Megatrials in type 2 diabetes. From excitement to frustration?

Abstract

Whether glycaemic control may result in a reduction of cardiovascular (CV) risk has been a matter of continuous discussion and investigation. Epidemiological analyses have extensively suggested a relationship between glycaemic control and CV events; however, the results of intervention trials have been less conclusive. The UKPDS reported a 16% reduction in the risk of myocardial infarction, but this reduction was not statistically significant. The results of the Kumamoto and PROactive studies could not allow any firm conclusions to be drawn either, because of limited size and the defined primary endpoint, respectively. The results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials and the Veteran Administration Diabetes Trial (VADT) were published in rapid succession over the second half of 2008 and at the beginning of 2009. A total number of almost 25,000 type 2 diabetic patients were recruited in these three trials, which assessed the effect of intensive glycaemic control vs conventional treatment on well-defined CV endpoints. In spite of the achievement and maintenance of strict glycaemic control (HbA 1c <7.0%), no beneficial effect of intensive therapy was apparent in any of the studies. At the same time these results were presented, the results of an analysis of the 10 year follow-up of the UKPDS also became available and provided a more optimistic view of the potential benefit of achieving good glycaemic control. The relative risk reductions for myocardial infarction and all-cause mortality were significantly lower in the patients who initially received the 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. Once again the debate on the importance of glycaemic control in preventing macrovascular complications remains unsettled. These results, however, require some reconciliation, and the objective of this commentary is to analyse a series of elements, including the changes in the treatment approach to CV risk factors in type 2 diabetes, the effect of glucoselowering agents, and the characteristics of the patients included in the different trials, that should be taken into account when interpreting the results of intervention trials in type 2 diabetes.

Metabolic Memory and Individual Treatment Aims in Type 2 Diabetes – Outcome-Lessons Learned from Large Clinical Trials

“…Although the results of the recent large clinical trials sound clear-cut, it is worth critically analyzing their features [10]. The VADT, ACCORD, and ADVANCE studies included individuals at high CV risk.…”

“…The VADT, ACCORD, and ADVANCE studies included individuals at high CV risk. This is apparent from the high prevalence of patients with prior CV events (35%), and more than 50% having microvascular complications [8][9][10]. Because of the high CV risk, an aggressive treatment of CV risk factors was introduced to lower LDL-cholesterol (∼2.3 mmol/l) and blood pressure (∼120/70 mmHg).…”

“…One may assume that the lack of prior CV events, or microvascular complications, and a lower baseline HbA1c may reflect a shorter duration of the disease, and an overall better health status. Thus, duration of diabetes and prior CV events may be the key factors influencing the results of these recent trials, where strict glycemic control was achieved only after years of uncontrolled diabetes [10]. Ideal conditions for good glycemic control and health status prevail when diagnosis is made early and glycemic control is ensured from the time of diagnosis.…”

Clinical inertia in the management of type 2 diabetes mellitus: a focused literature review

“…22 The evidence summarised above demonstrates that clinical inertia is common both with OAD-and insulin-based therapies. A number of factors are associated with inertia including lack of knowledge, training, and education, along with inadequate resources.…”

Type 2 Diabetes Mellitus in Family Practice: Prevention and Screening

“…In the Hoorn Study, for example, at entry into the study, 39.5% of patients had ischaemic heart disease (Spijkerman et al, 2004) and 48.1% had impaired foot sensitivity (Spijkerman et al, 2003). In addition, since it is likely that having a high blood glucose for years on end may represent a harmful "legacy effect" (Del Prato, 2009), there is a greater imperative to diagnose early and theoretically reduce diabetic complications in later years. These characteristics raise the logical possibility of preventing patients progressing to Type 2 Diabetes during this latent phase and hence reducing the complications associated with Type 2 Diabetes, both at diagnosis and afterwards.…”