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- December 1, 2008 |
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"Shifting the paradigm: from stepwise to early combination therapy?"Prof. Rury Holman (biography)
English - 2003-08-26 - 27 minutes
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 | (24 slides) |
Summary :
The number of people worldwide with diabetes is predicted to exceed 300 million by the year 2025, more than all of the people living currently in North America. Despite major efforts to improve the management of diabetes, it remains in the 21st century the leading cause of blindness, end stage renal disease and lower extremity amputations in industrialized nations. The U.K. Prospective Diabetes Study (UKPDS) showed that intensive control of blood glucose with sulphonylurea or insulin, and with metformin in overweight patients, can reduce substantially the risk of diabetic complications. The Heart Protection Study has shown that lowering blood LDL cholesterol levels can also improve clinical outcomes significantly whilst the Steno-2 study, a trial in patients with Type 2 diabetes and microalbuminuria, has shown that a multiple risk factor intervention treat-to-target approach can reduce the risks of cardiovascular and microvascular events by as much as 50 percent.
Patients at highest absolute risk have the most to gain from interventions. Accordingly, it is desirable that all patients with type 2 diabetes have their cardiovascular risk evaluated in order that optimal management strategies can be implemented. Obtaining absolute cardiovascular risk estimates in male and female people with type 2 diabetes has been difficult, however, in the absence of diabetes-specific risk equations. The Framingham equations, which form the basis for most widely used risk calculators, are based on data from only 337 patients with diabetes. They are limited also by assessing only the presence or absence of diabetes rather than the degree of glycaemic control and not taking into account diabetes duration. The recently developed UKPDS Risk Engine (www.dtu.ox.ac.uk/riskengine) is a diabetes-specific cardiovascular risk calculator that uses glycaemia (as assessed by DCCT/UKPDS aligned HbA1c) and duration of diabetes with continuous measures of systolic blood pressure, total to HDL-cholesterol ratio and age in addition to sex, ethnic group and smoking status to provide ten-year CHD and stroke risk estimates with 95% confidence intervals.
The UKPDS demonstrated that prolonged monotherapy with sulphonylurea, insulin or metformin resulted in progressive hyperglycaemia with HbA1c levels increasing inexorably year on year. The reason for this was shown to be steady decline in beta-cell function, with patients losing on average 4% per year. UKPDS substudies investigated the earlier introduction of combination therapies including the addition of acarbose to any existing treatment regimen and the addition of insulin or metformin to sulphonylurea therapy. In none of these cases did there appear to be change in the underlying disease progression. Data from the DPP and TRIPOD studies suggest, however, that thiazolidinediones may maintain or enhance beta-cell function over time.
This possibility is being evaluated by the ADOPT Study (A Diabetes Outcome Progression Trial) which is examining the ability of rosiglitazone monotherapy to prevent or delay progressive hyperglycaemia over four years, compared with glibenclamide or metformin, in over 4,000 people with recently diagnosed type 2 diabetes. Meanwhile, the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) study is looking to see in 6,000 people with established type 2 diabetes the degree to which adding rosiglitazone to combination therapy with a sulphonylurea and metformin can reduce the risk of cardiovascular disease over six years.
Protracted stepwise addition of therapies for type 2 diabetes is no longer an option. Using an absolute risk based approach, it is now a question of how many therapies are needed and how soon.
Learning objectives :
The participant will review evidence supporting the need for early combination therapy:
Treating progressive hyperglycemia:
- Existing hypoglycaemic therapies can be given in combination at a much earlier stage, whenever therapeutic targets are not met
- Combination therapy is required to address the multiple risk factors in T2DM
- Thiazolidinediones offer additional therapeutic possibilities
Summary:
- Early combination therapy is essential if glycaemic targets are to be achieved and maintained in T2DM
- Therapies with different modes of action can be combined to address:
o Both fasting and postprandial hyperglycemia
o Insulin resistance and loss of B-cell function
- Outcome trials are evaluating potential benefits of new therapeutic options and combinations
Bibliographic references :
Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Wright A, Burden AC, Paisey RB, Cull CA, Holman RR; U.K. Prospective Diabetes Study Group.
Diabetes Care. 2002 Feb;25(2):330-6.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56). Stevens RJ, Kothari V, Adler AI, Stratton IM; United Kingdom Prospective Diabetes Study (UKPDS) Group. Clin Sci (Lond). 2001 Dec;101(6):671-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44). Holman RR, Cull CA, Turner RC. Diabetes Care. 1999 Jun;22(6):960-4.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
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