In diabetics, does a HbA1c

goal of 7.0 vs. 6.5 result in

less microvascular disease

and all cause mortality?Daniel Wu

ADA Standards of Medical Care 2012 Goals should be individualized based on

○ duration of diabetes

○ age/life expectancy

○ comorbid conditions

○ known CVD or advanced microvascular complications

○ hypoglycemia unawareness

○ individual patient considerations

More- or less-stringent glycemic goals may be appropriate for

individual patients

Postprandial glucose may be targeted if A1C goals are not

met despite reaching preprandial glucose goals

Lowering A1C to below or around 7% has been shown to reduce

microvascular complications of diabetes, and if implemented soon

after the diagnosis of diabetes is associated with long-term

reduction in macrovascular disease. Therefore, a reasonable A1C

goal for many nonpregnant adults is <7%. (B)

Providers might reasonably suggest more stringent A1C goals (such

as <6.5%) for selected individual patients, if this can be achieved

without significant hypoglycemia or other adverse effects of

treatment. Appropriate patients might include those with short

duration of diabetes, long life expectancy, and no significant

CVD. (C)

ADA Standards of Medical Care 2012

AACE Guidelines for Diabetes Plan 2011

Glucose targets should be individualized and take into account

residual life expectancy,

duration of disease,

presence or absence of microvascular and macrovascular

complications,

CVD risk factors,

comorbid conditions

risk for severe hypoglycemia.

Glucose targets should also be formulated in the context of the

patient’s psychological, social, and economic status

AACE Guidelines for Diabetes Plan 2011

In general, therapy should target a A1C level of 6.5% or

less for most nonpregnant adults, if it can be achieved

safely.

In certain patients, a less stringent goal may

be considered (A1C 7%-8%).

Such individuals as those with history of severe

hypoglycemia, limited life expectancy, advanced

microvascular or macrovascular complications,

extensive comorbid conditions, or long-standing DM in

which the general goal has been difficult to attain despite

intensive efforts

Same Evidence Base

Diabetes Control and Complications Trial

(1993)

U.K. Prospective Diabetes Study

(2000)

Diabetes Control and Complications Trial

Will intensive therapy prevent the development of diabetic

retinopathy in patients with no retinopathy (primary

prevention)

Will intensive therapy affect the progression of early

retinopathy (secondary intervention)?

Retinopathy was the principal study outcome, but they also

studied renal, neurologic, cardiovascular, and

neuropsychological outcomes and the adverse effects of the

two treatment regimens.

Eligibility Criteria

The major criteria for eligibility included

insulin dependence, as evidenced by deficient C-peptide

secretion;

an age of 13 to 39 years

absence of hypertension

absence of hypercholesterolemia

absence of severe diabetic complications or medical conditions

Therapy

Conventional therapy consisted of one or two daily injections of insulin, including mixed intermediate and rapid-acting insulins, daily self-monitoring of urine or blood glucose, and education about diet and exercise

Intensive therapy included the administration of insulin three or more times daily by injection or an external pump. The dosage was adjusted according to the results of self-monitoring of blood glucose performed at least four times per day, dietary intake, and anticipated exercise.

The goals of intensive therapy included preprandial blood glucose concentrations between 70 and 120 mg per deciliter (3.9 and 6.7 mmol per liter), postprandial concentrations of less than 180 mg per deciliter (10 mmol per liter), a weekly 3-a.m. measurement greater than 65 mg per deciliter (3.6 mmol per liter), and hemoglobin A1c (glycosylated hemoglobin), measured monthly, within the normal range (less than 6.05 percent).

A1c Levels

Differences in Intervention Outcomes:

Retinopathy in Cohorts

Differences in Intervention Outcomes

Rate of Progression of Retinopathy vs.

Rate of Severe Hypoglycemia

U.K. Prospective Diabetes Trial

To determine the relation between exposure to glycemia over

time and the risk of macrovascular or microvascular

complications in patients with type 2 diabetes.

Primary predefined aggregate clinical outcomes: any end

point or deaths related to diabetes and all cause mortality.

Secondary aggregate outcomes: myocardial infarction,

stroke, amputation (including death from peripheral vascular

disease), and microvascular disease (predominantly retinal

photo-coagulation).

Participants

The 3867 patients who had fasting plasma glucose

concentrations between 6.1 and 15.0 mmol/l and no

symptoms of hyperglycemia were randomized to a policy of

conventional glucose control, primarily with diet, or to an

intensive policy with sulfonylurea or insulin.

Stratton I M et al. BMJ 2000;321:405-412

©2000 by British Medical Journal Publishing Group

Incidence Rates for MI and Microvascular Complications

Stratton I M et al. BMJ 2000;321:405-412

©2000 by British Medical Journal Publishing Group

Hazard Ratios for Any End Point, Death, and All Cause Mortality

ACCORD Trial: Glycemic Control

Investigated whether intensive therapy to target normal

glycated hemoglobin levels would reduce cardiovascular

events in patients with type 2 diabetes who had either

established cardiovascular disease or additional

cardiovascular risk factors.

10,251 patients (mean age, 62.2 years) with a median

glycated hemoglobin level of 8.1% were assigned to receive

intensive therapy (targeting a glycated hemoglobin level

below 6.0%) or standard therapy (targeting a level from 7.0

to 7.9%).

HbA1c Levels Achieved

Primary Outcomes

This trend was not

significant, with rates

of 6.9% in the

intensive-therapy

group and 7.2% in

the standard-therapy

group (hazard ratio,

0.90; 95%

confidence interval

[CI], 0.78 to 1.04;

P=0.16)

All Cause Mortality

The rate of death

from any cause

was higher in the

intensive-therapy

group than in the

standard-therapy

group (5.0% vs.

4.0%; hazard ratio,

1.22; 95% CI, 1.01

to 1.46; P=0.04).

Cessation of Study

The finding of higher mortality in the intensive-therapy group

led to a decision to terminate the intensive regimen in

February 2008, 17 months before the scheduled end of the

study.

Rates of death in the two study groups began to separate

after 1 year, and the differences persisted throughout the

follow-up period.

The effect on mortality was consistent within the subgroups

with no evidence of heterogeneity and persisted in models

adjusting for differences in the receipt of medications for

blood pressure and lipids.

Adverse Events

Analysis of the ACCORD Trial

The prespecified composite outcomes were

dialysis or renal transplantation

high serum creatinine (>291.7 μmol/L) or retinal photocoagulation

or vitrectomy (first composite outcome)

or peripheral neuropathy plus the first composite outcome

(second composite outcome)

Faramarz Ismail-Beigi , Timothy Craven , Mary Ann Banerji , Jan Basile , Jorge Calles , Robert M Cohen , Robert C...

Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD

randomised trial

The Lancet Volume 376, Issue 9739 2010 419 - 430

http://dx.doi.org/10.1016/S0140-6736(10)60576-4

Primary Composite Outcomes

All Microvascular Outcomes

Analysis of the ACCORD Trial

The primary composite outcome of advanced nephropathy

and diabetic eye complications did not differ between groups

at transition or at study end.

The second composite endpoint, which added a peripheral

neuropathy outcome to the primary composite outcome, also

did not differ at transition or at study end.

Intensive glycemia therapy led to a 21% reduction in

development of microalbuminuria at transition and this effect

was attenuated (15%) but remained significant at study end.

Incidence of macroalbuminuria was reduced in the intensive

group compared with the standard group at transition and at

study end.

Changes to ADA Recommendations

Providers might reasonably suggest more stringent A1C

goals (such as <6.5%) for selected individual patients, if this

can be achieved without significant hypoglycemia or other

adverse effects of treatment. Appropriate patients might

include those with short duration of diabetes, long life

expectancy, and no significant cardiovascular disease. (C)

Less stringent A1C goals (such as <8%) may be appropriate

for patients with a history of severe hypoglycemia, limited life

expectancy, advanced microvascular or macrovascular

complications, extensive comorbid conditions, and those with

longstanding diabetes in whom the general goal is difficult to

attain despite diabetes self-management education,

appropriate glucose monitoring, and effective doses of

multiple glucose-lowering agents including insulin. (B)

Conclusions from Studies

DCCT

Intensive therapy of patients delays the onset and slows the

progression of clinically important retinopathy, including vision-

threatening lesions, nephropathy, and neuropathy, by a range of

35 to more than 70 percent.

Because of the risk of hypoglycemia, intensive therapy should be

implemented with caution, especially in patients with repeated

severe hypoglycemia or unawareness of hypoglycemia.

UKPDS

No threshold of glycemia was observed for a substantive change

in risk for any of the clinical outcomes examined

The lower the glycemia the lower the risk of complications

Suggests that there is no specific target value of hemoglobin

A1c for which one should aim but that the nearer to normal the

hemoglobin A1c concentration the better.

Conclusions from Studies

ACCORD

No significant effect of intensive glycemia therapy on the two

prespecified composite microvascular outcomes—1) advanced

renal or eye complications, or 2) these two outcomes or

peripheral neuropathy.

The beneficial effects of intensive therapy on surrogate

secondary microvascular outcomes compared with standard

therapy should be balanced against observed risks.

Therapeutic strategy targeting HbA1c levels of 6.0% increased

the rate of all cause death as compared with a target level of 7.0

to 7.9%.

Recommendation for Patient

Target level for HbA1c of 7.0%

Long duration of diabetes and significant CVD- rules out the

criteria for possible intensive management

Side effects of intensive therapy: weight gain, fluid retention,

and hypoglycemia

Benefit of decreased micro- and macroalbuminuria does not

outweigh the side effects of intensive therapy

Target of 7.0% has a significantly lower risk of all cause death

General goal of attaining the 7.0% is difficult for many patients

and is reasonable to reduce microvascular disease and all cause

death

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3. Handelsman Y, Mechanick JI, Blonde L, Grunberger G, Bloomgarden ZT, Bray GA, Dagogo-Jack S, Davidson JA, Einhorn D, Ganda O, Garber AJ, Hirsch IB, Horton ES, Ismail-Beigi F, Jellinger PS, Jones KL, Jovanovič L, Lebovitz H, Levy P, Moghissi ES, Orzeck EA, Vinik AI, Wyne KL; AACE Task Force for Developing Diabetes Comprehensive Care Plan. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011 Mar-Apr;17 Suppl 2:1-53. PubMed PMID: 21474420.

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