Download PDF
Horm Metab Res 2009; 41(2): 116-122
DOI: 10.1055/s-0028-1128144
Review

© Georg Thieme Verlag KG Stuttgart · New York

Early Insulin Treatment to Prevent Cardiovascular Disease in Prediabetes and Overt Diabetes

G. Roman 1 , N. Hancu 1
  • 1“Iuliu Hatieganu” University of Medicine and Pharmacy, Clinical Center of Diabetes, Nutrition, Metabolic Diseases, Cluj-Napoca, Romania
Further Information

Publication History

received 06.09.2008

accepted 20.12.2008

Publication Date:
12 February 2009 (online)

Also available at
    Permissions and Reprints

Abstract

Type 2 diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD), and CVD represents the leading cause of death in people with type 2 DM. The cardiovascular risk is increased long before diabetes is diagnosed, in the prediabetes stage, when impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) develop. These stages are characterized by dysglycemia, defined as any elevated fasting or postprandial glycemia, extending from the normal range into diabetic range, associated with an increased risk of CVD. Due to metabolic memory demonstrated for type 2 DM as well, early interventions addressed to achieve and maintain glycemic control are required for long-term benefits in terms of both microvascular and macrovascular complications. The recommendation of early insulin therapy in type 2 DM is sustained by its pleiotropic effects, which may be cardioprotective and potentially anti-atherosclerotic. Insulin therapy in prediabetes and earlier in type 2 DM, could be a strategy in preventing cardiovascular disease and type 2 DM progression. To test this hypothesis, a large trial has been designed. Outcome Reduction with an Initial Glargine Intervention trial (ORIGIN) is an international, multicenter, randomized controlled, 2 × 2 factorial trial, investigating the possibility to prevent cardiovascular morbidity and mortality in people with type 2 DM, IGT, and/or IFG, and high cardiovascular risk by treating the normoglycemia with either insulin glargine or omega-3 fatty acid, compared to the standard intervention.

Key words

prediabetes - insulin - dysglycemia - cardiovascular disease

References

  • 1 International Diabetes Federation . Diabetes Atlas, third edition, 2007. , Available from http://www.eatlas.idf.org , Accessed on 23 August 2008
  • 2 International Diabetes Federation . Diabetes and Cardiovascular Disease: Time to Act 2001. , Available from http://http//:www.idf.org , Accessed on 23 August 2008
  • 3 Fox CS, Coady S, Sorlie PD, D’Agostino  Sr  RB, Pencina MJ, Vasan RS, Meigs JB, Levy D, Savage PJ. Increasing cardiovascular disease burden due to diabetes mellitus: The Framingham Heart Study.  Circulation. 2007;  115 1544-1550
    Google Scholar
  • 4 American Diabetes Association, National Heart, Lung, and Blood Institute, Juvenile Diabetes Foundation International, National Institute of Diabetes and Digestive and Kidney Diseases, American Heart Association . Diabetes mellitus: a major risk factor for cardiovascular disease: a joint editorial statement by the American Diabetes Association; the National Heart, Lung, and Blood Institute; the Juvenile Diabetes Foundation International; the National Institute of Diabetes and Digestive and Kidney Diseases; and the American Heart Association.  Circulation. 1999;  100 1132-1133
    Google Scholar
  • 5 Gerich JE. Type 2 diabetes mellitus is associated with multiple cardiometabolic risk factors.  Clin Cornerstone. 2007;  8 53-68
    Google Scholar
  • 6 Expert Panel on Detection, Evaluation. Treatment of High Blood Cholesterol in Adults . Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).  JAMA. 2001;  285 2486-2497
    Google Scholar
  • 7 Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R, Fonseca V, Gerstein HC, Grundy S, Nesto RW, Pignone MP, Plutzky J, Porte D, Redberg R, Stitzel KF, Stone NJ. Primary prevention of cardiovascular diseases in people with diabetes mellitus: A scientific statement from the American Heart Association and the Amercian Diabetes Association.  Diabetes Care. 2007;  30 162-172
    Google Scholar
  • 8 Ho JE, Paultre F, Mosca L. Diabetes mellitus a cardiovascular disease risk equivalent for fatal stroke in women? Data from the women's pooling project.  Stroke. 2003;  34 2812-2816
    Google Scholar
  • 9 Jeerakathil T, Johnson JA, Simpson SH, Majumdar SR. Short-term risk for stroke is doubled in persons with newly treated type 2 diabetes compared with persons without diabetes. A population-based cohort study.  Stroke. 2007;  38 1739-1743
    Google Scholar
  • 10 Yusuf S, Hawken S, Ounpuu S. on behalf of the INTERHEART Study Investigators . Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.  Lancet. 2004;  364 937-952
    Google Scholar
  • 11 Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.  N Engl J Med. 1998;  339 229-234
    Google Scholar
  • 12 Pajunen P, Koukkunen H, Ketonen M, Jerkkola T, Immonen-Räihä P, Kärjä-Koskenkari P, Kuulasmaa K, Palomäki P, Mustonen J, Lehtonen A, Arstila M, Vuorenmaa T, Lehto S, Miettinen H, Torppa J, Tuomilehto J, Kesäniemi YA, Pyörälä K, Salomaa V. Myocardial infarction in diabetic and non-diabetic persons with and without prior myocardial infarction: the FINAMI Study.  Diabetologia. 2005;  48 2519-2524
    Google Scholar
  • 13 Schramm TK, Gislason GH, Køber L, Rasmussen S, Rasmussen JN, Abildstrøm SZ, Hansen ML, Folke F, Buch P, Madsen M, Vaag A, Torp-Pedersen C. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk. A population study of 3.3 million people.  Circulation. 2008;  117 1945-1954
    Google Scholar
  • 14 American Diabetes Association . Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 2008;  31 S55-S60
    Google Scholar
  • 15 IDF/WHO . Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. 2006; 
  • 16 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals.  Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA. 1990;  263 2893-2898
    Google Scholar
  • 17 Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes.  Diabetes Care. 2002;  25 1129-1134
    Google Scholar
  • 18 Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, Day N. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk).  BMJ. 2001;  322 15-18
    Google Scholar
  • 19 Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: The European prospective investigation into cancer in Norfolk.  Ann Intern Med. 2004;  141 413-420
    Google Scholar
  • 20 Gerstein HC. Glucose: a continuous risk factor for cardiovascular disease.  Diabetic Med. 1997;  14 S25-S31
    Google Scholar
  • 21 Simmons RK, Sharp S, Boekholdt SM, Sargeant LA, Khaw KT, Wareham NJ, Griffin SJ. Evaluation of the Framingham risk score in the European Prospective Investigation of Cancer-Norfolk cohort: does adding glycated hemoglobin improve the prediction of coronary heart disease events?.  Arch Intern Med. 2008;  168 1209-1216
    Google Scholar
  • 22 Gerstein HC, Yusuf S. Dysglycaemia and risk of cardiovascular disease.  Lancet. 1996;  347 949-950
    Google Scholar
  • 23 Gerstein HC, Capes SE. Dysglycemia: A Key Cardiovascular Risk Factor.  Seminars in Vascular Medicine. 2002;  2 165-174
    Google Scholar
  • 24 Bjornholt JV, Erikssen G, Aaser E, Sandvik L, Nitter-Hauge S, Jervell J, Erikssen J, Thaulow E. Fasting blood glucose: an underestimated risk factor for cardiovascular death.  Diabetes Care. 1999;  22 45-49
    Google Scholar
  • 25 Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A meta regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years.  Diabetes Care. 1999;  22 233-240
    Google Scholar
  • 26 Myint PK, Sinha S, Wareham NJ, Bingham SA, Luben RN, Welch AA, Khaw KT. Glycated hemoglobin and risk of stroke in people without known diabetes in the European Prospective Investigation Into Cancer (EPIC)–Norfolk Prospective Population Study: A Threshold Relationship?.  Stroke. 2007;  38 271-275
    Google Scholar
  • 27 Selvin E, Coresh J, Golden SH, Brancati FL, Folsom AR, Steffes MW. Glycemic control and coronary heart disease risk in persons with and without diabetes: The Atherosclerosis Risk in Communities Study.  Arch Intern Med. 2005;  165 1910-1916
    Google Scholar
  • 28 Selvin E, Coresh J, Shahar E, Zhang L, Steffes M, Sharrett A. Glycaemia (haemoglobin A) and incident ischaemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study.  Lancet Neurol. 2005;  12 821-826
    Google Scholar
  • 29 Nichols GA, Hillier TA, Brown JB. Normal fasting plasma glucose and risk of type 2 diabetes diagnosis.  Am J Med. 2008;  121 519-524
    Google Scholar
  • 30 Nathan DM, Davidson MB, Defronzo RA, Heine RJ, Henry RR, Pratley R, Zinman B. Impaired Fasting Glucose and Impaired Glucose Tolerance. Implications for care.  Diabetes Care. 2007;  30 753-759
    Google Scholar
  • 31 Rasmussen SS, Glumer C, Sandbaek A, Lauritzen T, Borch-Johnsen K. Determinants of progression from impaired fasting glucose and impaired glucose tolerance to diabetes in a high-risk screened population: 3 year follow-up in the ADDITION study, Denmark.  Diabetologia. 2007;  50 293-297
    Google Scholar
  • 32 Asia Pacific Cohort Studies Collaboration . Blood glucose and risk of cardiovascular disease in the Asia Pacific region.  Diabetes Care. 2004;  27 2836-2842
    Google Scholar
  • 33 Park S, Barrett-Connor E, Wingard DL, Shan J, Edelstein S. GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes:the Rancho Bernardo Study.  Diabetes Care. 1996;  19 450-456
    Google Scholar
  • 34 Barrett-Connor E, Ferrara A. Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older women and men: the Rancho Bernardo Study.  Diabetes Care. 1998;  21 1236-1239
    Google Scholar
  • 35 Wedick N, Wingard D, Barrett-Connor E. A prospective study to identify the best glycemic predictors of nonfatal coronary heart disease (CHD) and cardiovascular disease (CVD) mortality; the Rancho Bernardo Study.  Am J Epidemiol. 2000;  151 ((Suppl)) S38
    Google Scholar
  • 36 Kanaya AM, Christina L, Fyr W, Rekeneire N de, Shorr RI, Schwartz AV, Goodpaster BH, Newman AB, Harris T, Barrett-Connor E. Predicting the development of diabetes in older adults: The derivation and validation of a prediction rule.  Diabetes Care. 2005;  28 404-408
    Google Scholar
  • 37 Grundy SM, Brewer  Jr  HB, Cleeman JI, Smith  Jr  SC, Lenfant C. for the Conference Participants. . Definition of Metabolic Syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition.  Circulation. 2004;  109 433-438
    Google Scholar
  • 38 International Diabetes Federation . The IDF consensus worldwide definition of the metabolic syndrome. http://available at www.idf.org/idf_metasyndrome_definition.pdf , Accessed 24 August 2008
  • 39 Després JP, Lemieux I. Abdominal obesity and metabolic syndrome.  Nature. 2006;  444 881-887
    Google Scholar
  • 40 Despres JP, Poirier P, Bergeron J, Tremblay A, Lemieux I, Almeras N. From individual risk factors and the metabolic syndrome to global cardiometabolic risk.  Eur Heart J Suppl. 2008;  10 ((Suppl B)) B24-B33
    Google Scholar
  • 41 The 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
    Google Scholar
  • 42 Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes.  N Engl J Med. 2008;  358 580-591
    Google Scholar
  • 43 Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.  Diabetes Res Clin Pract. 1995;  28 103-117
    Google Scholar
  • 44 UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet. 1998;  352 837-853
    Google Scholar
  • 45 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
    Google Scholar
  • 46 Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care. 2006;  29 1963-1972
    Google Scholar
  • 47 IDF Clinical Guidelines Task Force . Global guideline for Type 2 diabetes. 2005.  , Available from http://http//:www.idf.org , Accessed on 30 August 2008
    Google Scholar
  • 48 Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care. 2009;  32 1-11
    Google Scholar
  • 49 Malmberg K, Ryden L, Hamsten A, Herlitz J, Waldenstrom A, Wendel H. Effects of insulin treatment on cause specific one-year mortality and morbidity in diabetic patients with acute myocardial infarctions.  Eur Heart J. 1996;  17 1337-1344
    Google Scholar
  • 50 Malmberg K. Prospective randomized study of intensive insulin treatment of long-term survival after acute myocardial infarction in patients with diabetes mellitus.  Br Med J. 1997;  314 1512-1515
    Google Scholar
  • 51 Stettler C, Allemann S, Jüni P, Cull CA, Holman RR, Egger M, Krähenbühl S, Diem P. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: Meta-analysis of randomized trials.  Am Heart J. 2006;  152 27-38
    Google Scholar
  • 52 Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, Goldenet SH. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus.  Ann Intern Med. 2004;  141 421-431
    Google Scholar
  • 53 Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes.  N Engl J Med. 2008;  359 1-13
    Google Scholar
  • 54 The ADVANCE Collaborative Group . Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.  N Engl J Med. 2008;  358 2560-2572
    Google Scholar
  • 55 The Action to Control Cardiovascular Risk in Diabetes Study Group. . Effects of intensive glucose lowering in type 2 diabetes.  N Engl J Med. 2008;  358 2545-2559
    Google Scholar
  • 56 Duckworth WC. Cardiovascular outcomes by glycemic control treatment arm. ADA Meeting, San Francisco 2008
    Google Scholar
  • 57 UK Prospective Diabetes Study Group . UK prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes. A progressive disease.  Diabetes. 1995;  44 1249-1258
    Google Scholar
  • 58 Tibaldi J. Preserving insulin secretion in type 2 diabetes mellitus.  Expert Rev Endocrinol Metab. 2008;  3 147-159
    Google Scholar
  • 59 Kahn SE. Clinical review 135: The importance of beta-cell failure in the development and progression of type 2 diabetes.  J Clin Endocrinol Metab. 2001;  86 4047-4058
    Google Scholar
  • 60 Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes.  Diabetes Care. 2004;  27 1535-1540
    Google Scholar
  • 61 Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care. 2008;  31 173-175
    Google Scholar
  • 62 Westphal SA, Palumbo PJ. A case for introducing insulin early in the treatment of type 2 diabetes mellitus.  Insulin. 2006;  1 65-69
    Google Scholar
  • 63 Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment.  Diabetes Care. 1997;  20 1353-1356
    Google Scholar
  • 64 Li Y, Xu W, Liao Z, Yao B, Chen X, Huang Z, Hu G, Weng JP. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function.  Diabetes Care. 2004;  27 2597-2602
    Google Scholar
  • 65 Noh YN, Lee SM, Kim EJ, Kim DY, Lee H, Lee JH, Ju-Han Lee, Park SY, Koo JH, Wang JH, Lim IJ, Choi SB. Improvement of cardiovascular risk factors in patients with type 2 diabetes after long-term continuous subcutaneous insulin infusion.  Diabetes/Metabolism Res Rev. 2008;  24 384-391
    Google Scholar
  • 66 Park S, Choi SB. Induction of long-term normoglycemia without medication in Korean type 2 diabetes patients after continuous subcutaneous insulin infusion therapy.  Diabetes Metab Res Rev. 2003;  19 124-130
    Google Scholar
  • 67 Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, Hu Y, Zhou Z, Yan X, Tian H, Ran X, Luo Z, Xian J, Yan L, Li F, Zeng L, Chen Y, Yang L, Yan S, Lin J, Li M, Fu Z, Cheng H. Effect of intensive insulin therapy on β-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial.  Lancet. 2008;  371 1753-1760
    Google Scholar
  • 68 Nauck MA, Meier JJ, Creutzfeldt W. Incretins and their analogues as new antidiabetic drugs.  Drug News Perspect. 2003;  16 413-422
    Google Scholar
  • 69 Tews D, Werner U, Eckel J. Enhanced protection against cytokine- and fatty acid-induced apoptosis in pancreatic beta cells by combined treatment with glucagon-like peptide-1 receptor agonists and insulin analogues.  Horm Metab Res. 2008;  40 172-180
    Google Scholar
  • 70 Scarlett JA, Gray RS, Griffin J, Olefsky JM, Kolterman OG. Insulin treatment reverses the insulin resistance of type II diabetes mellitus.  Diabetes Care. 1982;  5 353-363
    Google Scholar
  • 71 Zhao L, Sun D, Cao F, Yin T, Wang H. Can insulin resistance be reversed by insulin therapy?.  Med Hypoth. 2009;  72 34-35
    Google Scholar
  • 72 Vinik AI. Benefits of early initiation of insulin therapy to long-term goals in type 2 diabetes mellitus.  Insulin. 2006;  1 2-12
    Google Scholar
  • 73 Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Use of insulin to improve glycemic control in diabetes mellitus.  Cardiovascul Drugs Ther. 2008;  22 241-251
    Google Scholar
  • 74 Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Potential use of insulin as an anti-inflammatory drug.  Drug Develop Res. 2008;  69 101-110
    Google Scholar
  • 75 Chaudhuri A, Janicke D, Wilson MF, Tripathy D, Garg R, Bandyopadhyay A, Calieri J, Hoffmeyer D, Syed T, Ghanim H, Aljada A, Dandona P. Anti-inflammatory and profibrinolytic effect of insulin in acute st-segment–elevation myocardial infarction.  Circulation. 2008;  109 849-854
    Google Scholar
  • 76 Bretzel RG, Nuber U, Landgraf W, Owens DR, Bradley C, Linn T. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomized controlled trial.  Lancet. 2008;  371 1073-1084
    Google Scholar
  • 77 Mathieu C, Robberecht S. Reaching glycaemic targets while minimizing hypoglycaemia in insulin-treated type 2 diabetes patients.  Diabetes Obes Metab. 2008;  10 ((Suppl 2)) 14-23
    Google Scholar
  • 78 Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group.  Diabetes Care. 2000;  23 1130-1136
    Google Scholar
  • 79 Riddle MC. The treat-to-target trial and related studies.  Endocr Pract. 2006;  12 ((Suppl 1)) 71-79
    Google Scholar
  • 80 Rosenstock J, Schwartz SL, Clark Jr CM, Park GD, Donley DW, Edwards MB. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin.  Diabetes Care. 2001;  24 631-636
    Google Scholar
  • 81 Schreiber S. Insulin glargine in type 2 diabetes in everyday clinical practice: 7 years on.  Diabetes Obes Metab. 2008;  10 ((Suppl 2)) 24-34
    Google Scholar
  • 82 Janka HU. Insulin therapy in elderly patients with type 2 diabetes.  Diabetes Obes Metab. 2008;  10 ((Suppl 2)) 35-41
    Google Scholar
  • 83 Dailey G. Beyond insulin replacement: addressing the additional needs of the diabetes patient.  Diabetes Obes Metab. 2008;  10 ((Suppl 2)) 85-99
    Google Scholar
  • 84 Dailey G. Optimum management of type 2 diabetes – timely introduction, optimization and intensification of basal insulin.  Diabetes Obes Metab. 2008;  10 ((Suppl 2)) 5-13
    Google Scholar
  • 85 Davies M, Khunti K. Insulin management in overweight or obese type 2 diabetes patients: the role of insulin glargine.  Diabetes Obes Metab. 2008;  10 ((Suppl 2)) 42-49
    Google Scholar
  • 86 Davies M, Sinnassamy P, Storms F, Gomis R. on behalf of the AT.LANTUS Study Group . Insulin glargine-based therapy improves glycemic control in patients with type 2 diabetes sub-optimally controlled on premixed insulin therapies.  Diabetes Res Clin Pract. 2008;  79 368-375
    Google Scholar
  • 87 Hammer H, Klinge A. Patients with type 2 diabetes inadequately controlled on premixed insulin: effect of initiating insulin glargine plus oral antidiabetic agents on glycaemic control in daily practice.  Int J Clin Pract. 2007;  61 2009-2018
    Google Scholar
  • 88 The ORIGIN Trial Investigators. . Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: The ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention).  Am Heart J. 2008;  155 26.e1-26.e13
    Google Scholar
  • 89 Schwartz S. Is there a rationale for insulin therapy in pre-diabetic individuals?.  Treat Endocrinol. 2006;  5 385-393
    Google Scholar
  • 90 Schacky C von. A review of omega-3 ethyl esters for cardiovascular prevention and treatment of increased blood triglyceride levels.  Vasc Health Risk Manag. 2006;  2 251-262
    Google Scholar
  • 91 Tsitouras PD, Gucciardo F, Salbe AD, Heward C, Harman SM. High omega-3 fat intake improves insulin sensitivity and reduces CRP and IL6, but does not affect other endocrine axes in healthy older adults.  Horm Metab Res. 2008;  40 199-205
    Google Scholar

Correspondence

G. RomanMD 

Clinical Center of Diabetes

Nutrition, Metabolic Diseases

2–4 Clinicilor Street

400006 Cluj-Napoca

Romania

Phone: +40/264/59 44 55

Fax: +40/264/59 95 78

Email: groman@umfcluj.ro

      >