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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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Drug therapy for the prevention of type 2 diabetes is there a medical rationale?
MARKOLF HANEFELD, FRANK SCHAPER
Abstract
ype 2 diabetes is a major risk factor for cardiovascular disease. At diagnosis more than 50% of patients already exhibit co-morbidities of the metabolic syndrome. Moreover, many individuals with prediabetes already show diabetes-related complications and cardiovascular disease. People with pre-diabetes represent a population already at high risk for cardiovascular and diabetes-related complications. Many of these people need a therapy with the focus on harmful effects of impaired glucose tolerance. Therefore prevention of diabetes, including drug treatment of people with abnormal glucose tolerance is of high medical and economic relevance. With a priority of lifestyle intervention drug treatment should be risk adjusted. Medical treatment should be considered for patients with diabetesrelated complications, cardiovascular diseases and with co-morbidities of the metabolic syndrome. Br J Diabetes Vasc Dis 2011;11:168-174 Key words: cardiovascular disease, pre-diabetes, prevention

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 - kB ON TARGET  Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial ORIGIN  Outcome Reduction with Initial Glargine Intervention PPAR 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. Already at diagnosis more than 50% of the patients exhibit co-morbidities of the metabolic syndrome.1 Moreover, many individuals with pre-diabetes already show diabetes-related complications.2,3 In the GAMI prospective study of patients with acute coronary syndrome, abnormal glucose tolerance was the strongest risk factor for subsequent re-infarction or death from coronary heart disease.4 Impaired glucose tolerance in the DECODE study was associated with a significantly increased all-cause mortality.5 This illustrates that people with pre-diabetes already represent a high-risk population for cardiovascular and diabetes-related complications. Thus, 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, Technical University Dresden, Germany. Correspondence to: Prof. Dr. Markolf Hanefeld, Fiedlerstrae 34, 01307 Dresden, Germany. Tel: +49 (0)351 4400580; Fax: +49 (0)351 4400581 E-mail: Hanefeld@gwtonline-zks.de

health outcomes. 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. The corresponding figures for IGT are 344 millions in 2010 and 472 millions in 2030.6 Whether we should intervene is of important medical and economic relevance.

The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651411403987

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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. 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. We now have an evidence base from RCTs that lifestyle intervention is efficacious, safe and cost effective.7-12 Extrapolation of data from RCTs is predictive of a reduction in the incidence of diabetes in people with IGT of ~ 3060% when lifestyle change is applied over a follow-up period of three years. 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. Moreover many elderly subjects and disabled persons are not able or willing to change their lifestyle to significantly reduce the risk of diabetes. Subjects at very high cardiovascular risk, or who already have existing diabetes-related diseases at the time of diagnosis of abnormal glucose tolerance, have much to gain by early and strict control of hyperglycaemia. If we consider drug therapy or medical intervention, a careful risk/benefit assessment is of utmost importance. Therefore in this review the focus is on the rationale for medical intervention based on an individualised, risk-adjusted assessment.

Figure 1. 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. 1999 Diabetes & Stoffw.

FFA, free fatty acids; HDL-C, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride.

Rationale for drug therapy based on pathophysiology


Diabetes is a chronic progressive disease. 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. 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.14 A loss of about 40% of -cell mass was shown in an autopsy study in subjects with IFG by Butler and colleagues.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). Furthermore, increased glycaemic variability with postprandial hyperglycaemia is associated with enhancement of low grade chronic inflammation.16 There is a growing evidence base that postprandial hyperglycaemia is associated with increased hsCRP, activity of NF-B receptors and expression of promoter genes regulating NF-B pathways.17 First-phase insulin secretion and processing of proinsulin is impaired in pre-diabetes. Proinsulin is a reliable biomarker of risk of progression of abnormal glucose tolerance to overt diabetes and of increased cardiovascular risk.18 Some recently published studies suggest that this can be reversed by strict glucose control in patients with newly diagnosed diabetes. Intensified early therapy with insulin resulted in a recovery of first phase insulin secretion capacity with lower levels of proinsulin. As shown in a small sub-study of patients in the ORIGIN study, early drug intervention was associated with a sustained normalisation of postprandial hyperglycaemia.20

Thus, people with pre-diabetes share in principle the same pathophysiology as patients of newly diagnosed type 2 diabetes.21 A CGMS measurement reveals abnormal glycaemic fluctuations before diabetes is diagnosed (figure 2). These changes are harmful to both -cells22 and endothelial function via increased oxidative stress.23 Therefore early drug intervention in favour of controlling hyperglycaemia and glucose fluctuations may prevent glucotoxicity and the progression of diabetes. Another guide to decision making in whether to intervene is the degree of glucose intolerance. 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.24 In addition to parameters of glucose intolerance, new biomarkers of inflammation and -cell mass may allow individuals with very high risk for progression to overt diabetes to be identified. In conclusion, the following parameters may be used in assessing the rationale for drug treatment: combined hyperglycaemia, excessive glycaemic variability in CGMS, and very high proinsulin levels.

Rationale for drug therapy based on health risk


Many individuals with pre-diabetes have early diabetes-related complications such as retinopathy, nephropathy, neuropathy or erectile dysfunction. In the DPP the incidence of newly diagnosed retinopathy in the group with stable IGT (HbA1c 5.9%) was 7.9% whereas a figure of 12.6% was reported for those who developed diabetes during follow-up.25 The prevention of diabetes-related complications by intensified glucose control was convincingly documented in the UKPDS26 and other trials.27 In a follow-up analysis of kidney function in the RIAD study, subjects with

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Figure 2. Continuous glucose measurements in patient with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT)

HbA1c, glycated haemoglobin A1c.

Table 1. Yearly conversation rate of glucose intolerance (IFG, IGT, CGI) to type 2 diabetes: RIAD Study (mean 2.9 years)24

IFG NGT IFG IGT CGI 1.3

IGT 3.9 3.7

CGI 0.5 6.5 0.9

T2D 0.6 2.4 2.7 9.9

STOP-NIDDM trial, treatment of postprandial hyperglycaemia with acarbose in people with IGT resulted in a significantly slower progression of IMT.31 A secondary analysis of the STOPNIDDM study with cardiovascular events as predefined endpoints, revealed a 49% reduction of events.32 The treatment of postprandial hyperglycaemia by acarbose reduced the incidence of newly diagnosed hypertension by 34%.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, particularly those with dyslipidaemia and visceral obesity. The conversion rate to diabetes among these patients was high.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 45 whereas the odds ratio for cardiovascular disease was around 2.34 In addition to glucose control, these patients may benefit from weight reduction, reduction in blood pressure and suppression of inflammatory activity. There is controversy regarding which component of the metabolic syndrome carries what weight.35 In people with prediabetes two components of the metabolic syndrome: hypertension and dyslipidaemia are of utmost importance in determining cardiovascular risk.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).37 The IDF considers metformin therapy as a secondary intervention to follow changes in lifestyle.38 The rationale is based on around 50 years of experience in clinical practice and the results of DPP39 and IDPP.11 At the moment, no data from RCTs on specific medical treatment of the metabolic syndrome as common soil for type 2

CGI, combined glucose intolerance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; T2D, type 2 diabetes.

stable glucose tolerance had a lower incidence of newly diagnosed albuminuria than those who converted to diabetes (F Pistrosch, personal communication of RIAD data). The nephro-protective effects of treatment of abnormal glucose tolerance with the PPAR agonist rosiglitazone was shown in the DREAM study.28 Rosiglitazone, however, was withdrawn from the European market in 2010 because of serious adverse effects and an increase in cardiovascular risk. It remains an open question whether pioglitazone, which has been shown to be equally effective in preventing diabetes but shares the same side effects (oedema, heart failure, weight gain), can be used in a special subgroup of people with pre-diabetes.29 Abnormal glucose tolerance is a major cardiovascular riskfactor. This applies to coronary heart disease as well as for peripheral arterial disease and stroke. In the RIAD study, IMT of the common carotid arteries in people with IGT, the 2 hr postchallenge glucose level was significantly correlated to IMT even when HbA1c was in the normal range.30 In a sub-study of the

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Figure 3. 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. Whereas we have good evidence for the efficacy and safety of lifestyle intervention in people with IGT from China,7 Finland,8 USA9,10 and India,11 few studies have been published with antidiabetic drugs (table 2). So far, none of the lifestyle studies has shown a significant effect on cardiovascular complications at the end of follow-up. This was mainly due to the low number of events since few cases with advanced cardiovascular diseases entered the studies. The same applies to recent studies with antidiabetic drugs which have focused on prevention of diabetes as the primary objective. The recently published NAVIGATOR trial was the first RCT in people with pre-diabetes with predefined cardiovascular events as primary objective.40,41 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. The favourable effects with pravastatin in the WOSCOPS study42 was not confirmed in other trials with statins.43 In the Jupiter study even an increase in diabetes incidence was observed with rosuvastatin.44 The same applies to the ACE inhibitor ramipril. 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).46 A study with the AT1receptor blocker telmisartan (ON TARGET). Treatment with telmisartan was associated with a higher number of newly diagnosed diabetes at the end of the 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).9 A fourth arm in this study included

Obesity, hypertension, dyslipidemia (HDL, TG ) Fatty liver Early atherosclerosis Early microangiopathy Albuminuria (~30%) Minor sexual, neural and psychological abnormalities Increased subclinical inflammation Intima-media thickness
HDL, high-density lipoprotein; LDL, low-density lipoprotein.

diabetes and cardiovascular disease are available. Thus it appears that individuals with abnormal glucose tolerance should be considered for therapy, particularly if diabetesrelated diseases co-exist at diagnosis. Furthermore, patients with major cardiovascular complications or documented atherosclerotic disease may benefit from strict glucose control. However, drug treatment of these patients must be based on an individual consideration of risk:benefit, particularly patients with both high risk of diabetes and of cardiovascular complications. 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, e.g. statins, antihypertensive and antiplatelet drugs. Furthermore, patients with advanced atherosclerosis are susceptible to pro-arrhythmogenic effects of hypoglycaemia and the risk of heart failure.

Table 2. 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=5,269) 3 60 NA +37 p=0.08

STOP NIDDM Acarbose IGT (n=1,368) 3 36 34 p=0.006 49 p=0.03

DPP Metformin IGT (n=2,155) 3 31 +25 p=n.s. NA

NAVIGATOR Nateglinide IGT (n=9,306) 5 No effect NA 6 p=0.43

CANOE Rosiglitazone Metformin IGT (n=207) 3.9 66 NA NA

CANOE, Canadian Normoglycemia Outcomes Evaluation; DREAM, Diabetes REduction Assessment with ramipril and rosiglitazone Medication; DPP, Diabetes Prevention Program;IFG, impaired fasting glucose; IGT, impaired glucose tolerance; , decrease; +, increase; NAVIGATOR, Nateglinide And Valsartan in Impaired Glucose Tolerance Outcome Research; STOP NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus.

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Figure 4. 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;344:1343-50.

Table 3. Subgroups with high risk for diabetes and complications

People with combined IFG/IGT and or HbA1c 5.7%  Patients with already existing diabetes-related diseases (retinopathy, neuropathy, albuminuria, fatty liver)  Patients with a history of atherosclerotic vascular disease or documented coronary, carotid or peripheral arterial lesions People with 2 components of the metabolic syndrome
HbA1c, glycated haemoglobin; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.

the PPAR agonist troglitazone but this had to be stopped because of idiosyncratic liver toxicity and withdrawal from the market. As shown in figure 4, metformin reduced the incidence of newly diagnosed diabetes by 31% with relatively few side effects. A subgroup analysis of the DPP revealed that metformin was particularly effective in young, very obese males with high fasting plasma glucose. Recently published 10-year follow-up data since randomisation to DPP have shown that the modest weight loss with metformin was maintained. Diabetes incidence in the metformin group was reduced by 18% compared with placebo.39 Metformin has only weak effects on postprandial glucose excursions.9 In the DPP, 53% of participants had the metabolic syndrome according to NCEP-III criteria, 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.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.11 So far, no significant reduction of blood pressure, atherogenic lipoproteins or of cardiovascular events has been reported in pre-diabetic subjects in any of these RCTs with metformin. However, in the UKPDS study with newly diagnosed patients

with diabetes, metformin was the only drug to significantly reduce cardiovascular events and premature mortality in 11 years of follow-up.50 These findings await confirmation from other RCTs. Without doubt metformin has a strong efficacy and safety evidence base from decades of clinical use in diabetes treatment. With pioglitazone and rosiglitazone a reduction of 80% and 60% respectively of newly diagnosed diabetes was achieved, however, treatment was associated with serious adverse events such as bone fractures and heart failure. In the DREAM trial rosiglitazone increased heart failure rate to 0.53 versus 0.08% (hazard ratio 7.04).51 The STOP-NIDDM trial was a multinational trial with the -glucosidase inhibitor acarbose which specifically acts to suppress postprandial hyperglycaemia.52 Diabetes incidence was reduced by 34% if the same criteria for diagnosis were applied as used in the DPP. Additionally acarbose reduced incidence of predefined cardiovascular events and newly diagnosed hypertension.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. Interestingly only valsartan (and not nateglinide) showed a modest effect in preventing progression to diabetes, but neither drug showed an effect in preventing cardiovascular disease.40,41 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.53 In conclusion there are only two drugs acarbose and metformin with proven efficacy and safety for prevention of diabetes. Costs were acceptable for both drugs.54,55 Because of a high rate of adverse events in the studies with PPAR- agonists they cannot be recommended for primary prevention in subjects with pre-diabetes at the moment.

Treatment approaches
Lifestyle change is an essential requirement for good glucose control with near to normal glucose control as the target. This implies treatment of chronic hyperglycaemia and restoration to within the normal range in the fasting and postprandial state. Effective therapy should protect the cells from glucotoxicity and support cell regeneration. In addition, the treatment approach should take account of co-morbidities and cardiovascular risk factors associated with the metabolic syndrome. 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).

Which drugs can be recommended?


Currently evidence from RCTs is inconclusive for differen tiation between primary prevention, delay or masking of hyperglycaemia. Limited information exists from wash-out periods after major RCTs directed at diabetes prevention. To
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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. Hanefeld M, Koehler C, Gallo S et al. 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. Cardiovasc Diabetol 2007;6:13. 2. Smith AG, Singleton JR. Impaired glucose tolerance and neuropathy. Neurologist 2008;14:23-9. 3. Fox CS, Larson MG, Leip EP et al. Glycemic status and development of kidney disease: the Framingham Heart Study. Diabetes Care 2005;28:2436-40. 4. Wallander M, Bartnik M, Efendic S et al. Beta cell dysfunction in patients with acute myocardial infarction but without previously known type 2 diabetes: a report from the GAMI study. Diabetologia 2005;48:2229-35. 5. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet 1999;354:617-21. 6. International Diabetes Federation. Diabetes Atlas, 4th edn. International Diabetes Federation, Brussels, 2009;104. 7. Pan XR, Li GW, Hu YH 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. 8. Tuomilehto J, Lindstrom J, Eriksson JG et al. Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50. 9. Knowler WC, Barrett-Connor E, Fowler SE et al. 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. 10. Liao D, Asberry PJ, Shofer JB et al. Improvement of BMI, body composition, and body fat distribution with lifestyle modification in Japanese Americans with impaired glucose tolerance. Diabetes Care 2002;25: 1504-10. 11. Ramachandran A, Snehalatha C, Mary S et al. Indian Diabetes Prevention Programme (IDPP). 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. 12. Kosaka K, Noda M, Kuzuya T. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract 2005;67:152-62. 13. Hanefeld M, Koehler C, Fuecker K et al. Impaired Glucose Tolerance for Atherosclerosis and Diabetes study. 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. Diabetes Care 2003;26:868-74. 14. Gastaldelli A, Ferrannini E, Miyazaki Y et al. San Antonio metabolism study. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia 2004;47:31-9. 15. Butler AE, Janson J, Bonner-Weir S et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52:102-10. 16. Monnier L, Mas E, Ginet C et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006;295:1681-7. 17. Rudofsky G, Reismann P, Schiekofer S et al. Reduction of postprandial hyperglycemia in patients with type 2 diabetes reduces NF-B activation in PBMCs. Horm Met Res 2004;36:630-8. 18. Forst T, Hohberg C, Pftzner A. Cardiovascular effects of disturbed insulin activity in metabolic syndrome and in type 2 diabetic patients. Horm Metab Res 2009;41:123-31.

date, 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. Decades of clinical experience exist for metformin and acarbose, with evidence of long-term safety. Both antihyperglycaemic drugs are associated with very low risk of hypoglycaemia and do not need vigilant monitoring of blood glucose. Based on data from subgroup analysis of the DPP and STOP-NIDDM trials, both drugs may be considered for certain patient profiles at high risk of diabetes. In the sub-group analysis of the DPP, metformin was particularly effective in young obese men with the highest level of fasting plasma glucose but not with postchallenge hyperglycaemia.9 In the STOP-NIDDM trial acarbose was particularly effective in the elderly, less obese subjects with high postchallenge glucose excursions52 as well as subjects with the metabolic syndrome.33 From a global perspective acarbose for prevention of diabetes is approved in 26 countries including China, Turkey and Mexico (BAYER AG info) whereas metformin is recommended by the ADA37 and the IDF38 acting as the worldwide diabetes authority for prevention. Acarbose is widely used for type 2 diabetes treatment in Asia, whereas metformin is the foundation therapy in North America, South and Central America, and most European countries. 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.

Conclusions
The risk of diabetes and cardiovascular disease develops across a continuum of glycaemia far below cut-off limits for newly diagnosed diabetes. Progression of glucose intolerance and harmful effects on the vessel wall are not only a consequence of chronic hyperglycaemia but also of glycaemic variability. Lifestyle change should be the cornerstone of diabetes prevention. 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. Drug based intervention should be individualised and account taken of the risk:benefits. At present, evidence of efficacy, safety and cost effectiveness only exist for acarbose and metformin.

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