation in schizophrenic patients treated with olanzapine. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:925–31.PubMed
149.
Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry. 2006;163:2072–9.PubMed
150.
Baptista T, Rangel N, Fernández V, Carrizo E, El Fakih Y, Uzcátegui E, et al. Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo–controlled trial. Schizophr Res. 2007;93:99–108.PubMed
151.
Praharaj SK, Jana AK, Goyal N, Sinha VK. Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis. Br J Clin Pharmacol. 2011;71:377–82.PubMedCentralPubMed
152.
Ehret M, Goethe J, Lanosa M, Coleman CI. The effect of metformin on anthropometrics and insulin resistance in patients receiving atypical antipsychotic agents: a meta-analysis. J Clin Psychiatry. 2010;71:1286–92.PubMed
153.
Björkhem-Bergman L, Asplund AB, Lindh JD. Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis. J Psychopharmacol. 2011;25:299–305.PubMed
154.
Arman S, Sadramely MR, Nadi M, Koleini N. A randomized, double-blind, placebo-controlled trial of metformin treatment for weight gain associated with initiation of risperidone in children and adolescents. Saudi Med J. 2008;29:1130–4.PubMed
155.
Baptista T, Martínez J, Lacruz A, Rangel N, Beaulieu S, Serrano A, et al. Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial. Can J Psychiatry. 2006;51:192–6.PubMed
156.
Baptista T, Sandia I, Lacruz A, Rangel N, de Mendoza S, Beaulieu S, et al. Insulin counter-regulatory factors, fibrinogen and C-reactive protein during olanzapine administration: effects of the antidiabetic metformin. Int Clin Psychopharmacol. 2007;22:69–76.PubMed
157.
Hernan WH, Brandle M, Zhang P, Williamson DF, Matulik MJ, Ratner RE, et al. Costs associated with the primary prevention of type 2 diabetes mellitus in the diabetes prevention program. Diabetes Care. 2003;26:36–47.PubMed
158.
Diabetes Prevention Program Research Group. Within-trial cost-effectiveness of lifestyle intervention or metformin for the primary prevention of type 2 diabetes. Diabetes Care. 2003;26:2518–23.
159.
Diabetes Prevention Program Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care. 2012;35:723–30.
160.
Eddy DM, Schlessinger L, Kahn R. Clinical outcomes and cost-effectiveness of strategies for managing people at high risk for diabetes. Ann Intern Med. 2005;143:251–64.PubMed
161.
Palmer AJ, Roze S, Valentine WJ, Spinas GA, Shaw JE, Zimmet PZ. Intensive lifestyle changes or metformin in patients with impaired glucose tolerance: modeling the long-term health economic implications of the diabetes prevention program in Australia, France, Germany, Switzerland, and the United Kingdom. Clin Ther. 2004;26:304–21.PubMed
162.
Palmer AJ, Tucker DM. Cost and clinical implications of diabetes prevention in an Australian setting: a long-term modeling analysis. Prim Care Diabetes. 2012;6:109–21.PubMed
163.
Icks A, Rathmann W, Haastert B, Gandjour A, Holle R, John J, et al. Clinical and cost-effectiveness of primary prevention of Type 2 diabetes in a ‘real world’ routine healthcare setting: model based on the KORA Survey 2000. Diabet Med. 2007;24:473–80.PubMed
164.
Ramachandran A, Snehalatha C, Yamuna A, Mary S, Ping Z. Cost-effectiveness of the interventions in the primary prevention of diabetes among Asian Indians: within-trial results of the Indian Diabetes Prevention Programme (IDPP). Diabetes Care. 2007;30:2548–52.PubMed
165.
Bertram MY, Lim SS, Barendregt JJ, Vos T. Assessing the cost-effectiveness of drug and lifestyle intervention following opportunistic screening for pre-diabetes in primary care. Diabetologia. 2010;53:875–81.PubMed
166.
Passey ME, Shrestha RN, Bertram MY, Schofield DJ, Vos T, Callander EJ, et al. The impact of diabetes prevention on labour force participation and income of older Australians: an economic study. BMC Public Health. 2012;12:16.PubMedCentralPubMed
167.
Schaufler TM, Wolff M. Cost effectiveness of preventive screening programmes for type 2 diabetes mellitus in Germany. Appl Health Econ Health Policy. 2010;8:191–202.PubMed
168.
Caro JJ, Getsios D, Caro I, Klittich WS, O’Brien JA. Economic evaluation of therapeutic interventions to prevent type 2 diabetes in Canada. Diabet Med. 2004;21:1229–36.PubMed
169.
Chatterjee R, Narayan KM, Lipscomb J, Phillips LS. Screening adults for pre-diabetes and diabetes may be cost-saving. Diabetes Care. 2010;33:1484–90.PubMedCentralPubMed
170.
Chatterjee R, Narayan KM, Lipscomb J, Jackson SL, Long Q, Zhu M, et al. Screening for diabetes and prediabetes should be cost-saving in patients at high risk. Diabetes Care. 2013;36:1981–7.PubMedCentralPubMed
171.
Twigg SM, Kamp MC, Davis TM, Neylon EK, Flack JR. Australian Diabetes Educators Association. Prediabetes: a position statement from the Australian Diabetes Society and Australian Diabetes Educators Association. Med J Aust. 2007;186:461–5.PubMed
172.
Guzman JR. Documentos Selectos de Posición y Consenso de ALAD (Associatión Lationoamericano de diabetes) Ac Farmacéutica; 2011. ISBN: 9788560549559.
173.
Committee Canadian Diabetes Association Clinical Practice Guidelines Expert. Reducing the risk of developing diabetes. Can J Diabetes. 2013;37:S16–9.
174.
175.
Alberti KG, Zimmet P, Shaw J. International Diabetes Federation: a consensus on type 2 diabetes prevention. Diabet Med. 2007;24:451–63.PubMed
176.
177.
Rosenzweig JL, Ferrannini E, Grundy SM, Haffner SM, Heine RJ, Horton ES, et al. Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:3671–89.PubMed
178.
179.
180.
Guía Clínica Práctica en Diabetes Mellitus. Revista Venezolana de Endocrinologia y Metabolismo. 2012;10(Suppl 1):1–155.
181.
Sociedade Brasiliera de Diabetes (SBD). Algoritmo para o tratamento do diabetes tipo 2. Atualização 2011. Posicionamento Oficial SBD n°3, 2011.
182.
183.
184.
185.
Lindström J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, Hemiö K, et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006;368:1673–9.PubMed
186.
Dombrowski SU, Knittle K, Avenell A, Araújo-Soares V, Sniehotta FF. Long term maintenance of weight loss with non-surgical interventions in obese adults: systematic review and meta-analyses of randomised controlled trials. BMJ. 2014;348:g2646.PubMedCentralPubMed
187.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55:1577–96.PubMed
188.
Kung J, Henry RR. Thiazolidinedione safety. Expert Opin Drug Saf. 2012;11:565–79.PubMed
189.
190.
Arungarinathan G, McKay GA, Fisher M. Drugs for diabetes: part 4 acarbose. Br J Cardiol. 2011;18:78–81.
191.
Neff KJ, le Roux CW. Incretins: new targets for the prevention of diabetes and obesity. Clin Lipidol. 2013;8:109–21.
192.
Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, et al. Pancreatic safety of incretin-based drugs: FDA and EMA assessment. N Engl J Med. 2014;370:794–7.PubMed
193.
194.
195.
Schabert J, Browne JL, Mosely K, Speight J. Social stigma in diabetes: a framework to understand a growing problem for an increasing epidemic. Patient. 2013;6:1–10.PubMed
Metadata
Title
Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention
Authors
Ulrike Hostalek
Mike Gwilt
Steven Hildemann
Publication date
01-07-2015
Publisher
Springer International Publishing
Published in
Drugs / Issue 10/2015
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-015-0416-8

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