Glucose Control: Does it lower CV risk?
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Incidence per 1000 Person Years (%) Incidence Rates of MI and Microvascular Endpoints by Mean Hemoglobin A 1c : UKPDS 80 60 40 Myocardial Infarction 20 0 Microvascular Endpoints 5 6 7 8 9 10 11 Updated Mean Hemoglobin A 1c Concentration (%) Adjusted for age, sex, and ethnic group Stratton IM et al. BMJ 2000;321:405-412. Slide Source: ukpds Lipids Online www.lipidsonline.org
2008
Cumulative incidence of non-fatal MI, stroke or death from CVD HbA 1C (%) DCCT/EDIC: glycaemic control reduces the risk of non-fatal MI, stroke or death from CVD in type 1 diabetes 9 Conventional treatment 8 Intensive treatment 0.06 7 0 1 2 3 4 5 6 7 8 9 DCCT (intervention period 10 11 12 13 14 15 16 17 EDIC (observational follow-up) Years 0.04 0.02 57% risk reduction in non-fatal MI, stroke or CVD death* (P = 0.02; 95% CI: 12 79%) Intensive treatment Conventional treatment 0.00 *Intensive vs conventional treatment 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 DCCT (intervention period) EDIC (observational follow-up) Years Adapted from DCCT. N Engl J Med 1993; 329:977 986. DCCT/EDIC. JAMA 2002; 287:2563 2569. DCCT/EDIC. N Engl J Med 2005; 353:2643 2653.
3 major studies that are referred to, ADVANCE, ACCORD, VADT to provide answers All studies of Intensive glucose control vs looser glucose control All were in very high risk patients who had their diabetes for 8-11 years Either had documented vascular disease or Very high risk based on risk factors
Mean A1c 7.5% Mean A1c 6.4%
Non-fatal MI, non-fatal CVA, death from CV causes ACCORD: Mean A1c 7.5% Mean A1c 6.4%
Mean A1c s 9.4% to 8.4% 9.4% to 6.9% VADT
And 6.9% 8.4% hazard ratio in the intensive-therapy group of 0.88 (95% confidence interval [CI], 0.74 to 1.05). VADT
VADT
P =.o3 VADT
NEJM Vol 358, No 24, June12, 2008: ACCORD heterogeneity
Benefits of early vs late glycaemic intervention HbA 1c (%) Metabolic Memory = Glycaemic legacy 10 9 Estimated HbA 1c timecourse based on UKPDS data Enters VADT intensive treatment arm 8 7 Bad glycaemic legacy drives risk of complications HbA 1c time course in VADT 6 Ideal time-course of glycaemic control 0 0 2 4 6 8 10 12 14 16 Time since diagnosis (years) UKPDS: United Kingdom Prospective Diabetes Study VADT: Veterans Affairs Diabetes Trial Adapted from Del Prato S. Diabetologia 2009;52:1219 26.
Proportion of patients with events overweight patients 0.4 0.3 0.2 0.1 0.0 Myocardial Infarction Conventional (411) Intensive (951) Metformin (342) M v C p=0.010 M v I p=0.12 0 3 6 9 12 15 Years from randomisation RRR 31% ukpds
Delay in Treatment Intensification Increases the Risks of Cardiovascular Events in Patients with Type 2 Diabetes Compared to patients with HbA1c <7%, in patients with HbA1c 7%, a 12 month delay in receiving treatment intensification was associated with significantly increased risk: MI 67% STROKE 51% HF 64% CVE 62% HR 1.67 (CI: 1.39, 2.01)* HR 1.51 (CI: 1.25, 1.83)* HR 1.64 (CI: 1.40, 1.91)* HR 1.62 (CI: 1.46, 1.80)* MI= myocardial infarction, HF=Heart Failure, CVE= composite MI, Stroke & HF Retrospective cohort study (N = 105,477) from the United Kingdom Clinical Practice Research Datalink Not Proof of Cause and Effect * P <0.01 Adapted from Paul SK et al. Cardiovasc Diabetol. 2015 Aug 7;14:100.
NEJM Vol 358, No 24, June12, 2008 HR 1.22, p =.04
What does ACCORD really tell us? Tight glycemic control shows CV benefit after 5 years People who died had higher A1c s People who died were people in whom it was not possible to lower their A1c s People who died had a high Hemoglobin Glycation Index People who died tended not to be on beta blockers
When you look at who actually died.
Hemoglobin Glycation Index (HGI) Someone has a high HGI, (i.e., rapid glycator) if their glucoses are good but their A1c is high Someone has a low HGI, (i.e., slow glycator) if their glucoses are high but their A1c is low
Low HGI High HGI
High HGI Low HGI
People on beta blockers had more events (not as surprise they had more disease) but being on intensive therapy lowered the event rate People not on beta blockers didn t have as many events (less disease) but intensive therapy did not lower the event rate
People on beta blockers had more events (not as surprise they had more disease) but being on intensive therapy did not increase the event rate People not on beta blockers didn t have as many events (less disease) but intensive therapy increased the event rate
Summary and Conclusions (1): Good glycemic control lowers risk of microvascular disease Aggressive glucose control prior to the development of a large atherosclerotic burden seems to be best strategy Aggressive glucose control early in the course of diabetes seems to be the best strategy This does not mean that if an individual has had their diabetes for a long period or has had a CV event that they won t benefit will take more time
Summary and Conclusions (2): A1c does not always tell the whole story. Look at the glucoses Look at the Pt s glucose meter!!! If A1c is high but glucoses are good, this patient is a rapid glycator with a high HGI. This is a higher risk patient There seems no gain in pushing his glucoses down further to lower his A1c It won t happen It would increase risk of hypoglycemia Concentrate on other risk factors
Summary and Conclusions (3): In people with vascular disease, beta blockers appear to be synergistic with tightening glucose control to lessen CV complications Protection for adrenergic stimulation from either Hypoglycemia? Further hyperinsulinemia????
Individualizing A1C Targets 2013 Consider 7.1-8.5% if: which must be balanced against the risk of hypoglycemia guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association
Hardin s suggestion for A1c target: Keep the above targets in mind, but Try to achieve the lowest A1c possible with the best balance of minimal highs and minimal lows The determination of best balance of minimal lows depends on risk of hypoglycemia and other general factors To do this, you must look at the meter and the logbook