HbA1C and DM control

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HbA1C and DM control

• By Ri ???

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Introduction

• microvascular complications in type 1 diabetes
  --slowed by treating hyperglycemia
• ?increased use of intensive insulin regimens
  to attain strict glycemic control
• The efficacy of these regimens requires an
  accurate method to estimate

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a given mean blood glucose value ?associated with
different mean glycemic excursions and mean daily
differences
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Estimation of mean blood glucose by A1C

• glucose can attach to many proteins via a
  nonenzymatic, posttranslational process
• (1)A reversible reaction leads to the formation
  of an aldimine
• (2)followed by an Amadori rearrangement to form
  an irreversible ketoamine.

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Glycated hemoglobin

• most widely used clinical test
• ?measurement of blood glycated hemoglobin (also
  called hemoglobin A1C, glycohemoglobin, and
  glycosylated hemoglobin HbA1c).
• the average amount of A1C
• ?changes in a dynamic way
• ?reflects the mean blood glucose concentration
  over the previous six to eight weeks.  
• Nathan, DM, Singer, DE, Hurxthal, K.
  Goodson, JD. The clinical information value of
  the glycosylated hemoglobin assay. N Engl J Med
  1984 310341.

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Diabetes Control and Complications Trial (DCCT)

• mean blood glucose concentrations from seven
  measurements a day (before and 90 minutes after
  each meals, and before bedtime)
• ?compared with A1C values in 278 patients with
  type 1 DM
• A strong correlation
• A1C value of 7 percent --150 mg/dL
• A1C value of 9 percent --210 mg/dL

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Factors causing misleading results

• A1C values influenced by red cell survival.
• (1) falsely high values -- low red cell
  turnover--disproportionate number of older red
  cells
• ex iron, vitamin B12, or folate deficiency
  anemia.
• (2) falsely low values -- rapid red cell
  turnover
• greater younger red cells
• ex hemolysis , treated for iron, vitamin B12,
  or folate deficiency
• Panzer, S, Kronik, G, Lechner, K, et al.
  Glycosylated hemoglobins (GHb) An index of red
  cell survival. Blood 1982 591348.

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Fructosamine

• nonenzymatic glycation ?formation of advanced
  glycosylation end products ?direct role in the
  development of diabetic microvascular
  complications
• good correlation between serum fructosamine and
  A1C values
• variation for fructosamine higher than that for
  A1C
• serum fructosamine values reflect mean blood
  glucose values over a much shorter period of time
  (one to two weeks).

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About type 1 DM--Introduction

• nephropathy and retinopathy --more likely to
  occur in patients with poorer glycemic control
• The risk is highest if HbA1c value above 12
• Barzilay, J, Warram, JH, Bak, M, et al.
  Predisposition to hypertension risk factor for
  nephropathy and hypertension in IDDM. Kidney
  Int 1992 41723.
• The severity of hyperglycemia
• ?correlated with recurrent diabetic nephropathy
  in patients who have received a renal transplant
  
• Mauer, SM, Goetz, FC, McHugh, LE, et al.
  Long-term study of normal kidneys transplanted
  into patients with type I diabetes. Diabetes
  1989 38516.

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Prospective Diabetes Control and Complications
Trial (DCCT)

• mean A1C values during the nine-year study
• ?7.2 percent with intensive therapy-- 155 mg/dL
• 9.1 percent with conventional therapy--235
  mg/dL
• The DCCT provided conclusive evidence strict
  glycemic control
• a) delay the onset of microvascular
  complications (primary prevention)
• b) low the rate of progression of already
  present complications (secondary intervention)

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Pathogenesis

• 1. Advanced glycosylation end products (AGE)
• a) tissue accumulation of AGEs-- crosslinking
  with collagen-- renal and microvascular
  complications
• b) modify LDL-- less cleared by LDL receptors
  -- hyperlipidemia commonly present in diabetic
  patients
• 2. Sorbitol
• a) accumulation within the cells --rise
  intracellular osmolality and decrease
  intracellular myoinositol-- interfere with cell
  metabolism
• b) major contribution of sorbitol --the
  cataract formation induced by hyperglycemia
   Lee, AY, Chung, SK, Chung, SS.
• Demonstration 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
  922780.

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Retinopathy

• major end-point in many of the prospective
  diabetes trials because it is the most common
  microvascular complications
• the incidence of new retinopathy
• ?12 in the intensive therapy group
• 54 in the conventional therapy group.
• progressive retinopathy -- uncommon at A1C values
  below 7

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the risk of severe hypoglycemic episodes was
also continuously, but inversely, related to
glycemic controlranging from approximately 105
to 25 episodes per 100 patient-years at mean A1C
values of 5.5 and 10.5 percent, respectively
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Established retinopathy

• intensive insulin therapy -- slow the rate of
  progression of mild to moderate retinopathy.
• The incidence of worsening retinopathy in
  intensively treated patients -- higher than in
  those receiving conventional therapy at one year
  (7.4 versus 3 percent) but much lower at nine
  years (25 versus 53 percent).

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Intensive insulin therapy for 6.5 years during
the DCCT reduced the risk of retinopathy over the
next seven years despite an increase in A1C
values. Effect of intensive therapy on the
microvascular complications of type 1 diabetes
mellitus. AMA 2002 2872563.
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Nephropathy

• DCCT included many patients with no detectable
  microalbuminuria at baseline.
• After 6.5 years of study, the prevalence of
  new microalbuminuria -- much lower 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 J Med 1993.
• the benefits of intensive therapy for primary
  prevention of nephropathy persist for a number of
  years

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

• At late stage--often marked glomerulosclerosis.
• Only antihypertensive therapy (preferably with
  ACEI) and perhaps dietary protein restriction
• --slow the rate of progressive disease or
  reverse established lesions.

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Neuropathy

• Intensive insulin therapy --
• ? reduced the incidence of abnormal nerve
  conduction
• ?associated with improvement in nerve
  conduction velocity
• The Oslo study -- graded effect of hyperglycemia
  on disease progression
• ?each 1 rise in A1C values associated with
  1.3 m/sec slowing of nerve conduction at eight
  years   Amthor, KF, Dahl-Jorgensen, K, Berg, TJ,
  et al. The effect of 8 years of strict glycaemic
  control on peripheral nerve function in IDDM
  patients The Oslo Study. Diabetologia 1994
  37579

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Macrovascular disease

• nonsignificant trend toward fewer cardiovascular
  events with intensive therapy (3.2 versus 5.4
  percent, p 0.08)
• The intensive insulin therapy group -- lower
  serum LDL but some weight gain due to the
  increase in insulin administration
• Mean progression of intima-media thickness of
  carotid artery
• ?significantly less in intensive therapy
  compared with conventional therapy (0.032 versus
  0.046 mm).
• ?not known about reduction in cardiovascular
  disease-related events.

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About type 2 diabetes mellitus- The United
Kingdom Prospective Diabetes Study (UKPDS)

• strict control also reduced risk of
  microvascular disease in type 2 DM
• Over 10 years, the average A1C value was 7.0
  percent in the intensive-therapy group compared
  with 7.9 percent in the conventional-therapy
  group

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Most of the risk reduction in the intensive
therapy group --due to 25 risk reduction in
microvascular disease (P 0.001) There was no
reduction in macrovascular disease.

• The benefits of intensive therapy -independent of
  the type of treatment administered.
• The reduction in microvascular complications in
  intensive therapy -- a smaller magnitude than in
  patients with type 1 diabetes in the DCCT

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Macrovascular disease in type 2DM

• Conflicting data on the importance of glycemic
  control on the development of macrovascular
  disease in type 2 DM
• To date, no randomized clinical trial has
  convincingly demonstrated a beneficial effect of
  intensive therapy on macrovascular outcomes in
  type 2 DM
• The most effective approach for prevention of
  both micro- and macrovascular complications
• ?multifactorial risk factor reduction
• (glycemic control, stopping smoking,
  aggressive blood pressure control, treatment of
  dyslipidemia, and daily aspirin).

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Summary(1-1)-Type 1 DM

• strict glycemic control-- before irreversible
  end-organ damage -- reduces the incidence of
  microvascular disease and neurologic dysfunction
  in type 1 diabetes.
• From a renal viewpoint, this regimen --
  beneficial in all patients except overt
  proteinuria in whom strict blood pressure control
  with an ACE inhibitor appears to be more
  important
• Beginning intensive therapy as early as possible
  after the diagnosis and measure HbA1C three to
  six months.

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Summary(1-2)-Type 1 DM

• In general, we aim for a A1C value of
  approximately 7 in optimally compliant and
  non-pregnant patients.
• Achieve A1C lt7 should only be considered
• a) hypoglycemia is not an important problem
• b) during pregnancy in type 1 and type 2
  diabetic women, since the demonstrated benefits
  to the fetus and neonate drive the therapeutic
  goals.

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Summary(2-1)-Type 2 DM

• Outcomes improved for every 1 drop in A1C and
  there was no threshold effect, a reasonable goal
  of therapy might be a A1C value of 7.0 for most
  patients
• The ADA also recommends a target of less than 7.0
  for most patients, while the American Academy
  of Clinical Endocrinologists (AACE) and the
  European Association for the Study of Diabetes
  (EASD) both recommend a target of A1C less than
  6.5

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Summary(2-1)-Type 2 DM

• From a practical standpoint, we are limited from
  pushing A1C lower due to increased risk of
  hypoglycemia, weight gain, and the cost of using
  multiple drugs to achieve the goal
• Vigorous cardiac risk reduction (smoking
  cessation, aspirin, blood pressure, reduction in
  serum lipids, diet, exercise, and, in high-risk
  patients, an ACEI) should be a top priority for
  all patients with type 2 diabetes
• The HbA1C goal should be set somewhat higher for
  older patients and those with a limited life
  expectancy.

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