Glucose and CV disease

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Diabetes and glucose How common is diabetes? Diabetes as a risk for CVD Does improving glucose control prevent complications? Does too tight glucose control cause death? Glucose vs glycation Hemoglobin Glycation Index What should our A1c target be?

Diabetes-related complications in the USA, 1990-2010 Acute myocardial infarction Adapted from Gregg EW, et al. N Engl J Med 2014;370:1514 1523. Presented at the American Diabetes Association 76 th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Diabetes and glucose How common is diabetes? Diabetes as a risk for CVD. Does improving glucose control prevent complications? Does too tight glucose control cause death? Glucose vs glycation Hemoglobin Glycation Index What should our A1c target be?

Diabetes and glucose How common is diabetes? Diabetes as a risk for CVD. Does A1c make a difference? Does improving glucose control prevent complications? Does too tight glucose control cause death? Glucose vs glycation Hemoglobin Glycation Index What should our A1c target be?

Relative Risk A1C and Relative Risk of Microvascular Complications: DCCT 20 15 13 11 9 7 5 3 Retinopathy Nephropathy Neuropathy Microalbuminuria 1 6 7 8 9 10 11 12 A1C (%) DCCT, Diabetes Control and Complications Trial. 1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. 2. DCCT. N Engl J Med. 1993;329:977-986. 3. DCCT. Diabetes. 1995;44:968-983.

HbA1c predicts Coronary Heart Disease in Type 2 Diabetics 17

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

CV Death, MI, or Ischemic Stroke Rate of CVD, MI, or Ischemic Stroke Increases as Baseline HbA1c Increases* 12 Adj HR (95% CI) 10 9% 1.76 (1.48, 2.11) 8 6 4 2 8%-<9% 7%-<8% <7% 1.37 (1.14, 1.65) 1.14 (0.96, 1.35) Reference 6 12 18 24 Months *Adjusted for age, gender, duration of DM, glomular filtration rate (GFR), established atherosclerosis vs primary prevention, and microalbumin:creatinine ratio (malb:cr) Cavender, MA, et al. American Heart Association Scientific Sessions. November 2013, data from SAVOR 21

DCCT: Reduction in Retinopathy NEJM Volume 329: Number 14; 977-986

DCCT: Reduction in Albuminuria Primary Prevention Secondary Intervention 34% RRR (p<0.04) 43% RRR (p=0.001) 56% RRR (p=0.01) Solid line = risk of developing microalbuminuria Dashed line = risk of developing macroalbuminuria RRR = relative risk reduction CI = confidence interval The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986. guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association ukpds

DCCT: Reduction in neuropathy The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986. ukpds

ukpds

Does tighter glycemic control offer CV benefits?

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

ACCORD 10,251 pts with T2DM + CV risk Average diabetes duration 10 yrs Median baseline A1c = 8.1% Intensive target <6.0% (actual 6.4%) Standard target 7-7.9% (actual 7.5%)

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%

We ll discuss at much greater length HR 1.22, p =.04

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

Does VADT tell us anything?

VADT

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.

P =.o3 VADT

NEJM Vol 358, No 24, June12, 2008: ACCORD heterogeneity

Early intervention! VADT

IS IT POSSIBLE TO PROVE THAT IMPROVED GLYCEMIC CONTROL CAN DECREASE CVD? ASSUME CVD event rate = 1.5% per year 25% risk reduction with intervention Alpha = 0.05 FOR 90% POWER Number 3 year study.28,000 5 year study.14,700 10 year study.6,800

Are there any studies looking at glucose control early in the course of the diabetes?

HbA 1c (%) HbA 1c 9 cross-sectional, median values 8 7 Conventional Intensive Mean difference.9% 6 0 6.2% upper limit of normal range 0 3 6 9 12 15 Years from randomisation ukpds

% of patients with an event Myocardial Infarction (cumulative) 30% 20% 10% 0% Intensive p=0.052 fatal or non fatal myocardial infarction, sudden death 573 of 3867 patients (15%) Conventional Risk reduction 16% (95% CI: 0% to 29%) 0 3 6 9 12 15 Years from randomisation ukpds

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 5 6 9 12 15 Years from randomisation RRR 31% ukpds

Abstract 1338

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.

The earlier you start while the blood vessels are clean, the more benefit you expect from tighter glucose control

Who died in ACCORD?

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

But when you adjust for glucose control.

What is it about this group of people that it wasn t possible to lower their A1c

A1c s do not accurately describe glucose profiles in ALL people (Even excluding people with hemoglobinopathy, hemolysis, anemia, etc which are known to affect A1c)

Mr. R. R.

Mr. F. S.

Hemoglobin Glycation Index (HGI) (Actual A1c) minus (Predicted A1c based on glucose values) 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

Survivors High HGI Moderate HGI Low HGI Standard: dashed Intensive: solid

Mr. F. S

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 early in the course of diabetes seems to be the best strategy Aggressive glucose control prior to the development of a large atherosclerotic burden seems to be 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

Non-fatal MI, non-fatal CVA, death from CV causes NEJM Vol 358, No 24, June12, 2008

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????

Diabetes and glucose How common is diabetes? Why do we treat it? Does glycemic control predict complications? Does improving glucose control prevent complications? Does too tight glucose control cause death? Glucose vs glycation Hemoglobin Glycation Index What should our A1c target be?

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