To lower or not to lower? Making sense of the latest research on intensive glycaemic control and cardiovascular outcomes
- 1School of Nursing, McMaster University, Hamilton, Ontario, Canada
- 2McMaster University Medical Centre, Hamilton, Ontario, Canada
Diabetes is an extremely burdensome and costly chronic disease. It affects an estimated 4–6% of the world’s population, and its prevalence continues to rise.1 2 Diabetes is a major cause of blindness, end stage renal disease, and cardiovascular complications, all of which are preventable.3 4 Clinical practice guidelines for the management of diabetes emphasise the importance of optimal glycaemic control. Specifically, some clinical practice guidelines have suggested targeting a glycated haemoglobin (Hb) A1c concentration ⩽7%, or ⩽6% for those able to safely achieve it.5
ACCORD, ADVANCE, AND UKPDS 10-YEAR FOLLOW-UP
With the recent publication of 3 notable trials, a great deal of debate and confusion has been created about the cardiovascular effects of lowering glucose to near-normal concentrations in people with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the Action in Diabetes and Vascular Disease: Preterax and Damicron Modified Release Controlled Evaluation (ADVANCE) trial, and the 10-year follow-up of the UK Prospective Diabetes Study (UKPDS) provide complementary information about cardiovascular risk reduction with glucose lowering that can be used to help patients to develop evidence-based goals of therapy individualised to their own circumstances. See abstracts in this issue on pages 12–14.
ACCORD, ADVANCE, and the 10-year follow-up of the UKPDS all reported the effects of intensive glucose lowering on vascular outcomes.6–8 All 3 studies were randomised controlled trials, with an intensive glucose-lowering group and a “standard” control group with less stringent glycaemic targets. The trials differed in many respects (table 1) that may help to reconcile the differences in results (table 2).
Participants and duration of follow-up
There were important differences in the types of participants recruited and the duration of follow-up. ACCORD enrolled >10 000 patients starting in 2001 and followed them for a median of 3.4 years, at which point the intervention was discontinued (17 mo before the planned completion date) because of unexplained excess mortality in the intensive treatment group.6 ACCORD participants were selected to be a high cardiovascular risk group, and they had a fairly long duration of diabetes and poor glucose control before the study. However, most patients were receiving proven vascular protection interventions.
ADVANCE, conducted in the same era, followed up patients for 5 years.7 ADVANCE enrolled similar patients to ACCORD, except that their glucose control was better at baseline and they were less well treated with other vascular protective agents.
The 4209 UKPDS participants were quite different from those in the other 2 trials. They had newly diagnosed diabetes, were younger, and had a lower cardiovascular risk profile. The UKPDS began in the 1970s when there was much less evidence for other strategies of vascular protection, so rates of use of statins and antihypertensive agents were much lower. The earlier start of the UKPDS has allowed a much longer follow-up (approximately 17 y) but has also meant a 10–14% loss to follow-up in the various study groups.8
The 3 trials also differed substantially in the intervention, despite all of them comparing “intensive” with “standard” glucose control. ACCORD had the most aggressive glycaemic target HbA1c of <6.0% in the intensive group. ACCORD did not use a specific intervention strategy, allowing any marketed antihyperglycaemic drugs (including insulin) and lifestyle modifications to be used for glucose lowering. The ACCORD trial aggressively lowered median HbA1c concentrations from 8.1% to 6.7% in just 4 months of treatment in the intensive group, a much more rapid reduction than either of the other trials. However, the final median HbA1c concentration was 6.4% in the intensive group compared with 7.5% in the standard group.6
ADVANCE targeted an HbA1c concentration of ⩽6.5% in the intensive group using gliclazide-based therapy, with the addition of other antihyperglycaemic drugs as required. In the ADVANCE trial, mean HbA1c concentrations in the intensive group were reduced from 7.2% to 6.5% after 3 years, and to 6.4% by the end of the study (compared with 7% in the standard group).7
The UKPDS had 2 intervention groups, one using sulfonylurea and/or insulin and the other using metformin and/or insulin in overweight patients.9 10 In the intensive groups, target fasting glucose concentration was <6 mmol/l (<108 mg/dl), and preprandial glucose was 4–7 mmol/l (72–126 mg/dl) for a mean duration of 10 years. At the end of active treatment, median HbA1c concentrations were 7% in the active insulin/sulfonylurea group and 7.9% in the standard group. Active treatment was followed by a 10-year passive follow-up phase, in which no attempt was made to maintain randomised treatments; instead, patients were monitored to determine the long-term effects of previous intensive glycaemic control on vascular end points.8
The outcomes of all 3 trials included a macrovascular component. The primary outcome of ACCORD was a composite of non-fatal myocardial infarction or stroke, or death from cardiovascular causes. In ADVANCE, the same outcome was one of the major secondary endpoints. UKPDS included separate outcomes of myocardial infarction, stroke, and all-cause mortality. ADVANCE and UKPDS have also reported on microvascular outcomes (eye and kidney disease).6–8
INTERPRETATION OF DISCORDANT RESULTS
The results of the 3 trials, although apparently different, may have a common interpretation. In ACCORD, at the time the intervention was stopped, all-cause and cardiovascular mortality were significantly higher in the intensive group than the standard group, but a non-significant divergence in rates of the primary outcome favouring the intensive group began to emerge after the third year of the trial. This paradox remains to be explained.6
In ADVANCE, there was no significant benefit or harm seen in the cardiovascular composite outcome, although, a divergence in rates favouring intensive control seemed to begin after 4.5 years, raising the possibility of long-term benefit.7
The initial reports of the UKPDS indicated that intensive treatment with insulin/sulfonylurea did not significantly reduce myocardial infarction or all-cause mortality.9 10 However, after a further 10 years of follow-up, the beneficial effects became apparent even though the intervention had stopped 10 years earlier.8 The metformin treatment also showed benefit.
All of these results suggest that there is no cardiovascular benefit of glucose lowering for several years, but benefit may become apparent later on. Of note, both ADVANCE and the UKPDS showed early microvascular benefit of intensive glucose lowering.
The difference in the findings of the 3 studies may be explained by the selection of patients, length of follow-up, glycaemic control targets, rapidity of glucose lowering, or the various intervention strategies implemented. Although the findings of the trials denote 3 different scenarios with respect to cardiovascular risk reduction, they present relevant information for the management of type 2 diabetes across a spectrum of diabetes duration and severity, and baseline cardiovascular risk. Specifically, the UKPDS follow-up findings suggest that early intensification of glycaemic control in newly diagnosed type 2 diabetes leads to long-term cardiovascular benefit. The ADVANCE trial found no cardiovascular risk reduction, and the ACCORD trial found an increase in mortality. Since both ADVANCE and ACCORD trials recruited patients at high cardiovascular risk, the trials highlight the importance of managing these patients cautiously with respect to the use of aggressive glucose-lowering interventions to achieve glycaemic targets, managing cardiovascular risks and monitoring for adverse events.
IMPLICATIONS FOR PRACTICE
The cardiovascular results of ACCORD, ADVANCE, and UKPDS follow-up need to be considered in the broader context of diabetes care and education. First, both ADVANCE and UKPDS follow-up clearly showed a benefit in reducing microvascular complications with intensive glucose control, even to HbA1c concentrations <6.5%. Therefore, it is important to translate these findings to clinical practice and patient education. Explaining to patients that the investment they make day-to-day in managing their diabetes and achieving tight glycaemic control will pay off with reductions in microvascular complications and perhaps reductions in macrovascular complications in the long term. Furthermore, ongoing assessments and follow-up with patients will not only provide opportunities to assess self-management ability to achieve glycaemic targets, it will also allow non-glycaemic interventions for cardiovascular risk modification, with lifestyle and pharmacological interventions focused on healthy weight and eating habits, routine physical activity, lowering blood pressure and lipids, and smoking cessation.
Second, the findings suggest that the time at which aggressive interventions are initiated and the speed at which they progress are important considerations. The UKPDS follow-up found that targeted glucose concentrations reduced cardiovascular risk in patients with newly diagnosed type 2 diabetes. Because the ACCORD and ADVANCE trials found no cardiovascular risk reduction after the rapid intensification of glucose control in high-risk patients with type 2 diabetes, it is important that clinicians and educators recognise a patient’s diabetes history and cardiovascular risk and tailor glucose targets and lowering strategies accordingly. Patients with a pre-existing cardiovascular history and long-standing poorly controlled diabetes should therefore be advised to carefully lower glucose concentrations to meet optimal targets, while monitoring for cardiovascular symptoms or risk factors, adverse effects of medication, and hypoglycaemia.
To that end, the importance of individualised care continues to play a vital role in diabetes management, especially in light of the recent research findings. Although the findings may be generalised to patients with type 2 diabetes, all 3 studies were very specific in terms of their patient populations (ie, age, cardiovascular disease history, diabetes duration, and glycaemic control). Therefore, diabetes education and management (glycaemic targets and risk reduction strategies) need to be individualised and responsive to a patient’s glycaemic control, cardiovascular risk, and behavioural and psychosocial requirements, while minimising hypoglycaemic episodes and adverse events.
Type 2 diabetes is a dynamic and chronic condition that requires daily management of glucose concentrations to achieve short-term and long-term benefit. Evidence-based practice requires clinicians and educators to integrate best research evidence with patient preferences, clinical setting, and resources to facilitate adherence to glycaemic targets and cardiovascular risk modification. Evidence from the recent studies supports current glycaemic targets and does not support further lowering of targets currently proposed by clinical practice guidelines11–13 (table 3). Some clinical practice guidelines (eg, Canadian Diabetes Association guidelines) have already incorporated the latest findings from ACCORD and ADVANCE and as a result, have not changed or lowered glycaemic targets to achieve further cardiovascular risk reduction.12 However, clinical expertise and judgment is still important when interpreting guidelines and individualising therapy. In doing so, the latest research evidence will assist clinicians and educators in optimising glycaemic control and ultimately improving the short-term and long-term outcomes of patients living with type 2 diabetes.