Advances in diabetes care?

There are now many cardiovascular outcome studies on treating hypertension and dyslipidaemia in people with diabetes, but there are still few outcome studies on the most difficult aspect of diabetes: the management of hyperglycaemia. It is noteworthy, therefore, when the results of two large, international, multi-centre studies on glycaemic management are presented at a meeting of the American Diabetes Association and published the same week in the New England Journal of Medicine.1, 2 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study has been described in a recent leading article,3where we speculated that the increased mortality observed in the intensive therapy group might be related to adverse cardiovascular effects of hypoglycaemia, when striving for a normal target HbA1c. Further analysis following presentation and publication of the ACCORD results does not offer a clear alternative explanation. Many of the excess deaths were described as ‘unexpected or presumed cardiovascular disease’; it remains likely that hypoglycaemia-induced arrhythmias or acute vascular events were partly responsible.4 The Action in Diabetes and Vascular disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) glycaemic arm was due to be presented at the autumn meeting of the European Association for the Study of Diabetes. Presentation and publication of ADVANCE were brought forward when the ACCORD trial was prematurely stopped. The results of ADVANCE have received less publicity in the medical and lay press, mainly because the ADVANCE glycaemic results were largely as expected and a lack of effect on mortality, either beneficial or adverse, is much less newsworthy than the increased mortality related to intensive therapy that was found in ACCORD. So do the results of the ADVANCE study offer a real advance in the management of patients with diabetes? ADVANCE was designed as a combined 2 x 2 factorial blood pressure and glycaemia study, following on from the blood pressure and glycaemia arms of the United Kingdom Prospective Diabetes Study (UKPDS).5, 6The study was investigator-initiated and conducted, with international coordination from Australia and regional coordinating centres in Europe, China, Australia and Canada. It was funded by the Institut de Recherches Internationales Servier, and Servier products were featured, so that the blood pressure lowering arm compared a combination of perindopril and indapamide against placebo, and intensive glycaemic control was based on therapy with gliclazide MR.7 Entry criteria included type 2 diabetes and either existing macrovascular or microvascular disease, or high cardiovascular risk based on the presence of another major cardiovascular risk factor, but it was not essential that the patient had hypertension. After a six-week run in period of open label fixed low-dose perindopril-indapamide and usual glucose lowering treatment, patients were randomised to perindopril-indapamide or placebo, and standard glycaemic therapy or intensive therapy with a target HbA1c of less than 6.5%. Initial therapy was with open-label gliclazide MR, with the addition of other oral agents and insulin as required to reach target. Recruitment was completed by March 2003 with 11 140 subjects (57% male) with a mean age of 66 years and a mean duration of diabetes of eight years.8At baseline 32% had a history of macrovascular disease, and 10% had a history of major microvascular disease, including macroalbuminuria, proliferative retinopathy, retinal photocoagulation or macular oedema. Mean blood pressure at baseline was 145/81mmHg and mean HbA1c was 7.5%, so prior treatment of blood pressure and glycaemia was not particularly sub-optimal. The study had two primary outcomes. The macrovascular outcome was a composite of non-fatal stroke, nonfatal myocardial infarction or cardiovascular death, which is a composite outcome that is frequently used in cardiovascular studies, and includes only clinical outcomes. The microvascular composite was new or worsening nephropathy (development of macroalbuminuria, doubling of serum creatinine, need for renal replacement therapy, death due to renal disease) or retinopathy (development of proliferative retinopathy, macular oedema, diabetes-related blindness or retinal photocoagulation therapy). The microvascular composite was therefore a mixture of clinical outcomes (development of proliferative retinopathy, macular oedema, diabetes-related blindness, death due to renal disease), procedural outcomes (retinal photocoagulation, need for renal replacement therapy), and surrogate markers (development of macroalbuminuria, doubling of serum creatinine). (See also ‘Drug Notes’, pages 290–291.) Patients were followed for a mean of 4.3 years in the ADVANCE blood pressure study.9As would be expected when the patients in the active treatment group received a combination of two additional antihypertensive drugs at randomisation, there was an early and sustained separation in mean blood pressure readings. During follow up there was a mean reduction in systolic blood pressure of 6mmHg and diastolic blood pressure of 2mmHg in patients assigned the active combination of perindoprilindapamide compared to placebo, and the average blood pressure in the intervention group was 135/85mmHg. The combined primary outcome was significantly reduced by 9% with the combination. The separate reductions in macrovascular and microvascular events at 8% and 9% were not statistically significant, but secondary outcomes of cardiovascular and all-cause mortality were significantly reduced. Interestingly, much of the reduction in macrovascular events was because of a reduction in coronary rather than cerebrovascular events, and most of the reduction in microvascular events was in the development of new or worsening nephropathy. There was also a significant reduction in new microalbuminuria. The ADVANCE glycaemia arm was extended and ran for a median follow up of five years.2In the standard control group there was a slight reduction in HbA1c down to 7.3% in the first six months, with no major change for the remainder of the study. The intensive control group received gliclazide at randomisation, and HbA1c was reduced to 7.0% at six months, but it was not until 36 months of follow up that the mean HbA1c approached the intended HbA1c target of 6.5%. The average difference in HbA1c between the intensive and standard control groups throughout follow up was 0.7%. The use of most classes of oral antidiabetic drugs was higher in the intensive group, as was the use of insulin. Intensive control significantly reduced the combined primary macrovascular and microvascular outcome by 10%. There was no effect on major macrovascular events or all-cause mortality. Intensive control significantly reduced major microvascular events by 14%, and similar to the blood pressure arm most of the microvascular benefit was due to reductions in new or worsening nephropathy. New-onset microalbuminuria was also significantly reduced. The main adverse effects of intensive treatment were increases in minor and severe hypoglycaemia. The results of the ADVANCE blood pressure arm are very reminiscent of the results of the MICRO-HOPE substudy of the HOPE study.10In MICRO-HOPE, 3577 patients with diabetes were treated with ramipril or placebo, and there was a significant reduction in the primary macrovascular composite of myocardial infarction, stroke or cardiovascular death. Data for microalbuminuria were not often collected in MICRO-HOPE, and although there was a significant reduction in overt nephropathy in MICRO-HOPE the reduction in new microalbuminuria was not statistically significant. Both ADVANCE and MICRO-HOPE compared an active intervention with placebo and not an active antihypertensive comparator; it is therefore not possible to determine if the macrovascular and microvascular benefits observed were due to blood pressure lowering in a high-risk group of subjects, or due to specific effects of the drugs that were used, with the added complexity for ADVANCE that the active therapy was a fixed combination of ACE inhibitor and diuretic (see also ‘Drug Notes’, pages 290–291). From a clinical perspective the results of the ADVANCE blood pressure lowering study add some support for the use of diuretics as second-line therapy in people with diabetes in addition to an ACE inhibitor or angiotensin-II receptor blocker, as recommended by the National Institute for Health and Clinical Excellence (NICE) in the blood pressure management part of the type 2 diabetes management guideline.11The mean blood pressure of 135/75mmHg that was obtained in ADVANCE is considerably lower than the blood pressures that were obtained in the UKPDS (144/82mmHg)5and the Hypertension Optimal Treatment (143/81mmHg)12blood pressure studies, and demonstrate that lower blood pressure targets can be safely reached by using multiple drugs, with further macrovascular and microvascular benefit. The systolic blood pressure of 135mmHg is higher than the target of 130/80mmHg set in the NICE type 2 diabetes management guideline for diabetic patients with kidney, eye or cerebrovascular damage. There is very little evidence to support this lower target, and it is difficult to see how this target can be realistically achieved in routine clinical practice. The results of the ADVANCE glycaemia study are strongly reassuring that a policy of slowly increasing antidiabetic therapies from an entry HbA1c of 7.5% to a target HbA1c of 6.5% is associated with further reductions in renal outcomes, with no adverse effect on macrovascular events or mortality, extending the results of the UKPDS. It is perhaps disappointing that there was no reduction in macrovascular events, but glycaemic control in the standard control group improved slightly, and a reduction in macrovascular events might have occurred with a greater separation in HbA1c. The NICE type 2 diabetes guideline is confusing when addressing targets for HbA1c, and appears to have a target HbA1c of 6.5% for initiating metformin or second-line antidiabetic therapy and a target of 7.5% for initiating third-line therapy. The ADVANCE results would support a target HbA1c of 6.5% at all points in the treatment pathway. In reality, in the United Kingdom at the present time the real targets for blood pressure and glycaemia are contained within the Quality and Outcomes Framework, where a percentage of patients within a general practice have to have a last blood pressure of 145/85mmHg or less, or a last HbA1c of 7.4% or less. Coincidentally, these values are almost the same as the baseline blood pressure and glycaemia values for the ADVANCE participants. It might be argued that the results of the ADVANCE blood pressure and glycaemia studies are not major scientific advances on the studies that are described above. However, if the results of ADVANCE and other studies could be incorporated into new, lower targets for the Quality and Outcomes Framework, then this would indeed be a major clinical and public-health advance, especially as diabetic renal disease remains the single most common diagnosis for patients entering end-stage renal replacement therapy. Glasgow Royal Infirmary was a centre in the ADVANCE study. Dr Fisher was the principal investigator for the centre and a member of the ADVANCE collaborative group.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.