Type 2 Diabetes. Treat to: limit complications maintain quality of life Improve survival

Transcription

1 Type 2 Diabetes Treat to: limit complications maintain quality of life Improve survival 1

2 Criteria for the diagnosis of diabetes 1. HbA1C 6.5% (rounded to 50mmol/mol). 2. FPG 7.0 mmol/l h plasma glucose 11.1 mmol/l during an OGTT. 4. In a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis, a random plasma glucose 11.1 mmol/l. BUT: glucose is a continuous variable for risk and the risk association depends on whether the outcome is CVD, retinopathy, neuropathy etc 2

3 Diabetes: so why were the criteria set in the first place. 3

4 Reducing glucose levels and effect on retinopathy May seem obvious now but in the 1970 s there was considerable debate as to the utility of aggressive intervention DCCT commenced finally in 1983 with the express purpose of proving/disproving benefit of tight glycaemic control in type 1 DM (not type 2) EDIC (Epidemiology of Diabetes Interventions and Complications) was the follow up study lasting 20 years 4

5 Median HbA1c concentrations during DCCT, the training period between DCCT and EDIC, and EDIC. P < for INT vs. Nathan D M, and for the DCCT/EDIC Research Group Dia Care 2014;37:9-16 Copyright 2014 American Diabetes Association, Inc.

6 Cumulative incidence of DR progression (three-step or greater by ETDRS criteria) in the DCCT primary prevention cohort. Aiello L P, and for the DCCT/EDIC Research Group Dia Care 2014;37:17-23 Copyright 2014 American Diabetes Association, Inc.

7 Cumulative incidence of DR progression in the DCCT secondary intervention cohort. Aiello L P, and for the DCCT/EDIC Research Group Dia Care 2014;37:17-23 Copyright 2014 American Diabetes Association, Inc.

8 The risk of DR progression as related to mean HbA1c during DCCT. The rate of DR progression per 100 patient-years (100 PYR) was similar and highly associated with HbA1c in the DCCT for both the INT and the CON groups. Aiello L P, and for the DCCT/EDIC Research Group Dia Care 2014;37:17-23 Copyright 2014 American Diabetes Association, Inc.

9 After adjustment for DR severity at DCCT closeout, the cumulative incidence of further DR progression during the first 10 years of EDIC follow-up is shown Aiello L P, and for the DCCT/EDIC Research Group Dia Care 2014;37:17-23 Copyright 2014 American Diabetes Association, Inc.

10 The cumulative incidence of any major eye disease end point (PDR, CSME, application of laser, or development of blindness) is shown in relation to diabetes duration. Aiello L P, and for the DCCT/EDIC Research Group Dia Care 2014;37:17-23 Copyright 2014 American Diabetes Association, Inc.

11 But the focus on glucose control as a key target is somewhat clouded by type 2 DM data

12 Fig 10 Forest plot for retinopathy. Hemmingsen B et al. BMJ 2011;343:bmj.d by British Medical Journal Publishing Group

13 Effects of Intensive Glycaemic Control and Intensive Blood-Pressure Control on Progression of Diabetic Retinopathy and Moderate Vision Loss (ACCORD). Treatment Progression of Diabetic Retinopathy Adjusted Odds Ratio (95% CI) P Value Moderate Vision Loss Adjusted Hazard Ratio (95% CI) P Value no./total no. (%) no./total no. (%) Glucose 0.67 ( ) ( ) 0.56 Intensive 104/1429 (7.3) 266/1629 (16.3) Standard 149/1427 (10.4) 273/1634 (16.7) Dyslipidemia therapy With fenofibrate 0.60 ( ) ( ) /806 (6.5) 145/908 (16.0) With placebo 80/787 (10.2) 136/893 (15.2) BP therapy 1.23 ( ) ( ) 0.06 Intensive 67/647 (10.4) 145/749 (19.4) Standard 54/616 (8.8) 113/713 (15.8)

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15 Fig 4 Forest plot for cardiovascular mortality. Hemmingsen B et al. BMJ 2011;343:bmj.d by British Medical Journal Publishing Group

16 Fig 13 Forest plot for severe hypoglycaemia. Hemmingsen B et al. BMJ 2011;343:bmj.d by British Medical Journal Publishing Group

17 ACCORD STUDY

18 Intensive control in type 2 DM: what holds us back (quote from UpToDate) No clinical trial data (except UKPDS) have demonstrated a macrovascular benefit with intensive (glucose reducing) therapy in patients with type 2 diabetes. Furthermore, data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial suggest that lowering A1C to near normal may be unsafe in patients with a long history of diabetes at higher risk for cardiovascular disease The results of the ACCORD trial suggest that a target A1C of 7.0 to 7.9 percent may be safer for patients with long-standing type 2 diabetes. This target is supported by the results of a retrospective cohort study of approximately 48,000 patients with type 2 diabetes. After a mean follow-up of approximately 4.5 years, all-cause mortality was highest in those with the lowest (less than 6.7 percent) and highest (9.9 percent) A1C values. An A1C level of 7.5 percent was associated with the lowest all-cause mortality.

19 Furthermore, funded treatments for restoration of glucose levels in type 2 DM are not greatly effective and more effective ARR outcome results are achieved by focusing on CVD reducing strategies (statins, BP, antiplatelet Rx, renoprotection)

20 Treatment targets in DM Islet B-cell Reduced Incretin Effect Impaired Insulin secretion Increased Lipolysis Islet a-cell Increased Glucagon secretion Increased glucose resorption Increased HGO Neurotransmitter dysregulation Reduced Glucose uptake

21 Available glucose reduction treatments Name Basic mechanism Insulin Metformin SU Pioglitazone Acarbose Increase systemic insulin levels Reduce HGO etc Insulin release Insulin sensitizer Gut uptake CHO 11B-HSD1 inhibition DPP4 inhibitors / GLP-1 agonists Pramlintide Bromocriptine quick release Resins (colesevelam) Peptide delivery implants Glucose transport inhibitors FGF19 Smart Insulin delivery systems Cellular cortisol Insulin/glucagon release etc Gut / glucagon / central Central effect? mechanisms Glucose absorption / HGO etc?? Steady state 3 month supply Renal glucose uptake Multiple sites

22 Treatment targets for DM for NZ 3 out of 8 are available as funded agents!! Islet B-cell Impaired Insulin secretion Increased glucose resorption Increased HGO Reduced Glucose uptake

23 Summary: Diabetes Care in type 2 DM Key organ targets Retinopathy, maculopathy CVD BP, glucose, dyslidaemia Lipids, BP, renal progression, (glucose) Kidney damage BP, glucose