1. Changes in levels of haemoglobin A 1c during the first 6 years after diagnosis of clinical type 2 diabetes Clinical implications Niels de Fine Olivarius Volkert Siersma Lars J. Hansen Thomas Drivsholm Mogens Hørder

2. Glucose-lowering trials in type 2 diabetes UGDP 1970 :2.9 times higher death rate from CVD in tolbutamide group (p=0.005 vs. placebo) UKPDS 1998 :96% increase in DM-related death for those treated with both metformin and sulfonylurea (p=0.04 vs. conventional / sulphonylurea) Metaanalysis 2007 :Rosiglitazone: 64% increase in deaths from CVD (p=0.06 vs. placebo or other agents) ACCORD 2008 :35% increase in deaths from CVD (p=0.02 vs. less intensive glucose-lowering therapy)

3. Lesson to be learned Treatment regimens aiming at normalizing blood glucose for all patients may be detrimental, at least in middle-aged and older adults with diabetes of long duration.

4. Against generalized thought Average figures used to describe changes in HbA 1c may conceal a clinically important diversity in the way the blood glucose level deteriorates or even improves, especially immediately after diabetes diagnosis.

5. Objective To assess the variability in levels of glycosylated haemoglobin (HbA 1c ) during the first six years after diagnosis of clinical type 2 diabetes in relation to possible predictors.

6. Flow chart

7. All measurements of HbA 1c Upper limit of reference range

8. HbA 1c for 50 randomly selected patients

9. Modelling the course of HbA 1c Years since diabetes diagnosis Haemoglobin A1c (%) Level of HbA 1c one year after diabetes diagnosis Slope of the HbA 1c -curve

10. Predictors of level and slope of HbA 1c Gender Age BMI HbA1c Systolic BP Total cholesterols Urinary albumin Multivariate linear regression models

11. Predictors of level and slope of HbA 1c Gender Age BMI HbA1c Systolic BP Total cholesterols Urinary albumin Diabetic retinopathy Coronary heart disease Peripheral vascular disease Peripheral neuropathy Familial disposition to diabetes Smoking Physical activity Marital status Residence GP's acquaintance with the patient Multivariate linear regression models

12. Predictors of level and slope of HbA 1c Gender Age BMI HbA1c Systolic BP Total cholesterols Urinary albumin Diabetic retinopathy Coronary heart disease Peripheral vascular disease Peripheral neuropathy Familial disposition to diabetes Smoking Physical activity Marital status Residence GP's acquaintance with the patient Multivariate linear regression models SLOPE LEVEL

13. Changes in HbA 1c according to HbA 1c at diagnosis Years since diabetes diagnosis HbA 1c > 10% Haemoglobin A 1c (%) HbA 1c ≤ 10%

14. Changes in HbA 1c according to age Years since diabetes diagnosis Haemoglobin A 1c (%) Age ≤ 65 y. Age > 65 y.

15. Years since diabetes diagnosis HbA 1c > 10 at diagnosis Haemoglobin A 1c (%) Patients are grouped according to quartiles of the slope of HbA 1c after 1-year follow-up Changes in HbA 1c (I) From generalisation to individualisation

16. Changes in HbA 1c (II) From generalisation to individualisation Years since diabetes diagnosis HbA 1c ≤ 10 at diagnosis Haemoglobin A 1c (%) Patients are grouped according to quartiles of the slope of HbA 1c after 1-year follow-up

17. Conclusion 1 ACCORD – ADVANCE – VADT – UKPDS – UGDP Lowering glucose levels for all patients with T2DM has limited benefit and can lead to significant harm

18. Conclusion 2 Diabetes Care in General Practice Individualization: A more appropriate strategy to reduce the level and variability of HbA 1c could be to monitor changes in HbA 1c more closely and intensify treatment of those patients who actually experience the beginning of an apparently inexorable deterioration of their glycaemic control

19. Years since diabetes diagnosis HbA 1c > 10 at diagnosis Haemoglobin A 1c (%) Patients are grouped according to quartiles of the slope of HbA 1c after 1-year follow-up Changes in HbA 1c (I) From generalisation to individualisation

21. DCGP vs. UKPDS Years since diabetes diagnosis Fasting plasma glucose (mmol/l) conventional treatment intensive treatment structured care comparison group (=conventional treatment) UKPDS DCGP

22. DCGP vs. UKPDS % treated with diet alone Fasting plasma glucose (mmol/l) UKPDS DCGP 90% 70% 45% 17% 7% 13% 55% 40% 29% 32% Years since diabetes diagnosis