Presentation on theme: "Blood glucose: is lower better for diabetic patients?"— Presentation transcript:
1 Blood glucose: is lower better for diabetic patients? Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes
2 Miracle of insulinBefore insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset4
3 Chronic complications of hyperglycemia Hyperglycaemia??
4 Glycemic Control on Diabetic Microvascular Complications Type 2UKPDS8 7%17-21%24-33%-HbA1cRetinopathyNephropathyNeuropathyType 1DCCT9 7%76%54%60%Kumamoto69%70%DCCT Research Group, NEJM 1993, Ohkubo et al., Diab Res Clin Pract 1995, UKPDS Group, Lancet 1998
5 UKPDS:Intensive glycemic control reduces microvascular complications All microvascular endpointsCataract extractionRetinopathyMicroalbuminuria25%24%21%33%Reference:UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–853.P =P = 0.046P = 0.015P =
6 Rationale for near-normoglycemia Lessons from UKPDS: Better control means fewer complications EVERY 1%reduction in HBA1CREDUCED RISK*1%-21%Deaths from diabetes-14%HeartattacksMicrovascular complicationsLessons from UKPDS: better control means fewer complicationsThe UKPDS has proven beyond doubt that intensive glycaemic control is strongly associated with significant clinical benefits for patients with type 2 diabetes. In an epidemiological analysis of the UKPDS cohort every 1% decrease in HbA1C was associated with clinically important reductions in the incidence ofdiabetes-related death ( 21%)myocardial infarction ( 14%)microvascular complications ( 37%)peripheral vascular disease ( 43%)There is no lower limit beyond which reductions in HbA1C cease to be of benefit. Taking diabetes-related death as an example, this means that: HbA1C of 2% delivers a 42% reduction in risk HbA1C of 3% delivers a 63% reduction in risk, and so on.Therefore, the greater the reduction in HbA1C, the greater the protection against complications.Stratton MI Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:-37%Peripheral vascular disorders-43%*p<0.0001UKPDS 35. BMJ 2000; 321:
7 chronic complications of hyperglycemia Hyperglycaemia??
8 Risk of myocardial infarction is increased in type 2 diabetes *†60%No prior myocardial infarctionPrior myocardial infarction40%Risk of fatal or non-fatal myocardial infarction*†20%In this Finnish-based, population study involving 2,432 individuals, patients with type 2 diabetes without any previous history of myocardial infarction (MI) were found to have as high a risk of an MI as non-diabetic patients with a history of MI.These results suggest that cardiovascular risk factors should be treated as aggressively in diabetic patients as they are in non-diabetic patients with a history of cardiovascular disease.Haffner SM. New Engl J Med 1998; 339:229–234.0%Non diabetic subjectsType 2 diabetic subjectsn = 1,Seven-year incidence in a Finnish-based cohort*P < vs no prior MI†P < vs no diabetesAdapted from Haffner SM. New Engl J Med 1998; 339:229–234.
9 Recent Studies Evaluating Effect of Glycemic Control on CVD ACCORDADVANCEVADT
10 ACCORD: Action to Control Cardiovascular Risk in Diabetes 10,251 Enrollees60% male 40% femaleMean age 62.2Baseline HgA1c 8.1%BMI - 3230% macrovascular dxDuration DM: 10 yearsMajority of intensive group on 3-5 oral agents plus insulinHypoglycemia 3 times greater in intensive group
11 ACCORD: Treatment effects on glucose control Time (years)Standard therapyIntensive therapy69.08.58.07.57.06.56.012345ACCORD Study Group. N Engl J Med. 2008;358:
12 ACCORD: Treatment effect on primary outcome 2520Standard therapyHR 0.90 ( ) P = 0.16Patients with events (%)1510Intensive therapy5123456Time (years)Primary Outcome: NFMI, NF Stroke or CVD DeathACCORD Study Group. N Engl J Med. 2008;358:
13 February 7, 2008Intensive glycaemic control arm terminated in 3.5 years (instead of 5.6 years as planned for)
14 ADVANCE Treatment effect on primary macrovascular outcome CV death, MI strokeFollow-up (months)252015105612182430364248546066HR 0.94 ( ) P = 0.32Standard controlIntensive controlCumulative incidence (%)ADVANCE Collaborative Group. N Engl J Med. 2008;358:
18 The intensive approach led to confusion over the best approach It does not result in a significantly lower number of major CVA after 5 yIt led to more deathReasons for the higher mortality in the intensive-therapy group are unknownsMany factors could be implicated :
19 The intensive approach led to confusion over the best approach Many factors could be implicated :The severe hypoglycemia ?The degree of reduction in A1c ?The relatively short intervention period (3.7 years) ?The observed The role of various drugs, drug combinationsor drug interactions; weight gain ?interaction between the blood-pressure and hyperlipidemiaand glycemia trials with respect to mortality ?It led to more death
20 Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus Lipid ValuesFigure 1. Lipid Values. Shown are mean plasma levels of total cholesterol (Panel A), low-density lipoprotein (LDL) cholesterol (Panel B), and high-density lipoprotein (HDL) cholesterol (Panel C) and median levels of triglycerides (Panel D) at baseline, 4 months, 8 months, 1 year, and annually thereafter. Nominal P values for differences between the study groups at 4 months and at the end of the study were, respectively: total cholesterol, P<0.001 and P=0.02; LDL cholesterol, P=0.11 and P=0.16; HDL cholesterol, P<0.001 and P=0.01; and triglycerides, P<0.001 for both comparisons with the use of nonparametric tests. End-of-study visits were those that occurred in early 2009 and included follow-up at years 4, 5, 6, and 7. The I bars represent 95% confidence intervals. To convert the values for cholesterol to millimoles per liter, multiply by To convert the values for triglycerides to millimoles per liter, multiply byThe ACCORD Study Group. N Engl J Med 2010; /NEJMoa
21 Mean Systolic Blood-Pressure Levels at Each Study Visit Effects of Intensive Blood-Pressure Control in Type 2 Diabetes MellitusMean Systolic Blood-Pressure Levels at Each Study VisitFigure 1. Mean Systolic Blood-Pressure Levels at Each Study Visit. I bars indicate 95% confidence intervals.The ACCORD Study Group. N Engl J Med 2010; /NEJMoa
22 Survival as a function of HbA1c in people with type 2 diabetes Currie CJ, Peters JR, Tynan A et al.:Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375: 481–89
23 Cardiovascular safety of diabetes drugs The Truth Is Not So SweetThe goal of marely lowering blood glucose levels in diabetes is too simplisticWith respect to CVD it appears important how you lower blood sugar as well as how muchDiabetes drugs, even within the same “class” may yield dramatically different CV outcomes
24 Conclusion: is lower better for diabetic patients? The optimal mechanism, speed, and extent of glycated hemoglobin reduction are different for differing populationsYesFor patients with recently diagnosed diabetes, aggressive treatment will lower cardiovascular riskNo :For patients who have diabetes of more than 15 years’ duration and are older and have other comorbidities, less aggressive treatment is indicatedAndFor all patients, treatment of the dyslipidemia and hypertension that are associated with diabetes further reduces CVD risk
25 The Promise Land of diabetes therapy Thank youMerciشكراً
26 Number of Participants With One or More Severe Hypoglycemia Events Requiring Medical Assistance (n and %)Intensive GroupStandard Group# Events **n%14007.81302.52821.6340.73 to 5430.8100.2>560.1**Cumulative number of eventsThe ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:26
27 No! Can we blame it all on hypoglycemia? Intensive Strategy Higher Rates ofHypoglycemiaHigher MortalityIntensive StrategyHigher Rates ofHypoglycemiaHigher MortalityNo!The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:27
29 ACCORD: Study designN = 10,251 with T2DM and existing CVD or additional CV risk factorsBP trial (n)Lipid trial* (n)SBP <120 mg HgSBP <140 mg HgGroup AGroup BA1C <6%11781193138313745128Glycemia trialA1C 7.0%-7.9%11841178137013915123236223712753276547335518*Statin + fibrate vs statin, treatment group assignment blinded until end of trial Primary outcome: CV death, MI, strokeACCORD Study Group. Am J Cardiol. 2007;99(suppl):21i-33i.
30 A1c Levels at Baseline, at the Intensive-Therapy Group's Transition to Standard Therapy, and After the Transition in the ACCORD TrialTime of A1c assessmentIntensive therapy, n=5128 (%)Standard therapy, n=5123 (%)Baseline8.3At transition6.67.7After transition7.47.8
31 Tight glycemic control Any benefitsmortalityTight glycemic control
32 Any Diabetes-related Endpoint: legacy effect Intervention Trial Median follow-up 10.0 yearsIntervention Trial + Post-trial monitoring Median follow-up 16.8 yearsRR=0.88 ( )P=0.029ConventionalSulfonylurea/ Insulin
33 DCCT/EDIC; Memory effect Metabolic ResultsDCCT InterventionS t u d y Y e a rDCCTEDIC ObservationTrainingEDICConventionalEDIC mean 8.2%IntensiveEDIC mean 8.0%DCCT/EDIC Study Research Group, NEJM 2005
34 Outcomes Primary Secondary First occurrence of nonfatal MI, nonfatal Stroke, or death from CV disease.SecondaryDeath from any cause.Also measured the effect of the intervention on microvascular disease, hypoglycemia, cognition, and quality of life.cardiovascular causes included death from myocardial infarction, heart failure, arrhythmia, invasive cardiovascular interventions, cardiovascular causes after noncardiovascular surgery, stroke, unexpected death presumed to be from ischemic cardiovascular disease occurring within 24 hours after the onset of symptoms, and death from other vascular diseasesThe ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:
35 ObservationsTargeting HbAIC levels below 6.0% increased the rate of death from any cause after a mean of 3.5 yearsMagnitude of reductionSpeed of reductionRate of hypoglycaemiaAdverse drug interactions at high dosescompared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors.The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:35
36 The intensive approach led to confusion over the best approach Many factors could be implicated :The patients selection ?
37 The intensive approach led to confusion over the best approach Many factors could be implicated :The patients selection ?The severe hypoglycemia ?
38 The intensive approach led to confusion over the best approach Many factors could be implicated :The patients selection ?The severe hypoglycemia ?The degree of reduction in A1c ?
39 ACCORD: Treatment effects on glucose control Time (years)Standard therapyIntensive therapy69.08.58.07.57.06.56.012345ACCORD Study Group. N Engl J Med. 2008;358:
40 The intensive approach led to confusion over the best approach Many factors could be implicated :The patients selection ?The severe hypoglycemia ?The degree of reduction in A1c ?The relatively short intervention period (3.7 years) ?
41 The intensive approach led to confusion over the best approach Many factors could be implicated :The patients selection ?The severe hypoglycemia ?The degree of reduction in A1c ?The relatively short intervention period (3.7 years) ?The observed The role of various drugs, drug combinations, or drug interactions; weight gain ?to
43 ACCORD: Treatment effect on all-cause mortality Time (years)25201510512346Standard therapyIntensive therapyHR 1.22 ( ) P = 0.04CVD Death:HR 1.35 (1.04–1.76)P=0.02Patients with events (%)ACCORD Study Group. N Engl J Med. 2008;358:
44 ADVANCE: Action in Diabetes and Vascular Disease Goal: To examine effects of reducing HgA1c to < 6.5% and routine use of fixed dose ACE-thiazide combination in >55 y/o Type 2 DM11,140 Enrollees60% male 40% femaleMean age 6650% macrovascular dx10% microvascularBaseline HgA1c: 7.51%“standard” : 7.30% Intensive: 6.53%
45 ADVANCE Treatment effect on glucose control Follow-up (months)Standard controlIntensive control10.09.08.07.06.05.00.0612182430364248546066P < 0.001Mean A1C (%)ADVANCE Collaborative Group. N Engl J Med. 2008;358:
46 ADVANCE 11,140 Patients, Age ~66, With Type 2 DM, And High CV Risk Intensive (A1c 6.4%) vs Conventional (A1c 7.3%)Benefit with regard to microvascular complicationsNo Excess Mortality In Intensive Group
48 confusion over the best approach to cardiovascular risk reduction
49 Patients selection in ACCORD & UKPDS Duration DM: 10 years30% macrovascular dxMajority of intensive group on 3-5 oral agents plus insulinUKPDSNewly diagnosedLess CVDLess therapeutic combinations
50 What HbA1c goal should we try to achieve? In newly diagnosed diabetes, the goal is clear:treat to a target HbA1c =6.5-7% (Take advantage of the legacy effect and metabolic memory)In older patients with multiple comorbidities and diabetes of long duration;The HbA1c =7.5% and 8% may be more appropriateTo reduce the CVD, treat the dyslipidemia and hypertensionIn some patients who have had diabetes for more than 10 years:may not be able to sense hypoglycemiaglucose monitoringIn patients whose hyperglycemia is not coming down despite our best efforts (multiple antihyperglycemic agents):it may be appropriate to try to determine the cause of the inadequate response