REVIEW doi: 10.1111/j.1742-1241.2005.00675.x Earlier intervention in type 2 diabetes: The case for achieving early and sustained glycaemic control C. J. BAILEY,1 S. DEL PRATO,2 D. EDDY3 AND B. ZINMAN4 ON BEHALF OF THE GLOBAL PARTNERSHIP FOR EFFECTIVE DIABETES MANAGEMENT* Aston University,1 Birmingham, UK, University of Pisa,2 Pisa, Italy, The Archimedes Project,3 Oakland, CA, USA, Mount Sinai Hospital,4 University of Toronto, Toronto, Canada glycaemic targets. This article reviews the evidence for SUMMARY early intervention, showing that intensive approaches, In type 2 diabetes, the onset and progression of complica- including earlier introduction of combination therapy, tions is significantly delayed by improving glycaemic con- allow more patients to achieve glycaemic targets and trol. However, the proportion of patients reaching and hence reduce complications and delay disease progression. sustaining guideline recommendations for glycaemic tar- gets remains unacceptably low. Recent clinical trials and Keywords: Type 2 diabetes; glycaemic control; Archimedes predictive physiologically based mathematical simulations model; early intervention; combination therapy (Archimedes model) indicate that benefits can be enhanced with earlier intervention and timely achievement of Ó 2005 Blackwell Publishing Ltd INTRODUCTION complications. Up to 50% of individuals with type 2 diabetes have complications at diagnosis (1,2), with, for example, Chronic hyperglycaemia, which often precedes diagnosis of nephropathy and retinopathy being present in approximately type 2 diabetes for more than a decade, causes extensive 20% of subjects (2,3). Progression of complications can be vascular damage and leads to the early development of clinical rapid: diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) (4), and diabetic retinopathy is the leading cause of new cases of blindness among adults (5). In *Global Partnership for Effective Diabetes Management Members: addition, peripheral neuropathy is associated with an George Alberti, University of Newcastle upon Tyne, Newcastle increased risk of non-traumatic lower extremity amputations upon Tyne, UK; Pablo Aschner, Javeriana University School of (6), and the high incidence of macrovascular complications Medicine, Bogota, Colombia; Cliff Bailey, Aston University, leads to deaths in 75% of type 2 diabetes patients (7). Birmingham, UK; Lawrence Blonde, Oschner Clinic Foundation, New Orleans, LA, USA; Stefano Del Prato, University of Pisa, Pisa, This burden of complications increases with severity and Italy (Chair); Anne-Marie Felton, Federation of European Nurses in duration of hyperglycaemia, but there is now substantial Diabetes, London, UK; Barry Goldstein, Jefferson Medical College evidence that good glycaemic control reduces the risk of of Thomas Jefferson University, PA, USA; Ramon Gomis, Hospital complications (8,9). It is essential therefore to address the Clinic, Barcelona, Spain; Edward Horton, Joslin Diabetes Center, management of type 2 diabetes by increasing the proportion Boston, MA, USA; James LaSalle, Medical Arts Research of patients who achieve the glycaemic targets outlined in Collaborative, Excelsior Springs, MO, USA; Hong-Kyu Lee, Seoul current guidelines (10–15). In this article, we report on the National University, College of Medicine, Seoul, Korea; Lawrence Leiter, St. Michael’s Hospital, Toronto, ON, Canada; Stephan importance of intensive glycaemic control and explore strate- Matthaei, Diabetes-Zentrum Quakenbruck, Quakenbruck, gies that might help to achieve this objective. Germany; Marg McGill, Diabetes Centre, Royal Prince Alfred Hospital, Sydney, Australia; Neil Munro, Primary Care Diabetes Europe, Surrey, UK; Richard Nesto, Lahey Clinic, Burlington, THE IMPORTANCE OF GOOD GLYCAEMIC MA, USA; Paul Zimmet, International Diabetes Institute, CONTROL Caulfield, Australia; and Bernard Zinman, Mount Sinai Hospital, University of Toronto, Toronto, Canada. Epidemiological analysis of the United Kingdom Prospective Correspondence to: Diabetes Study (UKPDS) demonstrated that a 1% decrease in Prof. Clifford Bailey, PhD, School Of Life and Health Sciences, glycosylated haemoglobin (HbA ) was associated with a risk Aston University, Aston Triangle, Birmingham B4 7ET, UK 1c Tel.: þ 44 121 204 3898 reduction of 37% for microvascular disease and 14% for Fax: þ 44 121 204 3892 myocardial infarction (MI). These data also indicate that Email: [email protected] there is no lower threshold to the benefits of glycaemic ª 2005 Blackwell Publishing Ltd Int J Clin Pract, November 2005, 59, 11, 1309–1316 1310 EARLIER INTERVENTION IN TYPE 2 DIABETES control (16). The Norfolk Cohort of the European approach, in which a period of lifestyle modification is fol- Prospective Investigation into Cancer and Nutrition also lowed by a slow process of uptitration of monotherapy and noted that higher HbA1c level predicts higher risk of death eventually combination therapy (21). When adopting this from cardiovascular disease (CVD), ischaemic heart disease conservative approach, there is often a reluctance to switch (IHD), and all cause mortality. Of particular note in this from traditional methods and habits, despite the recognition study was the strikingly greater risk of these events when the that glycaemic targets are not being achieved (22). HbA1c level rose above 7% (Figure 1) (17). These findings suggest that glycaemic-control strategies should aim to BENEFITS OF GLYCAEMIC CONTROL achieve HbA1c as close to normal as possible and as soon as possible, although the benefits of reaching this target should It would not be possible to review all the evidence relating to always be weighed against the risk of hypoglycaemia (10,13). the benefits of glycaemic control on micro- and macrovascu- The inadequacy of the current management of glycaemia is lar complications in diabetes. However, in this section, we exemplified by reports that the majority of individuals with type highlight two seminal studies that we feel are particularly 2 diabetes in both the US and Europe (63% and 69%, respec- relevant to the issue of early aggressive therapy of diabetes tively) do not achieve a 7% HbA1c target (18,19). National and its long-term benefits. Health And Nutrition Examination Study (NHANES) data also indicate that the proportion of individuals achieving The Diabetes Control and Complications Trial and HbA < 7% has not improved over time (18). The Steno-2 1c Epidemiology of Diabetes Interventions and Complications – study found poor attainment of HbA targets compared with 1c Evidence from Type 1 Diabetes greater attainment of targets for blood pressure and lipids amongst individuals with type 2 diabetes. In the Steno-2 It is well established from studies in type 1 diabetes that study, blood pressure and lipid values improved gradually over intensive therapy to reduce HbA1c will delay the onset, and the 8-year study period, whereas mean HbA1c tended to level reduce the progression, of microvascular complications. For out (20). Similarly, in NHANES, there were continued example, in the Diabetes Control and Complications Trial improvements over time in the proportion of individuals (DCCT), a large type 1 diabetes outcome study, intensive achieving goals for blood pressure and total cholesterol (18). diabetes management with three or more daily insulin injec- The reason for these differences is likely to be multifactor- tions or insulin pump therapy, aiming for an HbA1c target of ial. For example, there appears to be a much greater awareness 6.05%, was compared with conventional insulin treatment in the general population of the risks associated with hyper- with once- or twice-daily insulin injections. In addition, inten- tension and hypercholesterolaemia than the harmful effects of sively treated participants had more frequent clinical visits and hyperglycaemia. In addition, hyperglycaemia has been per- performed self-monitoring of blood glucose at least four times ceived by too many for too long as a benign condition, per day. A 2% difference in HbA1c was maintained between stemming from an unhealthy lifestyle and not requiring treat- the two treatment groups. The study was stopped early, ment. Another influential component may be the increasing because intensive therapy significantly reduced the risk of use of more efficacious treatments or rapid progression to nephropathy and retinopathy by 54% and 76%, respectively, management with combinations of treatments for hyperten- after 6.5 years (23). In the Epidemiology of Diabetes sion and dyslipidaemia. In comparison, procedures for manag- Interventions and Complications (EDIC) follow-up study to ing hyperglycaemia have seen relatively little change in recent the DCCT, all patients were encouraged to adopt intensive years. These generally focus on the traditional stepwise insulin therapy in their usual clinical setting (24). As a result, glycaemic control in the patients previously in the conventional 12 All causes (n = 135) CVD (n = 60) arm of the DCCT improved, while in the intensive group, it IHD (n = 42) Non-CVD (n = 75) 10 deteriorated somewhat. After 8 years of follow-up, HbA1c levels stabilised to around 8% in patients from both the former- 8 intensive and former-conventional groups (Figure 2A) (25). 6 However, despite similar HbA1c levels during this follow- 4 up period, some important differences remained. The cumu- 2 lative incidence of retinopathy remained much lower in those Relative risk of death Relative previously receiving intensive