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- November 20, 2008 |
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"UKPDS - Unanswered Questions?"Prof. Rury Holman (biography)
English - 2006-09-13 - 31 minutes
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Summary :
The UKPDS was a landmark 20-year trial which showed that the complications of type 2 diabetes could be reduced by more intensive management of glycaemia and blood pressure. In 5, 102 patients recruited with newly-diagnosed type 2 diabetes, the study demonstrated that maintaining improved blood glucose control with sulphonylurea or insulin monotherapy over median 10.3 years reduced the risk of the primary "any diabetes-related endpoint" by 12%, microvascular endpoints by 25% and microalbuminuria by 33%, with a non-significant 16% trend to a reduced risk of myocardial infarction (p = 0.052). In overweight patients allocated metformin as first-line monotherapy, the risk of the primary "any diabete s-related endpoint"was reduced by 32%, diabetes-related death by 42% and myocardial infarction by 39% with no weight gain and little increase in the risk of hypoglycaemia.The UKPDS showed also that maintaining improved blood pressure control using a step-wise treat-to-target therapeutic approach over median 8.4 years reduced the risk of the primary "any diabetes-related endpoint" by 24%, diabetes-related death by 32% and microvascular endpoints by 37%. Epidemiological analyses of the trial data have shown the benefits of improved glycaemic control and improved blood pressure control to be additive, emphasizing the need to manage both risk factors simultaneously.Despite the success of the UKPDS in informing diabetes management, many questions were left unanswered and new issues were raised. Lipid-lowering therapy was not included as a randomised therapy in UKPDS but its major importance has been demonstrated subsequently by studies such as HPS and CARDS, and the need for multiple risk factor interventions confirmed by the STENO-2 study.
The UKPDS highlighted the progressive nature of type 2 diabetes and showed that this was primarily related to declining b-cell function, rather than to increasing insulin resistance. It did not, however, identify a therapeutic approach that could alter disease progression using existing treatments, alone or in combination.The mechanisms for progressive b-cell dysfunction need to be elucidated and therapies identified that can halt or reverse this process, or be used to prevent the emergence of type 2 diabetes in susceptible individuals.
The borderline-significant result for reducing the risk of myocardial infarction in the glucose-lowering arm means that the potential macrovascular benefits of glycaemic improvement remain uncertain.This question is being addressed currently by the ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) and ORIGIN (Outcome Reduction with Initial Glargine INtervention) trials.
Whilst the UKPDS showed more intensive glucose control with sulphonylureas or insulin to be of net benefit, there remains uncertainty whether the presence of sulphonylurea therapy at the time a myocardial infarction occurs might be harmful. Additional UKPDS analyses suggest no increased case fatality with the agents used in the trial but further information is required on preparations that have a particular affinity for cardiac SUR receptors.
The metabolic syndrome and type 2 diabetes are both associated with increased cardiovascular disease risk.The degree, however, to which the presence of the metabolic syndrome in individuals who already have type 2 diabetes increases their risk of cardiovascular disease, is uncertain. Further analyses of UKPDS data show that the metabolic syndrome, whether diagnosed by ATP-III, WHO or IDF criteria, can identify diabetic patients at greater risk of macrovascular complications but with such poor discrimination that it is of limited clinical value.
Learning objectives :
After viewing this presentation the participant will be able to discuss:
- Additive effects of glucose and blood pressure control in T2DM
- Ongoing studies on glucose control and macrovascular risk
- Macrovascular benefits of metformin
- T2DM, metabolic syndrome and CVD mortality
- CHD case fatality with and without SU therapy in the UKPDS
- The progressive nature of T2DM
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