Presented by : mohammadreza khosravi Internist. Glycemic control and vascular complications in type 1 and 2 diabetes mellitus. - PowerPoint PPT Presentation
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Slide 1Internist
Glycemic control and vascular complications in type 1 and 2
diabetes mellitus
Morbidity from diabetes is a consequence of both macrovascular
disease (atherosclerosis) and microvascular disease (retinopathy,
nephropathy, and neuropathy). Epidemiologic studies first showed an
association between poor glycemic control and microvascular
complications .
This association was confirmed in the prospective Diabetes Control
and Complications Trial (DCCT), which demonstrated that intensive
therapy aimed at lower levels of glycemia results in decreased
rates of retinopathy, nephropathy, and neuropathy in type 1
diabetes patients
The importance of tight glycemic control for protection against
macrovascular disease in diabetes has also been established in the
DCCT/EDIC study for type 1 diabetes. In the EDIC follow-up study to
the DCCT, intensive insulin therapy in patients with type 1
diabetes decreased fatal and nonfatal cardiovascular events.
PATHOGENESIS:
1- Two proposed contributing factors are advanced glycosylation end
products and sorbitol; protein kinase C and other factors also may
contribute . In addition to systemic factors, organ-specific
factors also appear to be important. In the kidney, for example,
stimulation of mesangial matrix production by hyperglycemia,
activation of protein kinase C, and an increasing degree of
intraglomerular hypertension may contribute to the glomerular
injury.
2- Genetic predisposition may be another important factor. This was
illustrated in a report from the DCCT in which 372 patients and 467
first-degree was three times more frequent among the relatives of
patients with retinopathy than among relatives of patients who did
not have retinopathy. Familial clustering was also noted for
diabetic nephropathy.
MICROVASCULAR DISEASE
epidemiologic studies suggest that nephropathy and retinopathy are
more likely to occur in patients with poorer glycemic control
.
The risk is highest if the hemoglobin A1C (A1C) value is above 12
percent. but is still increased at all values above the
non-diabetic range
These associations were confirmed in the prospective Diabetes
Control and Complications Trial (DCCT)
In this study, patients with type 1 diabetes were randomly assigned
to receive either conventional therapy or intensive insulin
therapy, consisting of multiple daily injections or continuous
insulin administration using an insulin pump, and guided by
frequent self-monitoring of blood glucose.
Patients with no retinopathy or nephropathy at baseline were
evaluated in the primary prevention study, while those with
established disease were evaluated in the secondary intervention
study.
The mean A1C values during the nine-year study were 7.2 percent
with intensive therapy as opposed to 9.1 percent with conventional
therapy; the respective mean blood glucose concentrations were 155
mg/dL (8.6 mmol/L) and 235 mg/dL (12.8 mmol/L).
The DCCT provided conclusive evidence that strict glycemic control
can both delay the onset of microvascular complications (primary
prevention) and slow the rate of progression of already present
complications (secondary intervention).
Following completion of the DCCT in 1993, the conventional
treatment group was offered intensive treatment, and 93 % of DCCT
participants (n = 1394) agreed to participate in the observational
Epidemiology of Diabetes Interventions and Complications (EDIC)
study.
11 years of follow-up were concluded in February 2005. Differences
in A1C levels between the intensive and conventional treatment
groups at the end of the DCCT trial (7.4 and 9.1 %, respectively)
narrowed at the end of the 11 year follow-up EDIC (7.9 and 7.8 %,
respectively).
Retinopathy - Retinopathy has been chosen as the major end-point in
many of the prospective diabetes trials because it is the most
common microvascular complication and is relatively easy to
quantify and follow. Standard retinal photographs are taken and
scored, based upon the number of microaneurysms, hemorrhages,
exudates, and other abnormalities
Primary prevention
at nine years, the incidence of new retinopathy was 12 % in the
intensive therapy group versus 54 percent in the conventional
therapy group
There was a continuous relation between the degree of glycemic
control and the incidence of retinopathy (the only complication for
which such data were reported): the rate of progression increased
from one per 100 patient-years at a mean A1C value of 5.5 percent
up to 9.5 per 100 patient-years at a mean A1C value of 10.5
percent; progressive retinopathy was uncommon at A1C values below 7
percent.
Established retinopathy
In addition to its efficacy in primary prevention, intensive
insulin therapy also slows the rate of progression of mild to
moderate retinopathy.
However, during the first two years of intensive therapy, the DCCT
found that retinopathy may worsen most commonly in association with
an increased number of soft exudates (due to retinal infarcts in
the superficial layers). This probably represents the closure of
small retinal blood vessels that were narrowed but patent.
Correction of hyperglycemia lowers the plasma volume, which can put
marginal vessels at risk. Increased availability of insulin-like
growth factor-1 also may contribute.
This early worsening of retinopathy in the DCCT was transient,
largely resolving after 18 to 24 months, and there was clear
evidence of benefit from intensive therapy when patients with very
mild to moderate nonproliferative retinopathy were followed for
nine years
The incidence of worsening retinopathy in intensively treated
patients was higher than in those receiving conventional therapy at
one year (7.4 versus 3 percent) but much lower at nine years (25
versus 53 %).
At the end of the DCCT, the conventional treatment group was taught
intensive therapy, and the diabetes care of all of the participants
was returned to their own health care providers. During the
subsequent observational follow-up of the DCCT cohort, in the
Epidemiology of Diabetes Interventions and Complications (EDIC)
study, the difference in the median A1C values between the original
intensive and conventional therapy groups (7.2 and 9.1 percent,
respectively) narrowed during follow-up (8.1 and 8.2 percent,
respectively, by five years)
Thus, intensive insulin therapy for 6.5 years during the DCCT
reduced the risk of retinopathy over at least the next 10 years
compared with conventional therapy, despite an absence of a
difference in A1C values during the post-DCCT trial period. This
phenomenon has been called "metabolic memory”
Strict glycemic control is of little or no benefit in advanced
retinopathy. This has been best demonstrated in patients who have
undergone pancreas transplantation. In one study, for example, 22
transplanted patients (most of whom had advanced nephropathy) were
compared to 16 nontransplanted patients with similar disease
severity . Despite the attainment and maintenance of normoglycemia
in the transplant group, there was no difference between the groups
in the rates of progression of retinopathy or visual loss at two
years.
Nephropathy
Following a cohort of 20,000 individuals diagnosed with type 1
diabetes before the age of 20 years, a Finnish study reported a
prevalence of end-stage renal disease of 2.2 percent at 20 years
and 7.7 % at 30 years. These prevalence rates are significantly
lower than previous estimates of 30 to 40 percent, and likely
reflect, at least in part, the impact of improved glycemic
management
Primary prevention :
The DCCT included 1365 patients with normal albumin excretion at
baseline. At follow-up of up to nine years (mean 6.5 years),
intensive therapy was associated with a significantly lower rate of
new onset microalbuminuria in these patients (16.4 versus 23.9 %,
adjusted risk reduction 39 percent) . There was also a significant
reduction in new onset macroalbuminuria in the entire study
population (3.2 versus 7.2 %, adjusted risk reduction 51 %).
Similar to the case with retinopathy, metabolic memory applies to
the primary prevention of nephropathy. At year eight of the EDIC
follow-up study, significant persistent benefits were noted in
those who had received intensive therapy compared with those who
received conventional therapy during the DCCT.
Results:
New clinical albuminuria, also called macroalbuminuria, was less
common (1.4 versus 9 %)
The prevalence of hypertension was lower (30 versus 40 %)
Thus, previous intensive treatment with near-normal glycemia during
the DCCT had an extended benefit in delaying the onset and
progression of diabetic nephropathy.
Intensive insulin therapy may act in part by reversing the early
glomerular hyperfiltration and hypertrophy that are thought to be
important risk factors for glomerular.
Established microalbuminuria
Intensive insulin therapy is also effective at a somewhat later
stage, after microalbuminuria has developed
In addition to preventing progression, maintenance of relative
normoglycemia often diminishes the degree of protein excretion,
although one to two years are usually required for this
effect.
Established macroalbuminuria
In contrast to the benefit of aggressive therapy in patients with
microalbuminuria, it has been suggested that strict glycemic
control with intensive insulin therapy may not slow the rate of
progressive renal injury once overt dipstick-positive proteinuria
(equivalent to albuminuria >300 mg/day, called macroalbuminuria
or overt proteinuria) has developed.
the apparent lack of substantial benefit in overt diabetic
nephropathy from strict glycemic control alone suggests that other
factors (such as intraglomerular hypertension and glomerular
hypertrophy) may contribute to the progressive glomerular injury.
At this late stage, there is often marked glomerulosclerosis. Only
antihypertensive therapy (preferably with an angiotensin converting
enzyme inhibitor) and perhaps dietary protein restriction have been
shown to slow the rate of progressive disease or reverse
established lesions.
Neuropathy
The first evidence that improved glycemic control has a beneficial
effect on painful diabetic neuropathy came from a report of nine
patients
Initiation of intensive therapy led to symptomatic improvement in
all patients in association with increases in vibration sense and
motor (but not sensory) nerve conduction velocity.
In the DCCT
The incidence of confirmed clinical neuropathy (defined as findings
from the history and physical examination that were confirmed by
neurologic testing) was reduced with intensive insulin therapy by
64 % (5 versus 13 %).
Intensive insulin therapy also reduced the incidence of abnormal
nerve conduction by 44 percent (26 versus 46 %) and of autonomic
dysfunction by 53 percent (4 versus 9 %).
observations indicate that an intensive insulin regimen to improve
glycemic control delays or prevents clinical and physiological
evidence of diabetic neuropathy.
The Oslo study suggested that there was a graded effect of
hyperglycemia on disease progression, as each 1 percent rise in A1C
values was associated with a 1.3 m/sec slowing of nerve conduction
at eight years.
A number of other potentially modifiable risk factors appear to be
associated with the risk of diabetic neuropathy, including
hypertriglyceridemia, obesity, smoking, and hypertension.
MACROVASCULAR DISEASE
This represented a 42 % decrease in any cardiovascular event (95%
CI 9-63 percent); there was also a 57 percent reduction in a
serious cardiovascular event (non fatal MI, stroke, or CVD death)
(95% CI 12-79 percent) comparing the original DCCT intensive
therapy with the DCCT conventional treatment group.
Microalbuminuria and albuminuria were also independently associated
with cardiovascular outcome, but differences in outcome between the
two treatment groups remained after correction for these renal
factors.
The results are supported by similar findings from a cohort study
of 879 individuals with type 1 diabetes followed for 20 years. In
this study, individuals in the highest quartile of A1C (12 %) had
increased all-cause (relative risk [RR] 2.4, 95% CI 1.5-3.8) and
cardiovascular (RR 3.3, 95% CI 1.8-6.1) mortality compared with
individuals in the lowest quartile (9.4 %).
An earlier report from the EDIC study showed that progression of
carotid intima-media thickness, a measure of atherosclerosis, was
significantly less in those who had received intensive therapy
during the DCCT compared with those who had received conventional
therapy; (progression of intima-media thickness of the common
carotid artery 0.032 versus 0.046 mm)
GLYCEMIC GOALS
Additional data from the DCCT support the importance of beginning
intensive therapy as early as possible after the diagnosis of type
1 diabetes:
Long-term observational data from the DCCT/EDIC study showed that
patients with type 1 diabetes duration of 30 years, who were
initially assigned to intensive versus conventional therapy, had
the lowest cumulative incidences of proliferative retinopathy (21
versus 50 percent), nephropathy (9 versus 25 %), and cardiovascular
disease (9 versus 14 %).Thus, intensive insulin therapy should be
attempted in all appropriate patients with type 1 diabetes as early
in the course of disease as is safely feasible. Both patient and
physician education and support are required to perform this task
safely
From a renal viewpoint, this regimen has demonstrated to be
beneficial in all patients except those with overt proteinuria in
whom strict blood pressure control with an ACE inhibitor appears to
be more important.
In general, we aim for an A1C value of 7 percent or lower in
patients in whom the benefits outweigh the risks. Specific glycemic
targets should be set for individual patients, weighing benefits
related to life-expectancy and existing complications against the
risk of hypoglycemia.
In general A1C goals are set higher for children and adolescents,
especially in children with frequent hypoglycemia or hypoglycemia
unawareness.
Increasing the intensity of glycemic control to achieve A1C <7 %
is indicated during pregnancy in type 1 and type 2 diabetic women,
since the A1C level in nondiabetic women falls during pregnancy and
the demonstrated benefits to the fetus and neonate drive the
therapeutic goals.
Glycemic variability :
The effect of fluctuations in glucose levels, as measured within or
between days, on the risk of developing diabetic complications is
uncertain. This has theoretical clinical implications, as free
radicals have been implicated in endothelial damage and the
formation of atherosclerotic plaques. One may therefore hypothesize
that control of daily blood glucose fluctuations, in addition to
management of chronic hyperglycemia (as measured by A1C) in
diabetic patients, could be important in protection against micro-
and macrovascular disease .
Analysis of data from the DCCT demonstrated that while retinopathy
correlated directly with average glucose control, as measured by
the A1C, fluctuations of glucose within the day (glucose
variability) did not impact the development of retinopathy.
Microvascular complications - Improved glycemic control improves
the risk of microvascular complications in patients with type 2
diabetes. Every 1 percent drop in A1C is associated with improved
outcomes with no threshold effect.
Macrovascular complications :
To date, no randomized clinical trial has convincingly demonstrated
a beneficial effect of intensive therapy on macrovascular outcomes
in individuals with long-standing type 2 diabetes. In contrast, the
results of the UKPDS post-trial observation study suggest that
initial intensive control (A1C 7.0 %) in individuals with newly
diagnosed diabetes has long-term benefit in decreasing the risk of
myocardial infarction, diabetes-related death, and overall death.
In the aggregate, the clinical evidence supports initiating
intensive therapy with the goal of lowering A1C levels to <7.0 %
as early as possible in the course of diabetes.
Glycemic targets - Target A1C goals in patients with type 2
diabetes should be tailored to the individual, balancing the
improvement in microvascular complications with the risk of
hypoglycemia. A reasonable goal of therapy might be an A1C value of
7.0 percent for most patients (using an assay in which the upper
limit of normal is 6.0 percent). Glycemic targets are generally set
somewhat higher for older patients and those with comorbidities or
a limited life expectancy and little likelihood of benefit from
intensive therapy.
Multifactorial risk reduction - Vigorous cardiac risk reduction
(smoking cessation, aspirin, blood pressure control, reduction in
serum lipids, preferably using a statin, diet, exercise, and, in
high-risk patients, an angiotensin converting enzyme inhibitor)
should be a top priority for all patients with type 2
diabetes.
In spite of evidence that aggressive risk factor reduction lowers
the risk of both micro- and macrovascular complications in patients
with diabetes, the vast majority of patients do not achieve
recommended goals for A1C, blood pressure control, and management
of dyslipidemia.
Nutriton therapy in Diabet
Glycemic index (GI) was first defined by Jenkins et al. as an
indicator of the potential of glycemic carbohydrates in different
types of food to raise blood glucose levels within 2h of
ingestion.
Low-GI foods are classified as being digested and absorbed slowly
and high-GI foods as being digested and absorbed rapidly. Thus, a
food with a higher GI is asuemed to result in a higher glycemic
response, Which should induce various hormonal and metabolic
changes that negatively affect health conditions; foods eliciting
low glycemic responses should generally induce clinically important
benefits.
there is evidence that lowglycaemic foods (low-GI in particular)
have higher satietogenic properties than high-glycaemic
foods.
Low-GI foods help one to feel fuller for longer than equivalent
high-GI foods’ are substantiated health claims.