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Glycemic Control:When the Lower is Not the “Better”?
Stefano GenoveseUO di Endocrinologia e Diabetologia
Ninth International SymposiumHEART FAILURE & Co.
Rozzano (MI) - April 17-18, 2009
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Questions
• Is hyperglycemia an independent risk factor for cardiovascular disease?
• Is hyperglycemia an independent risk factor for cardiovascular disease in diabetic patients?
• Lowering glycemia reduces the risk for cardiovascular disease?
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Fasting blood glucose and cardiovascular mortality in healthy nondiabetic men
Bjornholt JV et al . Diabetes Care 1999;22:45.
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Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes
N Engl J Med 2005;353:2643-53.
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UKPDS
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Other Questions
Is it feasiblean intensive treatment
of hyperglycemia?
Are CV events reduced by an intensive treatment
of hyperglycemia?
Is there a first choice drugin intensive treatment to reduce CV events?
The use of an oralhypoglycemic drug vs placebo
can reduce CV events?
UGDPUKPDS 34
UKPDS 33DIGAMI
STOP-NIDDMPROactive
Kumamoto
ACCORDVADT
ADVANCE
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ACCORD Study Group et al. NEJM 2008;358:2545-59
ACCORD
• In the ACCORD study a HbA1c value <6,5% has been reached in less than one year and maintained
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ADVANCE Collaborative Group et al. NEJM 2008;358:2560-72
ADVANCE
• In the ADVANCE study a HbA1c value <6,5% has been reached in three years and maintained
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VADT
• In the VADT study a HbA1c value around 6,5% has been reached in one year and maintained
5.05.56.06.57.07.58.08.59.09.5
10.010.5
Baseline 1 year 2 years 3 years 4 years 5 years 6 years
Years on Study
HbA
1c (%
)
Standard
Intensive
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ACCORD Study Group et al. NEJM 2008;358:2545-59
Nonfatal myocardial infarction, nonfatal stroke, death from cardiovascular causes p=0,16
p=0,04
Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD
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ACCORD Study Group et al. NEJM 2008;358:2545-59
Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD
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ACCORD Study Group et al. NEJM 2008;358:2545-59
Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD
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ACCORD Study Group et al. NEJM 2008;358:2545-59
Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD
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Causes of death in the ACCORD
ACCORD Study Group et al. NEJM 2008;358:2545-59
• Causes of death:
• Unexpected or presumed cardiovascular disease
• Condition other than cancer or cardiovascular disease
• What is the role of hypoglycemia?
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VADT – Predictors of CVD death
Variable HazardRatio
PValue
Prior CVD event 3.116 0.0001
Age (per 10 yr) 2.090 <.0001
HDL (per 10 mg) 0.699 0.0079
Baseline HbA1cper 1%
1.213 0.0150
Severe Hypoglycemia 4.042 0.0076
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• The ACCORD suggests that outcomes differ according to– HbA1c below or abovea 8,0%– Presence of previous CV events
• Is there a study on the intensive treatment in T2DM in a population with– Basal HbA1c <8,0%– No previous CV events?
Hypothesis…..
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ACCORD vs ADVANCE
Characteristics ACCORD ADVANCE
Baseline data Participants, n 10 251 11 140 Mean age (years) 62 66 Duration of diabetes (years) 10 8 Mean HbA1C (%) 8.1 7.2 History of CVD (%) 35 32
Dluhy R.G. et al. NEJM 2008;358:2630-3
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Characteristics ACCORD ADVANCE
Intervention
Target HbA1C (%) <6.0 <6.5 Duration of the study (years) 3.4 5.0 Drugs at study end (intensive vs standard) (%)
Insulinn 77 vs 55 41 vs 24 Metformin 95 vs 87 74 vs 67 Secretagogues (sulfonilureas or glinides) 87 vs 74 94 vs 62 TZD 92 vs 58 17 vs 11 Incretin 18 vs 5 NA Statin 88 vs 88 46 vs 48 Any anti-hypertensive 91 vs 92 89 vs 88 ACE inhibitors 70 vs 72 NA Aspirin 76 vs 76 57 vs 55
ACCORD vs ADVANCE
Dluhy R.G. et al. NEJM 2008;358:2630-3
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Characteristics ACCORD ADVANCEResults (intensive vs standard) Median HbA1C mediana at study end(%) 6.4 vs 7.5* 6.4 vs 7.0* Total mortality (%) 5.0 vs 4.0* 8.9 vs 9.6 CV Mortality (%) 2.6 vs 1.8* 4.5 vs 5.2 Non fatal MI (%) 3.6 vs 4.6* 2.7 vs 2.8 Non fatal stroke (%) 1.3 vs 1.2 3.8 vs 3.8 Serious Hypoglycemia (%/anno) 3.1 vs 1.0* 0.7 vs 0.4 Weight gain(kg) 3.5 vs 0.4 0.0 vs -1.0* Smokers (%) 10 vs 10 8 vs 8
Dluhy R.G. et al. NEJM 2008;358:2630-3
ADVANCE does not confirm the reduction of MI suggested by ACCORD
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ADVANCE Collaborative Group et al. NEJM 2008;358:2560-72
Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type Diabetes
• In the ADVANCE the intensive treatment reduces the microvascular endpoint
• Mortality does not increase
p=0,01
p=0,01
p=0,32
p=0,28
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• Is there a study on the intensive treatment in T2DM in a population with– Basal HbA1c <8,0%– No previous CV events?
Hypothesis…….
Yes, the …….. UKPDS where participants had basal HbA1c of 7,0% without previous CV events
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UKPDS
• In the UKPDS the effect of intensive treatment showed p=0,052 and no effect on mortality
• In the UKPDS-PTM the reduction of MI was statistically significant
• According to the UKPDS duration the follow-up of ACCORD, ADVANCE e VADT seems to short
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UKPDS 34
• In the UKPDS an intensive treatment with metformin as a first choice drug in overweight patients reduced mortality
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Secondary prevention of macrovascolar events in patients with type 2 diabetes in the PROactive Study: a
randomised controlled trial
• 5238 T2DM patients with high CV risk • Pioglitazone 15-45 mg vs placebo with
median follow-up of 34,5 months• Primary endpoint (Total Mortality non
fatal MI, stroke, ACS, coronary and peripheral revascularizations, lower limb amputation)
• Secondary endpoint (Total mortality non fatal MI, stroke)
Dormandy J.A. et al. Lancet 2005;366:1279-89
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Wilcox R. et al. Stroke 2007;38:865-73 Erdmann E. et al. JACC 2007;49:1772-80
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Erdmann E. et al. Diabetes Care 2007;30:2773-8
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Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review
Eurich D.T. et al. BMJ 2007;335:497-506
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If……
• The number of events in the PROactive is similar to thata of CARE and HPS, but PROactive duration was 3 years vs 5-6 years
• We can only imagine the PROactive results at 5-6 years
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Answers
Are CV events reduced by an intensive treatmentof hyperglycemia?
YES, in patients with HbA1c <8% and
no previous CV events
Is it feasiblean intensive treatment of hyperglycemia?
YES
Pay attention to hypoglycemia and fragile patients
and ….. don't hurry