Collaborators on trials of lowering glucose (CONTROL)

Based on the successful BPLTTC model, CONTROL was established in 2008 to provide reliable evidence to clinicians and their patients about the effects of lowering glucose levels through an analysis of large scale trials. The first of these analyses, based on data from more than 27,000 patients worldwide, was able to resolve major uncertainty about the effects of intensive glucose control on major cardiovascular events and mortality.

The healthcare community is now looking to the CONTROL group to resolve other key clinical dilemmas in management of diabetic and pre-diabetic patients. CONTROL will be looking closely at which particular medications, or combinations of medications, can achieve the best glucose control to protect patients from heart attacks, stroke and death.

Diabetes mellitus is one of the most common non-communicable diseases globally. Around 285 million people are currently living with the disease and over the next two decades this is expected to increase to more than 430 million (around 7.8% of the total world population), largely due to the escalating prevalence of overweight and obesity. The evidence for the devastating effects of diabetes is overwhelming; in the presence of disease, the risk of a major cardiovascular event is increased two to four fold and the risk of death increased two to five fold. Glucose-lowering strategies are the treatment mainstay in the management of diabetes and the past decade has seen exponential growth in the number of pharmacological and non-pharmacological strategies to lower glucose.

Despite this growth, major uncertainty surrounds the clinical benefits (and risks) of different glucose-lowering strategies and, as a consequence the optimal way to manage diabetic patients has been unclear. Compounding the problem has been the rapid increase in the prevalence of patients in whom glucose levels are elevated but which do not reach the threshold for diagnosis of diabetes.  The effects of glucose-lowering strategies on serious health outcomes in this population group also remain very unclear.  Evidence from even large clinical trials has been insufficient to reliably inform clinical practice and treatment guidelines.

In response to this, key opinion leaders in diabetes and glucose trials have formed an international collaboration called CONTROL (Collaborators on Trials of Glucose Lowering). Established in 2008, CONTROL seeks to provide reliable evidence to clinicians and their patients about the effects of glucose-lowering through informed, pre-specified collaborative meta-analyses of all eligible, large randomized trials. The first of these analyses, based on data from more than 27,000 patients from the US, UK, Europe, Asia and Australia, was able to resolve major uncertainty about the effects of intensive glucose control on major cardiovascular and serious hypoglycemia and mortality. However, the clinical community is now looking to the CONTROL group to resolve other key clinical dilemmas in management of diabetic and prediabetic patients, including which particular agents or combinations of agents or approaches should be used to achieve optimal glucose control.

Aims

Among patients with diabetes:

  • To determine the effects of strategies targeting different intensities of glucose-lowering (ie. more compared with less intensive glucose control) on major microvascular outcomes, peripheral vascular disease and cognitive decline
  • To determine the effects of different active glucose-lowering therapies (ie. head-to-head comparisons) on major macrovascular and microvascular outcomes, peripheral vascular disease, major hypoglycaemia, cognitive decline and total mortality
  • To determine the effects of strategies employing different active glucose-lowering strategies on total mortality and major cardiovascular events across important patient subgroups defined by patient age, sex, ethnicity, HbA1c, duration of diabetes and existing cardiovascular disease

Among patients with prediabetes:

  • To determine the effects of glucose-lowering strategies on major macrovascular and microvascular outcomes, peripheral vascular disease and total mortality

Methods

This project will be a meta-analysis of individual patient data from randomised controlled trials of glucose lowering in adults with type 2 diabetes or prediabetes using standardised endpoints.

The primary study outcomes for this meta-analysis are:

  • Coronary heart disease defined as non-fatal myocardial infarction or death from coronary heart disease
  • Stroke defined as non-fatal stroke or death from cerebrovascular disease
  • Peripheral vascular disease defined as death due to peripheral vascular disease and amputation of at least one digit
  • Heart failure defined as heart failure resulting in death or hospitalization
  • Total major cardiovascular events comprising the composite of stroke or coronary heart disease as defined above
  • Cardiovascular death defined as death from stroke or coronary heart disease as defined above
  • Total mortality
  • Major microvascular events (diabetic retinopathy assessed by retinal imaging, visual loss, requirement for photocoagulation, end-stage renal disease, renal death)
  • Cognitive decline
  • Major hypoglycaemia defined as a hypoglycaemic episode (with or without transient central nervous system dysfunction) without other apparent cause, in which the individual was unable to treat him/herself and required help from another person. The secondary outcomes are glycated haemoglobin and mean systolic blood pressure.