2nd September 2009
Observational follow-up of two cohorts of people with type 1 diabetes over 30 years has found that the cumulative incidences of some serious complications are lower than reported historically. This is likely to reflect the increasing use of intensive blood glucose control over recent years. The incidence of complications appears to be substantially lower in people who started intensive blood glucose control early-on in their treatment.
Level of evidence:
Level 2 (cohort studies examining patient-oriented outcomes) according to the SORT criteria.
This paper reinforces the current approach of aiming for intensive blood glucose control in patients with type 1 diabetes. This is in sharp contrast to the evidence around type 2 diabetes as we have previously blogged. The current NICE guideline on the management of type 1 diabetes should continue to be followed. This recommends that adults with type 1 diabetes should be advised that maintaining a DCCT-harmonised HbA1c below 7.5% (59mmol/mol) is likely to minimise their risk of developing diabetic eye, kidney or nerve damage in the longer term. However, the target HbA1c in type 1 diabetes depends on the individual patient, taking into account their risk of microvascular and macrovascular complications, and their risk or experience of hypoglycaemia.
What is the background to this?
Over recent years, the management of type 1 diabetes has involved aiming for intensive blood glucose control, in order to minimise the risk of developing long-term complications. The importance of this approach was shown several years ago in the Diabetes Control and Complications Trial (DCCT), a randomised controlled trial (RCT) that compared insulin treatment using one or two injections each day with intensive insulin treatment (including either continuous subcutaneous infusion or at least three injections a day, guided by frequent blood glucose monitoring) in 1,441 young patients (aged 30 to 39 years) with type 1 diabetes. DCCT was stopped early after 6.5 years when fewer people in the intensive insulin group developed retinopathy or experienced worsening of retinopathy. At this point, patients in the intensive treatment group had a lower median HbA1c of 7.3% vs. 9.1% [56 vs. 76mmol/mol], P<0.001). Benefits on certain other measures of diabetic complications (i.e. secondary endpoints e.g. microalbuminuria and albuminuria, which are signs of nephropathy and neuropathy determined by neurologic examination) were also seen in the intensive treatment group.
Observational follow-up of 1,375 patients from the original DCCT cohort has been ongoing in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, in which all patients were advised to use intensive insulin treatment. Even though seven years after the end of DCCT, HbA1c narrowed between the original intensive and conventional therapy groups, the reduced risk of complications seen with initial intensive therapy in DCCT was maintained. A significant reduction in cardiovascular (CV) events with initial intensive therapy has also been reported 11 years after DCCT ended. This is further supported by a meta-analysis in 1,800 patients with type 1 diabetes (duration <10 years) which suggested that attempting to improve glycaemic control reduces the risk of macrovascular events in patients with type 1 diabetes.
Because of the shift towards more intensive blood glucose control in type 1 diabetes in recent years, most of the published descriptions of the clinical course of this disease are now considered to be outdated or limited (eg by small population sizes). This paper described the clinical care, metabolic results, and outcomes of the DCCT/EDIC conventional and intensive treatment groups over a diabetes duration of 30 years and compared them with a subset of patients from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study with similar baseline characteristics (EDC is another observational study of type 1 diabetes and its complications).
What does this paper claim?
This paper found that the frequencies of serious complications in patients with type 1 diabetes are lower than those reported historically. The incidence of complications appears to be substantially lower in people who started intensive blood glucose control early-on in their treatment. After 30 years of type 1 diabetes, the cumulative incidences of proliferative retinopathy, nephropathy and cardiovascular disease (CVD) were 50%, 25% and 14%, respectively in the DCCT non-intensive treatment group, and 47%, 17% and 14% in the EDC cohort. Substantially lower cumulative incidences of 21%, 9% and 9% were seen in the DCCT intensive treatment group, in which no more than 1% of patients went blind, required renal replacement or had an amputation because of their diabetes.
This paper reinforces the current approach of aiming for intensive blood glucose control in patients with type 1 diabetes. This is in sharp contrast to the evidence around type 2 diabetes as we have previously blogged. There are some limitations to the data. Firstly, it could be argued that the DCCT non-intensive treatment group who were advised to use intensive treatment during the EDIC follow-up may not represent the general type 1 diabetes population. However, the authors noted that the metabolic control and outcomes in this group were similar to those reported in the more population-based EDC population, which suggests these data may be generalisable to clinical practice. Secondly, it is likely that other interventions that have been adopted over recent years (eg more aggressive blood pressure control, lipid-lowering therapy etc) may have contributed to the improved outcomes reported.
The NICE guideline on the diagnosis and management of type 1 diabetes should continue to be followed. This recommends that adults with type 1 diabetes should be advised that maintaining a DCCT-harmonised HbA1c below 7.5% (59mmol/mol) is likely to minimise their risk of developing diabetic eye, kidney or nerve damage in the longer term. However, NICE also acknowledges that having only one target HbA1c will mean that a significant number of patients will fail to meet it. Therefore, the target HbA1c in type 1 diabetes depends on the individual patient i.e. their risk of microvascular and macrovascular complications, and their risk or experience of hypoglycaemia. Based on observational data from DCCT, NICE recommends a desirable HbA1C target for adults as less than 7.5% (59mmol/mol). Ideally, approaching lower levels (<6.5% [<48mmol/mol]) may be beneficial for patients at increased arterial risk. Nevertheless, the question is whether such a low HbA1c is achievable. It is important to avoid pursuing tight control without discussing the pros and cons with the patient, especially if their risk or experience of hypoglycaemia, or the effort to achieve target, curtails quality of life. Adults who want to achieve HbA1c down to, or towards, 7.5% (59mmol/mol) should also be given support to do so. HbA1c should be checked every two to six months, depending on the individual (e.g. previous control, change in insulin, stability of blood glucose control).
Study details –
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group. Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration. Arch Intern Med 2009;169:1307-16
Design This was an analysis of the cumulative incidence of the long-term complications of type 1 diabetes. Observational data from two different cohorts, the DCCT/EDIC study and the EDC study, were compared. DCCT was an RCT comparing insulin treatment using one or two injections each day with more intensive insulin treatment in type 1 diabetes. EDIC was a subsequent observational study of most of the patients from DCCT, who were all advised to continue on intensive insulin treatment and followed up annually. The EDC study is an observational study of type 1 diabetes and its complications that collected data on patients from the Children’s Hospital of Pittsburgh in Pennsylvania. The DCCT/EDIC cohort is not a population-based sample, whereas, although it was clinic-based, the EDC population was shown to be representative of the type 1 diabetes population in Allegheny County, Pennsylvania.
DCCT/EDIC cohort: DCCT included 1441 subjects
(aged 13 to 39 years), with a type 1 diabetes duration of 1 to 5 years in the primary prevention cohort and 1 to 15 years in the secondary prevention cohort. The EDIC study included 1375 subjects from the DCCT cohort.
EDC cohort: The EDC population has been described in a previous publication. For this comparison, the authors selected 161 subjects from the EDC population that was similar to the DCCT cohort (age at baseline 13 to 39 years; diabetes duration <15 years; and retinopathy grade<30). They differed from the DCCT/EDIC cohort by having a slightly longer type 1 diabetes duration (approximately 5 years) and a lower mean age (approximately 6 years).
Retinopathy, nephropathy and CVD are the primary diabetes outcomes reported in this paper. Only clinically important retinopathy was included ie proliferative diabetic retinopathy or worse, clinically significant macular oedema, photocoagulation therapy, and blindness. Nephropathy was defined as AER >300mg/24 hours, serum creatinine>2mg/dL, or dialysis or renal transplant. CVD events included any of the following: nonfatal myocardial infarction (MI) or stroke, death judged to be secondary to CVD, subclinical MI, angina confirmed by ischaemic changes with exercise tolerance testing or by clinically significant obstruction on coronary angiography, or revascularisation with angioplasty or coronary artery bypass.
Sponsorship DCCT/EDIC is supported by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Eye Institute; the National Institute of Neurological Disorders and Stroke; the General Clinical Research Centers Program; and the Clinical and Translation Science Centers Program, National Center for Research Resources; and by Genentech. Contributors of free or discounted supplies and/or equipment include Lifescan, Roche, Aventis, Eli Lilly, OmniPod, Can-Am, B-D, Animas, Medtronic, Medtronic Minimed, Bayer, and Omron. EDC is supported by a grant from the National Institute of Diabetes and Kidney Diseases.
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