Tailoring Treatment to the Individual in Type 2 Diabetes
Tailoring Treatment to the Individual in Type 2 Diabetes
Good glycaemic control continues to be the most effective therapeutic manoeuvre to reduce the risk of development and/or progression of microvascular disease, and therefore remains the cornerstone of diabetes management despite recent scepticism about tight glucose control strategies. The impact on macrovascular complications is still a matter of debate, and so glycaemic control strategies should be placed in the context of multifactorial intervention to address all cardiovascular risk factors. Approaches to achieve glycaemic targets should always ensure patient safety, and results from recent landmark outcome studies support the need for appropriate individualisation of glycaemic targets and of the means to achieve these targets, with the ultimate aim to optimise outcomes and minimise adverse events, such as hypoglycaemia and marked weight gain. The primary goal of the Global Partnership for Effective Diabetes Management is the provision of practical guidance to improve patient outcomes and, in this article, we aim to support healthcare professionals in appropriately tailoring type 2 diabetes treatment to the individual. Patient groups requiring special consideration are identified, including newly diagnosed individuals with type 2 diabetes but no complications, individuals with a history of inadequate glycaemic control, those with a history of cardiovascular disease, children and individuals at risk of hypoglycaemia. Practical guidance specific to each group is provided.
Good glycaemic control remains the cornerstone of diabetes management despite recent scepticism about tight glucose control strategies and concerns regarding safety of highly intensive treatment in the ACCORD study. Recent publications, including our 'Updated Recommendations from the Global Partnership for Effective Diabetes Management', continue to emphasise the essential role of good glycaemic control in reducing the risk of diabetes complications, although attempts to achieve glycaemic targets should always ensure patient safety. Some individuals may be unsuited to a particularly aggressive glucose-lowering regimen, for example, as illustrated in ACCORD, where all-cause mortality, risk of hypoglycaemia and weight gain were increased in patients exposed to this approach. Indeed, the treatment strategy adopted in this trial cannot be used as a benchmark for achieving optimal glycaemic control.
Ensuring good glycaemic control remains the most effective therapeutic manoeuvre to reduce the risk of development and/or progression of microvascular disease. In contrast, the impact on macrovascular complications is still a matter of debate. In the most recent outcome studies, ACCORD, ADVANCE and VADT, lowering HbA1c below 7% was not associated with any significant reduction in cardiovascular (CV) mortality. However, these results require further critical appraisal. For example, the overall CV mortality was much lower than the one initially used to calculate the sample power of these studies. Such an unexpectedly low mortality rate most likely reflects the substantial changes in type 2 diabetes management over the past 10 years that have incorporated multifactorial treatment strategies. These include extensive use of statins, newer and more effective agents for hypertension, increased use of aspirin and smoking cessation programmes. With such a comprehensive approach to patient care, it is more difficult to demonstrate a significant risk reduction that can be assigned to glucose lowering alone.
Another possible reason for these observations may be that the study duration of ACCORD, ADVANCE and VADT was too short to show a significant effect of intensive glucose control on macrovascular complications. In contrast, in the 10-year UKPDS follow-up, relative risk reductions for myocardial infarction (MI) and all-cause mortality were significantly lower in patients who initially received intensive treatment compared with those in the conventional treatment arm. Moreover, the initial benefit in terms of microvascular complications observed at the end of the intervention trial remained unaltered at follow-up. There was, however, quite a difference between the patients enrolled in the UKPDS compared with those in the ACCORD, ADVANCE and VADT trials: newly diagnosed patients with no prior CV events in the former, subjects with long-standing disease and a high prevalence of microvascular and macrovascular complications in the latter.
When all the large, long-term, prospective randomised controlled clinical trials (UKPDS, PROactive, ADVANCE, VADT and ACCORD) are included in a meta-analysis, blood glucose lowering appears to be associated with reduction of incident CV events. Overall, a 0.9% reduction in HbA1c with intensive therapy was associated with significant reductions of 17% in non-fatal MI [odds ratio (OR): 0.83, 95% confidence interval (CI): 0.75–0.93] and 15% in coronary heart disease (OR: 0.85, 95% CI: 0.77–0.93) vs. conventional therapy. In a meta-regression analysis, higher body mass index (BMI), duration of diabetes and incidence of severe hypoglycaemia were associated with greater risk of CV death in intensive treatment groups.
Altogether, these results support the need for appropriate individualisation of glycaemic targets and of the means to achieve these targets. Several factors can be taken into consideration when tailoring treatment including duration of diabetes, stage of disease, life expectancy, risk of hypoglycaemia and risk factors for CV disease (CVD). It should also be noted that even apparently acceptable levels of HbA1c can disguise wide daily fluctuations in plasma glucose that require control. Although these considerations may sound relatively straightforward, confusion exists in the healthcare community regarding how this information can be translated into clinical practice.
The primary goal of the Global Partnership for Effective Diabetes Management is the provision of practical guidance to improve patient outcomes in diabetes. Our recommendations have been updated after publication of the most recent outcome trials to incorporate a range for target HbA1c (6.5–7%) to provide flexibility to suit different patient populations. In this article, we aim to build on this by providing more explicit advice to support healthcare professionals in appropriately tailoring type 2 diabetes treatment. This includes: (i) identification of patient groups requiring special consideration, including newly diagnosed individuals with type 2 diabetes but no complications (overweight or obese adults, lean adults and children), individuals with a history of inadequate glycaemic control (no complications or history of CVD) and individuals at risk of hypoglycaemia; and (ii) provision of practical guidance specific to each group.
Note that, given the existence of considerable national and regional differences in the availability of therapeutic options, recommendations concerning the use of particular antidiabetic agents have been avoided. Other regional differences, e.g. variations in phenotype and genotype, should also be acknowledged. In addition, we have not included individuals with good glycaemic control as a separate population. For these patients, the guidance is to maintain the same regimen to keep patients at target and to react quickly if HbA1c starts to rise, e.g. by timely introduction of combination therapy or insulin as appropriate.
Abstract and Introduction
Abstract
Good glycaemic control continues to be the most effective therapeutic manoeuvre to reduce the risk of development and/or progression of microvascular disease, and therefore remains the cornerstone of diabetes management despite recent scepticism about tight glucose control strategies. The impact on macrovascular complications is still a matter of debate, and so glycaemic control strategies should be placed in the context of multifactorial intervention to address all cardiovascular risk factors. Approaches to achieve glycaemic targets should always ensure patient safety, and results from recent landmark outcome studies support the need for appropriate individualisation of glycaemic targets and of the means to achieve these targets, with the ultimate aim to optimise outcomes and minimise adverse events, such as hypoglycaemia and marked weight gain. The primary goal of the Global Partnership for Effective Diabetes Management is the provision of practical guidance to improve patient outcomes and, in this article, we aim to support healthcare professionals in appropriately tailoring type 2 diabetes treatment to the individual. Patient groups requiring special consideration are identified, including newly diagnosed individuals with type 2 diabetes but no complications, individuals with a history of inadequate glycaemic control, those with a history of cardiovascular disease, children and individuals at risk of hypoglycaemia. Practical guidance specific to each group is provided.
Introduction
Good glycaemic control remains the cornerstone of diabetes management despite recent scepticism about tight glucose control strategies and concerns regarding safety of highly intensive treatment in the ACCORD study. Recent publications, including our 'Updated Recommendations from the Global Partnership for Effective Diabetes Management', continue to emphasise the essential role of good glycaemic control in reducing the risk of diabetes complications, although attempts to achieve glycaemic targets should always ensure patient safety. Some individuals may be unsuited to a particularly aggressive glucose-lowering regimen, for example, as illustrated in ACCORD, where all-cause mortality, risk of hypoglycaemia and weight gain were increased in patients exposed to this approach. Indeed, the treatment strategy adopted in this trial cannot be used as a benchmark for achieving optimal glycaemic control.
Ensuring good glycaemic control remains the most effective therapeutic manoeuvre to reduce the risk of development and/or progression of microvascular disease. In contrast, the impact on macrovascular complications is still a matter of debate. In the most recent outcome studies, ACCORD, ADVANCE and VADT, lowering HbA1c below 7% was not associated with any significant reduction in cardiovascular (CV) mortality. However, these results require further critical appraisal. For example, the overall CV mortality was much lower than the one initially used to calculate the sample power of these studies. Such an unexpectedly low mortality rate most likely reflects the substantial changes in type 2 diabetes management over the past 10 years that have incorporated multifactorial treatment strategies. These include extensive use of statins, newer and more effective agents for hypertension, increased use of aspirin and smoking cessation programmes. With such a comprehensive approach to patient care, it is more difficult to demonstrate a significant risk reduction that can be assigned to glucose lowering alone.
Another possible reason for these observations may be that the study duration of ACCORD, ADVANCE and VADT was too short to show a significant effect of intensive glucose control on macrovascular complications. In contrast, in the 10-year UKPDS follow-up, relative risk reductions for myocardial infarction (MI) and all-cause mortality were significantly lower in patients who initially received intensive treatment compared with those in the conventional treatment arm. Moreover, the initial benefit in terms of microvascular complications observed at the end of the intervention trial remained unaltered at follow-up. There was, however, quite a difference between the patients enrolled in the UKPDS compared with those in the ACCORD, ADVANCE and VADT trials: newly diagnosed patients with no prior CV events in the former, subjects with long-standing disease and a high prevalence of microvascular and macrovascular complications in the latter.
When all the large, long-term, prospective randomised controlled clinical trials (UKPDS, PROactive, ADVANCE, VADT and ACCORD) are included in a meta-analysis, blood glucose lowering appears to be associated with reduction of incident CV events. Overall, a 0.9% reduction in HbA1c with intensive therapy was associated with significant reductions of 17% in non-fatal MI [odds ratio (OR): 0.83, 95% confidence interval (CI): 0.75–0.93] and 15% in coronary heart disease (OR: 0.85, 95% CI: 0.77–0.93) vs. conventional therapy. In a meta-regression analysis, higher body mass index (BMI), duration of diabetes and incidence of severe hypoglycaemia were associated with greater risk of CV death in intensive treatment groups.
Altogether, these results support the need for appropriate individualisation of glycaemic targets and of the means to achieve these targets. Several factors can be taken into consideration when tailoring treatment including duration of diabetes, stage of disease, life expectancy, risk of hypoglycaemia and risk factors for CV disease (CVD). It should also be noted that even apparently acceptable levels of HbA1c can disguise wide daily fluctuations in plasma glucose that require control. Although these considerations may sound relatively straightforward, confusion exists in the healthcare community regarding how this information can be translated into clinical practice.
The primary goal of the Global Partnership for Effective Diabetes Management is the provision of practical guidance to improve patient outcomes in diabetes. Our recommendations have been updated after publication of the most recent outcome trials to incorporate a range for target HbA1c (6.5–7%) to provide flexibility to suit different patient populations. In this article, we aim to build on this by providing more explicit advice to support healthcare professionals in appropriately tailoring type 2 diabetes treatment. This includes: (i) identification of patient groups requiring special consideration, including newly diagnosed individuals with type 2 diabetes but no complications (overweight or obese adults, lean adults and children), individuals with a history of inadequate glycaemic control (no complications or history of CVD) and individuals at risk of hypoglycaemia; and (ii) provision of practical guidance specific to each group.
Note that, given the existence of considerable national and regional differences in the availability of therapeutic options, recommendations concerning the use of particular antidiabetic agents have been avoided. Other regional differences, e.g. variations in phenotype and genotype, should also be acknowledged. In addition, we have not included individuals with good glycaemic control as a separate population. For these patients, the guidance is to maintain the same regimen to keep patients at target and to react quickly if HbA1c starts to rise, e.g. by timely introduction of combination therapy or insulin as appropriate.