HbA1C andHbA1C and DM control DM control

By Ri By Ri 陳信豪陳信豪

IntroductionIntroduction microvascular complications in type 1 dimicrovascular complications in type 1 di

abetes --slowed by treating hyperglycemiabetes --slowed by treating hyperglycemia a

increased use of intensive insulin regimincreased use of intensive insulin regimens to attain strict glycemic control ens to attain strict glycemic control

The efficacy of these regimens requires aThe efficacy of these regimens requires an accurate method to estimaten accurate method to estimate

a given mean blood glucose value a given mean blood glucose value associateassociated with different mean glycemic excursions and with different mean glycemic excursions an

d mean daily differencesd mean daily differences

Estimation of mean blood glucose by Estimation of mean blood glucose by A1C A1C

glucose can attach to many proteins via a noneglucose can attach to many proteins via a nonenzymatic, posttranslational process nzymatic, posttranslational process

(1)A reversible reaction leads to the formation (1)A reversible reaction leads to the formation of an aldimine of an aldimine

(2)followed by an Amadori rearrangement to f(2)followed by an Amadori rearrangement to form an irreversible ketoamine. orm an irreversible ketoamine.

Glycated hemoglobin Glycated hemoglobin most widely used clinical test most widely used clinical test measurement of blood glycated hemoglobin (ameasurement of blood glycated hemoglobin (a

lso called hemoglobin A1C, glycohemoglobin, lso called hemoglobin A1C, glycohemoglobin, and glycosylated hemoglobin [HbA1c]). and glycosylated hemoglobin [HbA1c]).

the average amount of A1C the average amount of A1C changes in a dynamic way changes in a dynamic way reflects the mean blood glucose concentration reflects the mean blood glucose concentration

over the previous six to eight weeks.  over the previous six to eight weeks.   Nathan, DM, Singer, DE, Hurxthal, K. Goodson, JD. The clinical information value Nathan, DM, Singer, DE, Hurxthal, K. Goodson, JD. The clinical information value

of the glycosylated hemoglobin assay. N Engl J Med 1984; 310:341. of the glycosylated hemoglobin assay. N Engl J Med 1984; 310:341.

Diabetes Control and Complications Diabetes Control and Complications Trial (DCCT) Trial (DCCT)

mean blood glucose concentratmean blood glucose concentrations from seven measurements ions from seven measurements a day a day (before and 90 minutes after each (before and 90 minutes after each meals, and before bedtime) meals, and before bedtime)

compared with A1C values in 278 patientcompared with A1C values in 278 patients with type 1 DMs with type 1 DM

A strong correlation A strong correlation

A1C value of 7 percent --150 mg/dLA1C value of 7 percent --150 mg/dL

A1C value of 9 percent --210 mg/dLA1C value of 9 percent --210 mg/dL

Factors causing misleading results Factors causing misleading results A1C values influenced by red cell survival. A1C values influenced by red cell survival.

(1) falsely high values -- low red cell turnover--d(1) falsely high values -- low red cell turnover--disproportionate number of older red cellsisproportionate number of older red cells

ex: iron, vitamin B12, or folate deficiency aneex: iron, vitamin B12, or folate deficiency anemia.mia.

(2) falsely low values -- rapid red cell turnover –(2) falsely low values -- rapid red cell turnover – greater younger red cells greater younger red cells ex: hemolysis , treated for iron, vitamin B12, oex: hemolysis , treated for iron, vitamin B12, o

r folate deficiency r folate deficiency

Panzer, S, Kronik, G, Lechner, K, et al. Glycosylated hemoglobins (GHb): An indPanzer, S, Kronik, G, Lechner, K, et al. Glycosylated hemoglobins (GHb): An index of red cell survival. Blood 1982; 59:1348. ex of red cell survival. Blood 1982; 59:1348.

Fructosamine Fructosamine nonenzymatic glycation nonenzymatic glycation formation of advanced glyformation of advanced gly

cosylation end products cosylation end products direct role in the developmdirect role in the development of diabetic microvascular complications ent of diabetic microvascular complications

good correlation between serum fructosamine and Agood correlation between serum fructosamine and A1C values 1C values

variation for fructosamine higher than that for A1C variation for fructosamine higher than that for A1C

serum fructosamine values reflect mean blood glucosserum fructosamine values reflect mean blood glucose values over a much shorter period of time (one to te values over a much shorter period of time (one to two weeks). wo weeks).

About type 1 DM--IntroductionAbout type 1 DM--Introduction nephropathy and retinopathy --more likely to onephropathy and retinopathy --more likely to o

ccur in patients with poorer glycemic control ccur in patients with poorer glycemic control

The risk is highest if HbA1c value above 12%The risk is highest if HbA1c value above 12% Barzilay, J, Warram, JH, Bak, M, et al. Predisposition to hypertension: risk factor for neBarzilay, J, Warram, JH, Bak, M, et al. Predisposition to hypertension: risk factor for ne

phropathy and hypertension in IDDM. Kidney Int 1992; 41:723.phropathy and hypertension in IDDM. Kidney Int 1992; 41:723.

*The severity of hyperglycemia*The severity of hyperglycemiacorrelated with recurrent diabetic nephropathy correlated with recurrent diabetic nephropathy

in patients who have received a renal transplain patients who have received a renal transplant nt

Mauer, SM, Goetz, FC, McHugh, LE, et al. Long-term study of normal kidneys transplanted Mauer, SM, Goetz, FC, McHugh, LE, et al. Long-term study of normal kidneys transplanted into patients with type I diabetes. Diabetes 1989; 38:516. into patients with type I diabetes. Diabetes 1989; 38:516.

Prospective Diabetes Control and Prospective Diabetes Control and Complications Trial (DCCT) Complications Trial (DCCT)

mean A1C values during the nine-year study mean A1C values during the nine-year study 7.2 percent with intensive therapy-- 155 mg/dL 7.2 percent with intensive therapy-- 155 mg/dL 9.1 percent with conventional therapy--235 mg/dL9.1 percent with conventional therapy--235 mg/dL

The DCCT provided conclusive evidence strict glThe DCCT provided conclusive evidence strict glycemic control ycemic control

a) delay the onset of microvascular complications a) delay the onset of microvascular complications (primary prevention) (primary prevention)

b) low the rate of progression of already present cb) low the rate of progression of already present complications (secondary intervention)omplications (secondary intervention)

PathogenesisPathogenesis 1. Advanced glycosylation end products (AGE) –1. Advanced glycosylation end products (AGE) – a) tissue accumulation of AGEs-- crosslinking with coa) tissue accumulation of AGEs-- crosslinking with co

llagen-- renal and microvascular complications llagen-- renal and microvascular complications b) modify LDL-- less cleared by LDL receptors -- hypb) modify LDL-- less cleared by LDL receptors -- hyp

erlipidemia commonly present in diabetic patients erlipidemia commonly present in diabetic patients

2. Sorbitol — 2. Sorbitol — a) accumulation within the cells --rise intracellular osa) accumulation within the cells --rise intracellular os

molality and decrease intracellular myoinositol-- intemolality and decrease intracellular myoinositol-- interfere with cell metabolism rfere with cell metabolism

b) major contribution of sorbitol --the cataract formatib) major contribution of sorbitol --the cataract formation induced by hyperglycemiaon induced by hyperglycemia  Lee, AY, Chung, SK, Chung, SS.  Lee, AY, Chung, SK, Chung, SS.

Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reduDemonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc Natl Acad Sci U S A 1995; 92:2780. ctase gene in the lens. Proc Natl Acad Sci U S A 1995; 92:2780.

Retinopathy Retinopathy major end-point in many of the prospective dimajor end-point in many of the prospective di

abetes trials because it is the most common miabetes trials because it is the most common microvascular complicationscrovascular complications

the incidence of new retinopathy the incidence of new retinopathy 12 % in the intensive therapy group 12 % in the intensive therapy group 54 %in the conventional therapy group. 54 %in the conventional therapy group.

progressive retinopathy -- uncommon at A1C progressive retinopathy -- uncommon at A1C values below 7 %values below 7 %

*the risk of severe hypoglycemic episodes was *the risk of severe hypoglycemic episodes was also continuously, but inversely, related to gly also continuously, but inversely, related to glycemic controlcemic control*ranging from approximately 105 to 25 episod*ranging from approximately 105 to 25 episodes per 100 patient-years at mean A1C values oes per 100 patient-years at mean A1C values o

f 5.5 and 10.5 percent, respectivelyf 5.5 and 10.5 percent, respectively

Established retinopathy Established retinopathy intensive insulin therapy -- intensive insulin therapy --

slow the rate of progression of slow the rate of progression of mild to moderate retinopathy. mild to moderate retinopathy.

The incidence of worsening The incidence of worsening retinopathy in intensively retinopathy in intensively treated patients -- higher than treated patients -- higher than in those receiving conventional in those receiving conventional therapy at one year (7.4 versus therapy at one year (7.4 versus 3 percent) but much lower at 3 percent) but much lower at nine years (25 versus 53 nine years (25 versus 53 percent).percent).

Intensive insulin therapy for 6.5 years during Intensive insulin therapy for 6.5 years during the DCCT reduced the risk of retinopathy ovethe DCCT reduced the risk of retinopathy over the next seven years despite an increase in Ar the next seven years despite an increase in A

1C values1C values. . Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. AEffect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. A

MA 2002; 287:2563.MA 2002; 287:2563.

NephropathyNephropathy

DCCT included many patients with no detectable microalbuminuria at baseline. DCCT included many patients with no detectable microalbuminuria at baseline.

After 6.5 years of study, the prevalence of new microalbuminuria -- much lower After 6.5 years of study, the prevalence of new microalbuminuria -- much lower with intensive therapy-- 16% versus 27 % with intensive therapy-- 16% versus 27 %

The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl

J Med 1993;J Med 1993;..

* * the benefits of intensive therapy for primary prevention of nephropathy persist for the benefits of intensive therapy for primary prevention of nephropathy persist for a number of years a number of years

*strict glycemic control with intensive insulin *strict glycemic control with intensive insulin therapy-- not slow the rate of progressive renatherapy-- not slow the rate of progressive renal injury once overt proteinuria developed (albl injury once overt proteinuria developed (albumin excretion greater than 300 mg/day).umin excretion greater than 300 mg/day).

At late stage--often marked glomerulosclerosis.At late stage--often marked glomerulosclerosis.

Only antihypertensive therapy (preferably with Only antihypertensive therapy (preferably with ACEI) and perhaps dietary protein restriction –ACEI) and perhaps dietary protein restriction –

--slow the rate of progressive disease or revers--slow the rate of progressive disease or reverse established lesions. e established lesions.

NeuropathyNeuropathy Intensive insulin therapy --Intensive insulin therapy -- reduced the incidence of abnormal nerve condureduced the incidence of abnormal nerve condu

ction ction associated with improvement in nerve conductiassociated with improvement in nerve conducti

on velocity on velocity

The Oslo study -- graded effect of hyperglycemia The Oslo study -- graded effect of hyperglycemia on disease progressionon disease progression

each 1% rise in A1C values associated with 1.each 1% rise in A1C values associated with 1.3 m/sec slowing of nerve conduction at eight yea3 m/sec slowing of nerve conduction at eight yearsrs     Amthor, KF, Dahl-Jorgensen, K, Berg, TJ, et al. The effect of 8 years of strict glycaemic control on peripheral nerve funcAmthor, KF, Dahl-Jorgensen, K, Berg, TJ, et al. The effect of 8 years of strict glycaemic control on peripheral nerve func

tion in IDDM patients: The Oslo Study. Diabetologia 1994; 37:579 tion in IDDM patients: The Oslo Study. Diabetologia 1994; 37:579

Macrovascular diseaseMacrovascular disease nonsignificant trend toward fewer cardiovascular evenonsignificant trend toward fewer cardiovascular eve

nts with intensive therapy (3.2 versus 5.4 percent, p = nts with intensive therapy (3.2 versus 5.4 percent, p = 0.08) 0.08)

The intensive insulin therapy group -- lower serum LThe intensive insulin therapy group -- lower serum LDL but some weight gain due to the increase in insuliDL but some weight gain due to the increase in insulin administrationn administration

Mean progression of intima-media thickness of carotMean progression of intima-media thickness of carotid arteryid artery

significantly less in intensive therapy compared witsignificantly less in intensive therapy compared with conventional therapy (0.032 versus 0.046 mm). h conventional therapy (0.032 versus 0.046 mm).

not known about reduction in cardiovascular diseasnot known about reduction in cardiovascular disease-related events.e-related events.

About type 2 diabetes mellitus-About type 2 diabetes mellitus- The United Kingdom Prospective Diabetes The United Kingdom Prospective Diabetes

Study (UKPDS)Study (UKPDS) strict control also reduced risstrict control also reduced ris

k of microvascular disease in tk of microvascular disease in type 2 DMype 2 DM

Over 10 years, the average AOver 10 years, the average A1C value was 7.0 percent in th1C value was 7.0 percent in the intensive-therapy group come intensive-therapy group compared with 7.9 percent in the cpared with 7.9 percent in the conventional-therapy grouponventional-therapy group

*Most of the risk reduction in the intensive th*Most of the risk reduction in the intensive therapy group --due to 25 % risk reduction in erapy group --due to 25 % risk reduction in microvascular disease (P = 0.001) microvascular disease (P = 0.001) *There was no reduction in macrovascular dis*There was no reduction in macrovascular disease.ease.

The benefits of intensive therapy -independent The benefits of intensive therapy -independent of the type of treatment administered. of the type of treatment administered.

The reduction in microvascular complications The reduction in microvascular complications in intensive therapy -- a smaller magnitude thain intensive therapy -- a smaller magnitude than in patients with type 1 diabetes in the DCCT n in patients with type 1 diabetes in the DCCT

Macrovascular disease in type 2DMMacrovascular disease in type 2DM Conflicting data on the importance of glycemic control on the Conflicting data on the importance of glycemic control on the

development of macrovascular disease in type 2 DMdevelopment of macrovascular disease in type 2 DM To date, no randomized clinical trial has convincingly demonTo date, no randomized clinical trial has convincingly demon

strated a beneficial effect of intensive therapy on macrovasculstrated a beneficial effect of intensive therapy on macrovascular outcomes in type 2 DMar outcomes in type 2 DM

The most effective approach for prevention of both micro- anThe most effective approach for prevention of both micro- and macrovascular complications d macrovascular complications

multifactorial risk factor reduction multifactorial risk factor reduction (glycemic control, stopping smoking, aggressive blood pressu(glycemic control, stopping smoking, aggressive blood pressu

re control, treatment of dyslipidemia, and daily aspirin). re control, treatment of dyslipidemia, and daily aspirin).

Summary(1-1)-Type 1 DMSummary(1-1)-Type 1 DM strict glycemic control-- before irreversible end-organ strict glycemic control-- before irreversible end-organ

damage -- reduces the incidence of microvascular disdamage -- reduces the incidence of microvascular disease and neurologic dysfunction in type 1 diabetes. ease and neurologic dysfunction in type 1 diabetes.

From a renal viewpoint, this regimen -- beneficial in aFrom a renal viewpoint, this regimen -- beneficial in all patients except overt proteinuria in whom strict bloll patients except overt proteinuria in whom strict blood pressure control with an ACE inhibitor appears to od pressure control with an ACE inhibitor appears to be more important be more important

Beginning intensive therapy as early as possible after Beginning intensive therapy as early as possible after the diagnosis and measure HbA1C three to six monththe diagnosis and measure HbA1C three to six months. s.

Summary(1-2)-Type 1 DMSummary(1-2)-Type 1 DM In general, we aim for a A1C value of In general, we aim for a A1C value of

approximately 7% in optimally compliant and approximately 7% in optimally compliant and non-pregnant patients.non-pregnant patients.

Achieve A1C <7 % should only be considered Achieve A1C <7 % should only be considered

a) hypoglycemia is not an important problem a) hypoglycemia is not an important problem

b) during pregnancy in type 1 and type 2 b) during pregnancy in type 1 and type 2 diabetic women, since the demonstrated diabetic women, since the demonstrated benefits to the fetus and neonate drive the benefits to the fetus and neonate drive the therapeutic goals. therapeutic goals.

Summary(2-1)-Type 2 DMSummary(2-1)-Type 2 DM

Outcomes improved for every 1% drop in A1C and there Outcomes improved for every 1% drop in A1C and there was no threshold effect, a reasonable goal of therapy might was no threshold effect, a reasonable goal of therapy might be a A1C value of 7.0 % for most patients be a A1C value of 7.0 % for most patients

The ADA also recommends a target of less than 7.0 % for The ADA also recommends a target of less than 7.0 % for most patients, while the American Academy of Clinical most patients, while the American Academy of Clinical Endocrinologists (AACE) and the European Association for Endocrinologists (AACE) and the European Association for the Study of Diabetes (EASD) both recommend a target of the Study of Diabetes (EASD) both recommend a target of A1C less than 6.5 % A1C less than 6.5 %

Summary(2-1)-Type 2 DMSummary(2-1)-Type 2 DM From a practical standpoint, we are limited from pushing From a practical standpoint, we are limited from pushing

A1C lower due to increased risk of hypoglycemia, weight A1C lower due to increased risk of hypoglycemia, weight gain, and the cost of using multiple drugs to achieve the gain, and the cost of using multiple drugs to achieve the goalgoal

Vigorous cardiac risk reduction (smoking cessation, aspirin, Vigorous cardiac risk reduction (smoking cessation, aspirin, blood pressure, reduction in serum lipids, diet, exercise, blood pressure, reduction in serum lipids, diet, exercise, and, in high-risk patients, an ACEI) should be a top priority and, in high-risk patients, an ACEI) should be a top priority for all patients with type 2 diabetesfor all patients with type 2 diabetes

The HbA1C goal should be set somewhat higher for older The HbA1C goal should be set somewhat higher for older

patients and those with a limited life expectancy.patients and those with a limited life expectancy.

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