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Drug therapy for the prevention of type 2 diabetes − is there a medical rationale?
Markolf Hanefeld and Frank Schaper British Journal of Diabetes & Vascular Disease 2011 11: 168 DOI: 10.1177/1474651411403987 The online version of this article can be found at: http://dvd.sagepub.com/content/11/4/168

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uk/journalsPermissions.kB ON TARGET  Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial ORIGIN  Outcome Reduction with Initial Glargine Intervention PPARγ peroxisome proliferation-activated receptors RCT randomised controlled trial RIAD  Risk Factors in IGT for Atherosclerosis and Diabetes STOP-NIDDM  Study to Prevent Non-Insulin-dependent diabetes mellitus UKPDS United Kingdom Prospective Diabetes Study WOSCOPS West Of Scotland Coronary Prevention Study Introduction Type 2 diabetes is a major risk factor for cardiovascular disease. The corresponding figures for IGT are 344 millions in 2010 and 472 millions in 2030. Tel: +49 (0)351 4400580. Moreover.1177/1474651411403987 168 Downloaded from dvd. 2011. Correspondence to: Prof. With a priority of lifestyle intervention drug treatment should be risk adjusted. Medical treatment should be considered for patients with diabetesrelated complications.co. Fiedlerstraße 34. including drug treatment of people with abnormal glucose tolerance is of high medical and economic relevance. 01307 Dresden. Germany. FRANK SCHAPER Abstract ype 2 diabetes is a major risk factor for cardiovascular disease.nav 10.1 Moreover.11:168-174 Key words: cardiovascular disease.3 In the GAMI prospective study of patients with acute coronary syndrome. Thus. Markolf Hanefeld. there is no doubt that a therapy to correct the harmful effects of abnormal glucose tolerance has the potential to improve Centre for Clinical Studies. GWT.4 Impaired glucose tolerance in the DECODE study was associated with a significantly increased all-cause mortality. © The Author(s). Global projections for the diabetes epidemic between 2010 and 2030 estimate an increase of prevalence from 285 million in 2010 to 438 million in the year 2030. 2013 .sagepub.2. Reprints and permissions: http://www. prevention T Abbreviations and acronyms ACE angiotensin-converting enzyme ADA American Diabetes Association AHA American Heart Association CANOE Canadian Normoglycemia Outcomes Evaluation DECODE  Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe DPP Diabetes Prevention Program DREAM  Diabetes Reduction Assessment with ramipril and rosiglitazone Medication GAMI  Glucose Abnormalities in Patients with Myocardial Infarction CGI combined glucose intolerance CGMS continuous glucose monitoring system HbA1c glycated haemoglobin A1c HOPE Heart Outcomes Prevention Evaluating Study hsCRP high sensitive C-reactive protein IDF International Diabetes Federation IDPP Indian Diabetes Prevention Program IFG impaired fasting glucose IGT impaired glucose tolerance IMT intima-media thickness Jupiter  Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin NAVIGATOR  Nateglinide And Valsartan in Impaired Glucose Tolerance Outcome Research NF-kB nuclear factor . Dr. Technical University Dresden.de health outcomes.com by guest on June 8. cardiovascular diseases and with co-morbidities of the metabolic syndrome. Therefore prevention of diabetes. abnormal glucose tolerance was the strongest risk factor for subsequent re-infarction or death from coronary heart disease.5 This illustrates that people with pre-diabetes already represent a high-risk population for cardiovascular and diabetes-related complications. Many of these people need a therapy with the focus on harmful effects of impaired glucose tolerance. many individuals with pre-diabetes already show diabetes-related complications. Fax: +49 (0)351 4400581 E-mail: Hanefeld@gwtonline-zks.6 Whether we should intervene is of important medical and economic relevance.REVIEW Drug therapy for the prevention of type 2 diabetes – is there a medical rationale? MARKOLF HANEFELD. Germany. Br J Diabetes Vasc Dis 2011. People with pre-diabetes represent a population already at high risk for cardiovascular and diabetes-related complications.sagepub. pre-diabetes. At diagnosis more than 50% of patients already exhibit co-morbidities of the metabolic syndrome. Already at diagnosis more than 50% of the patients exhibit co-morbidities of the metabolic syndrome. many individuals with prediabetes already show diabetes-related complications and cardiovascular disease.

7-12 Extrapolation of data from RCTs is predictive of a reduction in the incidence of diabetes in people with IGT of ~ 30–60% when lifestyle change is applied over a follow-up period of three years. Therefore in this review the focus is on the rationale for medical intervention based on an individualised.com by guest on June 8. 1999 Diabetes & Stoffw. triglyceride.27 In a follow-up analysis of kidney function in the RIAD study. activity of NF-κB receptors and expression of promoter genes regulating NF-κB pathways. These changes are harmful to both β-cells22 and endothelial function via increased oxidative stress. high-density lipoprotein. We now have an evidence base from RCTs that lifestyle intervention is efficacious. people with pre-diabetes share in principle the same pathophysiology as patients of newly diagnosed type 2 diabetes. have much to gain by early and strict control of hyperglycaemia. In conclusion.6% was reported for those who developed diabetes during follow-up. low-density lipoprotein. As shown in a small sub-study of patients in the ORIGIN study. HDL-C. nephropathy.  Pathophysiological consequences of hyperglycaemia blood coagulation↑ fibrinolysis↓ subclinical inflammation↑ endothelial dysfunction (NO release↓) HDL-C catabolism TG-rich lipoproteins LDL removal↑ FFA↑ Excessive hyperglycaemia oxidative stress↑ insulin resistance↑ B-cell function↓ plaque stability↓ Hanefeld M. free fatty acids.20 Thus. Rationale for drug therapy based on pathophysiology Diabetes is a chronic progressive disease. Whereas the risk of subjects with isolated IFG and isolated IGT converting to diabetes is rather low we can observe a four-times higher conversion rate in subjects with CGI (table 1) as shown by data from the RIAD study. Lifestyle intervention to correct over nutrition with food of high caloric value and low complex carbohydrate content as well as structured programmes for more physical activity is a rational solution and has first priority. LDL. risk-adjusted assessment. The lessons learnt from intervention and population-based studies have shown that such programmes have so far had little impact on the global wave of newly diagnosed diabetes so far. safe and cost effective.REVIEW This pandemic is fuelled by overnutrition and a rapid decrease in physical activity together with global urbanisation and rapid transition to a westernised lifestyle in developing countries. TG.17 First-phase insulin secretion and processing of proinsulin is impaired in pre-diabetes. excessive glycaemic variability in CGMS. FFA. 2013 .24 In addition to parameters of glucose intolerance. In the DPP the incidence of newly diagnosed retinopathy in the group with stable IGT (HbA1c 5. increased glycaemic variability with postprandial hyperglycaemia is associated with enhancement of low grade chronic inflammation.25 The prevention of diabetes-related complications by intensified glucose control was convincingly documented in the UKPDS26 and other trials.15 Glucotoxicity acts in a vicious cycle together with lipotoxicity as a driving force for the progression of glucose intolerance and cardiovascular disease (figure 1).sagepub. Subjects at very high cardiovascular risk. If we consider drug therapy or medical intervention. or who already have existing diabetes-related diseases at the time of diagnosis of abnormal glucose tolerance.9% whereas a figure of 12. early drug intervention was associated with a sustained normalisation of postprandial hyperglycaemia. In subjects with pre-diabetes we see the same extent of insulin resistance as in patients with newly diagnosed diabetes as shown in the RIAD13 and San Antonio studies. Moreover many elderly subjects and disabled persons are not able or willing to change their lifestyle to significantly reduce the risk of diabetes. a careful risk/benefit assessment is of utmost importance.21 A CGMS measurement reveals abnormal glycaemic fluctuations before diabetes is diagnosed (figure 2).16 There is a growing evidence base that postprandial hyperglycaemia is associated with increased hsCRP. Intensified early therapy with insulin resulted in a recovery of first phase insulin secretion capacity with lower levels of proinsulin.9%) was 7. Furthermore. subjects with THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 169 Downloaded from dvd.14 A loss of about 40% of β-cell mass was shown in an autopsy study in subjects with IFG by Butler and colleagues. neuropathy or erectile dysfunction. new biomarkers of inflammation and β-cell mass may allow individuals with very high risk for progression to overt diabetes to be identified. Proinsulin is a reliable biomarker of risk of progression of abnormal glucose tolerance to overt diabetes and of increased cardiovascular risk. the following parameters may be used in assessing the rationale for drug treatment: combined hyperglycaemia. Another guide to decision making in whether to intervene is the degree of glucose intolerance. and very high proinsulin levels. Figure 1.23 Therefore early drug intervention in favour of controlling hyperglycaemia and glucose fluctuations may prevent glucotoxicity and the progression of diabetes.18 Some recently published studies suggest that this can be reversed by strict glucose control in patients with newly diagnosed diabetes. Rationale for drug therapy based on health risk Many individuals with pre-diabetes have early diabetes-related complications such as retinopathy. The risk of type 2 diabetes and its complications develops across a continuum of plasma glucose levels far below the threshold values for the diagnosis of diabetes.

30 In a sub-study of the 170 VOLUME 11 ISSUE 4  . combined glucose intolerance.  JULY/AUGUST 2011 Downloaded from dvd.32 Individualised treatment for subjects with metabolic syndrome Another subgroup of subjects with a very high risk of both diabetes and cardiovascular disease are patients with the metabolic syndrome. 2013 .5 6.28 Rosiglitazone. which has been shown to be equally effective in preventing diabetes but shares the same side effects (oedema. no data from RCTs on specific medical treatment of the metabolic syndrome as common soil for type 2 CGI.33 In a statement of the AHA and ADA the odds ratio for diabetes in people with the metabolic syndrome was considered to be not less than 4–5 whereas the odds ratio for cardiovascular disease was around 2. type 2 diabetes. It remains an open question whether pioglitazone. IGT.36 The ADA in its latest clinical practice guidance recommends treatment with metformin in addition to lifestyle counselling and specific treatment of these co-morbidities (figure 3). particularly those with dyslipidaemia and visceral obesity.REVIEW Figure 2. Table 1. treatment of postprandial hyperglycaemia with acarbose in people with IGT resulted in a significantly slower progression of IMT. The conversion rate to diabetes among these patients was high. heart failure. revealed a 49% reduction of events. There is controversy regarding which component of the metabolic syndrome carries what weight.com by guest on June 8. CGI) to type 2 diabetes: RIAD Study (mean 2. reduction in blood pressure and suppression of inflammatory activity.6 2.29 Abnormal glucose tolerance is a major cardiovascular riskfactor. This applies to coronary heart disease as well as for peripheral arterial disease and stroke.34 In addition to glucose control.38 The rationale is based on around 50 years of experience in clinical practice and the results of DPP39 and IDPP. weight gain).  Yearly conversation rate of glucose intolerance (IFG. personal communication of RIAD data). was withdrawn from the European market in 2010 because of serious adverse effects and an increase in cardiovascular risk. however.sagepub. IFG.  Continuous glucose measurements in patient with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) HbA1c. impaired fasting glucose. IMT of the common carotid arteries in people with IGT.9 3.9 years)24 IFG NGT IFG IGT CGI 1.9 – T2D 0. glycated haemoglobin A1c. The nephro-protective effects of treatment of abnormal glucose tolerance with the PPARγ agonist rosiglitazone was shown in the DREAM study. NGT.32 The treatment of postprandial hyperglycaemia by acarbose reduced the incidence of newly diagnosed hypertension by 34%.35 In people with prediabetes two components of the metabolic syndrome: hypertension and dyslipidaemia are of utmost importance in determining cardiovascular risk. can be used in a special subgroup of people with pre-diabetes.9 STOP-NIDDM trial. stable glucose tolerance had a lower incidence of newly diagnosed albuminuria than those who converted to diabetes (F Pistrosch.3 – – – IGT 3.5 0. IGT. impaired glucose tolerance.7 – – CGI 0.4 2.37 The IDF considers metformin therapy as a secondary intervention to follow changes in lifestyle. the 2 hr postchallenge glucose level was significantly correlated to IMT even when HbA1c was in the normal range. T2D. these patients may benefit from weight reduction. normal glucose tolerance.7 9.11 At the moment.31 A secondary analysis of the STOPNIDDM study with cardiovascular events as predefined endpoints. In the RIAD study.

47 The DPP was the first large scale primary intervention trial to evaluate the potential of metformin in comparison to placebo and lifestyle (figure 4).8 USA9.9 A fourth arm in this study included • Obesity.269) 3 –60 NA +37 p=0. statins. NAVIGATOR. The favourable effects with pravastatin in the WOSCOPS study42 was not confirmed in other trials with statins. patients with advanced atherosclerosis are susceptible to pro-arrhythmogenic effects of hypoglycaemia and the risk of heart failure. patients with major cardiovascular complications or documented atherosclerotic disease may benefit from strict glucose control. The recently published NAVIGATOR trial was the first RCT in people with pre-diabetes with predefined cardiovascular events as primary objective.40. +. high-density lipoprotein.08 STOP NIDDM Acarbose IGT (n=1.  Risk:benefit balance in major randomised controlled trials with antidiabetic drugs DREAM Rosiglitazone Patients Study duration (years) Reduction in diabetes incidence (%) Impact on newly diagnosed hypertension (%) Impact on newly diagnosed cardiovascular events (%) IGT/IFG (n=5. DPP. NA NAVIGATOR Nateglinide IGT (n=9. The same applies to recent studies with antidiabetic drugs which have focused on prevention of diabetes as the primary objective. A decreasing incidence of newly diagnosed patients with diabetes in the HOPE study45 was not confirmed in a primary prevention trial with this drug (DREAM).306) 5 No effect NA –6 p=0.43 In the Jupiter study even an increase in diabetes incidence was observed with rosuvastatin. particularly patients with both high risk of diabetes and of cardiovascular complications. Furthermore.44 The same applies to the ACE inhibitor ramipril. However. decrease. Diabetes Prevention Program.155) 3 –31 +25 p=n. Study to Prevent Non-Insulin-Dependent Diabetes Mellitus. Thus it appears that individuals with abnormal glucose tolerance should be considered for therapy. LDL. Treatment with telmisartan was associated with a higher number of newly diagnosed diabetes at the end of the study. neural and psychological abnormalities • Increased subclinical inflammation • Intima-media thickness ↑ HDL.11 few studies have been published with antidiabetic drugs (table 2).41 Studies with statins and antihypertensive drugs to prevent cardiovascular disease and the incidence of newly diagnosed diabetes as secondary objectives have resulted in controversial results. DREAM.10 and India.7 Finland. antihypertensive and antiplatelet drugs. A careful individual risk:benefit calculation with the help of established risk scores is the way forward as many will already be moribund and be treated with multiple drugs. low-density lipoprotein. Whereas we have good evidence for the efficacy and safety of lifestyle intervention in people with IGT from China. diabetes and cardiovascular disease are available.REVIEW Figure 3. This was mainly due to the low number of events since few cases with advanced cardiovascular diseases entered the studies.IFG. Diabetes REduction Assessment with ramipril and rosiglitazone Medication. dyslipidemia (HDL↓.46 A study with the AT1receptor blocker telmisartan (ON TARGET). impaired fasting glucose.s. none of the lifestyle studies has shown a significant effect on cardiovascular complications at the end of follow-up. Furthermore. hypertension.368) 3 –36 –34 p=0. So far.  Comorbidities and diabetes-related diseases in people with pre-diabetes Lessons from RCTs with antidiabetic drugs When considering results of drug trials directed towards diabetes prevention a critical assessment of risk:benefit of antidiabetic drugs is essential.com by guest on June 8. –. Canadian Normoglycemia Outcomes Evaluation.sagepub. Nateglinide And Valsartan in Impaired Glucose Tolerance Outcome Research. increase.43 CANOE Rosiglitazone Metformin IGT (n=207) 3. STOP NIDDM.g. IGT. THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 171 Downloaded from dvd. e. impaired glucose tolerance. drug treatment of these patients must be based on an individual consideration of risk:benefit. particularly if diabetesrelated diseases co-exist at diagnosis. 2013 .03 DPP Metformin IGT (n=2.006 –49 p=0. TG ↑) • Fatty liver • Early atherosclerosis • Early microangiopathy • Albuminuria (~30%) • Minor sexual.9 –66 NA NA CANOE. Table 2.

sagepub. however. Limited information exists from wash-out periods after major RCTs directed at diabetes prevention. treatment was associated with serious adverse events such as bone fractures and heart failure. metformin reduced the incidence of newly diagnosed diabetes by 31% with relatively few side effects. IGT.51 The STOP-NIDDM trial was a multinational trial with the α-glucosidase inhibitor acarbose which specifically acts to suppress postprandial hyperglycaemia.53 versus 0.com by guest on June 8. at follow-up the incidence of the metabolic syndrome was reduced by 41% in the lifestyle group and by 17% in the metformin group compared with placebo.7% •  Patients with already existing diabetes-related diseases (retinopathy. carotid or peripheral arterial lesions • People with ≥ 2 components of the metabolic syndrome HbA1c. IFG.11 So far. no significant reduction of blood pressure.39 Metformin has only weak effects on postprandial glucose excursions. in the UKPDS study with newly diagnosed patients with diabetes.  Subgroups with high risk for diabetes and complications • People with combined IFG/IGT and or HbA1c ≥ 5. metformin was the only drug to significantly reduce cardiovascular events and premature mortality in 11 years of follow-up. Which drugs can be recommended? Currently evidence from RCTs is inconclusive for differen­ tiation between primary prevention. Without doubt metformin has a strong efficacy and safety evidence base from decades of clinical use in diabetes treatment. In addition.32 The NAVIGATOR trial assessed whether the antihypertensive agent valsartan or the oral antidiabetic agent nateglinide could delay progression to diabetes or reduce the incidence of cardiovascular events in people with IGT and cardiovascular disease or cardiovascular risk factors. delay or masking of hyperglycaemia. 2013 .  The DPP Study: Incidence of newly diagnosed diabetes in the Diabetes Prevention Progam (DPP) by treatment group8 Reproduced with permission from N Engl J Med 2001.55 Because of a high rate of adverse events in the studies with PPAR-γ agonists they cannot be recommended for primary prevention in subjects with pre-diabetes at the moment. Additionally acarbose reduced incidence of predefined cardiovascular events and newly diagnosed hypertension.REVIEW Figure 4.41 In a small study in Canadian Indians the low dose combination therapy with rosiglitazone and metformin in people with IGT resulted in a relative risk reduction of 66% with a low rate of adverse events. impaired glucose tolerance. impaired fasting glucose. Treatment approaches Lifestyle change is an essential requirement for good glucose control with near to normal glucose control as the target. Recently published 10-year follow-up data since randomisation to DPP have shown that the modest weight loss with metformin was maintained. Table 3.9 In the DPP. As shown in figure 4. With pioglitazone and rosiglitazone a reduction of 80% and 60% respectively of newly diagnosed diabetes was achieved.40.04).48 The efficacy and safety of metformin in the primary prevention of type 2 diabetes has been confirmed in a RCT from China49 and India. the PPARγ agonist troglitazone but this had to be stopped because of idiosyncratic liver toxicity and withdrawal from the market.53 In conclusion there are only two drugs – acarbose and metformin – with proven efficacy and safety for prevention of diabetes. neuropathy. In the DREAM trial rosiglitazone increased heart failure rate to 0. glycated haemoglobin. However. but neither drug showed an effect in preventing cardiovascular disease. Thus based on an individualised risk:benefit assessment the following subgroups of patients with prediabetes might be considered for treatment with antidiabetic drugs (table 3).50 These findings await confirmation from other RCTs. very obese males with high fasting plasma glucose. fatty liver) •  Patients with a history of atherosclerotic vascular disease or documented coronary.08% (hazard ratio 7. Effective therapy should protect the β cells from glucotoxicity and support β cell regeneration. atherogenic lipoproteins or of cardiovascular events has been reported in pre-diabetic subjects in any of these RCTs with metformin. albuminuria.52 Diabetes incidence was reduced by 34% if the same criteria for diagnosis were applied as used in the DPP.54. Diabetes incidence in the metformin group was reduced by 18% compared with placebo. Interestingly only valsartan (and not nateglinide) showed a modest effect in preventing progression to diabetes. the treatment approach should take account of co-morbidities and cardiovascular risk factors associated with the metabolic syndrome. Costs were acceptable for both drugs. 53% of participants had the metabolic syndrome according to NCEP-III criteria. A subgroup analysis of the DPP revealed that metformin was particularly effective in young.344:1343-50.  JULY/AUGUST 2011 172 Downloaded from dvd. This implies treatment of chronic hyperglycaemia and restoration to within the normal range in the fasting and postprandial state. To VOLUME 11 ISSUE 4  .

European Diabetes Epidemiology Group. Schiekofer S et al. Diabetes Care 1997. Fox CS. Insulin secretion and insulin sensitivity pattern is different in isolated impaired glucose tolerance and impaired fasting glucose: the risk factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes study. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. 10. Lifestyle change should be the cornerstone of diabetes prevention. metformin was particularly effective in young obese men with the highest level of fasting plasma glucose but not with postchallenge hyperglycaemia. Diabetes 2003. Decades of clinical experience exist for metformin and acarbose. Butler AE. Miyazaki Y et al. clinical data favour long-term use of the antidiabetic agents metformin or acarbose since they have the best evidence on long-term safety and efficacy. Gallo S et al.67:152-62. Noda M.25: 1504-10. The reasons for this are unclear but it could be due to ethnic differences in lifestyle (in most Asian countries the diet is rich in complex carbohydrates with rice as the major source of food) and/or the underlying pathophysiology. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. Koehler C. 14.6:13. At present. Cardiovascular effects of disturbed insulin activity in metabolic syndrome and in type 2 diabetic patients. 2009. The Da Qing IGT and Diabetes Study.  3. Turkey and Mexico (BAYER AG info) whereas metformin is recommended by the ADA37 and the IDF38 acting as the worldwide diabetes authority for prevention. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. The DECODE study group. Reismann P.  7. Larson MG. Tuomilehto J.9 In the STOP-NIDDM trial acarbose was particularly effective in the elderly. Impaired Glucose Tolerance for Atherosclerosis and Diabetes study. N Engl J Med 2002. Diabetologia 2005. with evidence of long-term safety. Rudofsky G. Leip EP et al.20:537-44. Cardiovasc Diabetol 2007. less obese subjects with high postchallenge glucose excursions52 as well as subjects with the metabolic syndrome.104. 52:102-10.  8. 15. Ferrannini E. Diabetologia 2004. whereas metformin is the foundation therapy in North America. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetes Care 2005. Diabetes Care 2002.48:2229-35.REVIEW References Key messages Acarbose and metformin: ● are the only agents with evidence of efficacy in the prevention of type 2 diabetes ● use is supported by clinical experience of long-term safety and cost effectiveness  1. Horm Metab Res 2009. 2013 . Wallander M. Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study. Bonner-Weir S et al. Asberry PJ. Impaired glucose tolerance and neuropathy. Kosaka K. International Diabetes Federation. 17. Reduction of postprandial hyperglycemia in patients with type 2 diabetes reduces NF-κB activation in PBMCs. Hanefeld M. San Antonio metabolism study. 11. and most European countries. Fuecker K et al. Glycemic status and development of kidney disease: the Framingham Heart Study. In the sub-group analysis of the DPP. South and Central America. Shofer JB et al. Gastaldelli A. Kuzuya T. Eriksson JG et al. Diabetes Prevention Program Research Group. Horm Met Res 2004. Efendic S et al. Bartnik M.49:289-97. Knowler WC. 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). Hohberg C. Impact of the individual components of the metabolic syndrome and their different combinations on the prevalence of atherosclerotic vascular disease in type 2 diabetes: the Diabetes in Germany (DIG) study. Both antihyperglycaemic drugs are associated with very low risk of hypoglycaemia and do not need vigilant monitoring of blood glucose. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Finnish Diabetes Prevention Study Group.41:123-31.com by guest on June 8. Pfützner A. evidence of efficacy. Koehler C. Diabetologia 2006. Li GW. In certain subgroups with a very high risk of progression of glucose intolerance and vascular complications an approach based on drug treatment is a practical option. safety and cost effectiveness only exist for acarbose and metformin. JAMA 2006. Lancet 1999. Monnier L. Mary S et al.346:393-403. 13.47:31-9. Mas E. and body fat distribution with lifestyle modification in Japanese Americans with impaired glucose tolerance. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Neurologist 2008. International Diabetes Federation.344:1343-50. Liao D. Based on data from subgroup analysis of the DPP and STOP-NIDDM trials. Hanefeld M. Snehalatha C. Progression of glucose intolerance and harmful effects on the vessel wall are not only a consequence of chronic hyperglycaemia but also of glycaemic variability. date. Acarbose is widely used for type 2 diabetes treatment in Asia. Smith AG.26:868-74. Improvement of BMI.33 From a global perspective acarbose for prevention of diabetes is approved in 26 countries including China. both drugs may be considered for certain patient profiles at high risk of diabetes. 18. body composition. Brussels. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Barrett-Connor E. Janson J. 12. Diabetes Care 2003. Pan XR. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lindstrom J. Fowler SE et al.  2. N Engl J Med 2001.  5. Hu YH et al. Diabetes Res Clin Pract 2005.28:2436-40.354:617-21.14:23-9. Indian Diabetes Prevention Programme (IDPP). Conclusions The risk of diabetes and cardiovascular disease develops across a continuum of glycaemia far below cut-off limits for newly diagnosed diabetes.  9. 4th edn. THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 173 Downloaded from dvd. Forst T. Ramachandran A.sagepub.  4. 16. Ginet C et al. Singleton JR.295:1681-7.  6. Diabetes Atlas. Drug based intervention should be individualised and account taken of the risk:benefits.36:630-8.

Diabetes Care 2000. and PRoFESS: new-onset diabetes. controlled study in patients with early type 2 diabetes. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. 23. Yao D et al.359:2195-207. 48. Diagnosis and management of the metabolic syndrome: an American Heart Association/ National Heart. JUPITER Study Group. Lung. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. Saely CH. International Diabetes Federation: a consensus on type 2 diabetes prevention. Remission of hyperglycemia following intensive insulin therapy in newly diagnosed type 2 diabetic patients: a long-term follow-up study. Dtsch Med Wochenschr 1999. American Heart Association. 22. 31. and Blood Institute Scientific Statement. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.205:2409-17. Josse RG. 40. Standards of medical care in diabetes – 2010. 2013 . Josse RG.103: 357-62. 45. Yusuf S. Hanefeld M. Lung. 50. Diabet Med 2007. Temelkova-Kurktschiev T. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. Koehler C et al. N Engl J Med 2006. Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress.57(S1):151. STOP-NIDDM Trial Research Group.13:449-59. 46. 36. Diabetes 2008. Chiasson JL. UK Prospective Diabetes Study (UKPDS) Group. DeFornzo R. Singh S.286(15):1882-5. Ridker PM.352:837-53. Gerstein HC. Lancet 2006. Hernan WH. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Chiasson JL. The Chinese diabetes prevention trial: preventive effect of Metformin on the progression to diabetes mellitus in the IGT population: a 3-year multicenter prospective study.355:1551-62. Schindler C.  JULY/AUGUST 2011 Downloaded from dvd.27(Suppl 2):S36-9. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Metabolic syndrome and its single traits as risk factors for diabetes in people with impaired glucose tolerance: the STOP-NIDDM trial. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis.35:1073-8. Koehler C et al. N Engl J Med 2008. Schmid F et al. Diabetologia 2010. Gomis R et al.362:1463-76. Prevalence of newly diagnosed type 2 diabetes. 28. 34. Niessen PM. Brasacchio D. 38. Effect of nateglinide on the incidence of diabetes and cardiovascular events. Alberti KG.29:901-7. Diab Vasc Dis Res 2009. atrial fibrillation. Diabetes Care 2010.24:137-44. 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