Glycemic control and vascular complications in type 1 and 2
diabetes mellitus
Slide 4
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
Slide 5
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.
Slide 6
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.
Slide 7
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.
Slide 8
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
Slide 9
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.
Slide 10
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).
Slide 11
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.
Slide 12
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).
Slide 13
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
Slide 14
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.
Slide 15
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.
Slide 16
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 %).
Slide 17
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)
Slide 18
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
Slide 19
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.
Slide 20
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
Slide 21
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 %).
Slide 22
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.
Slide 23
Results: New microalbuminuria was less common (7 versus 16 %)
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.
Slide 24
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.
Slide 25
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.
Slide 26
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.
Slide 27
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.
Slide 28
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.
Slide 29
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 %).
Slide 30
In tensive 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.
Slide 31
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.
Slide 32
A number of other potentially modifiable risk factors appear to
be associated with the risk of diabetic neuropathy, including
hypertriglyceridemia, obesity, smoking, and hypertension.
Slide 33
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.
Slide 34
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.
Slide 35
These results indicate that a sustained period of glycemic
control (6.5 years in the DCCT study) has lasting benefit in
reducing cardiovascular morbidity and mortality in type 1 diabetes.
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 %).
Slide 36
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)
Slide 37
GLYCEMIC GOALS The above findings provide conclusive evidence
that strict glycemic control, if achieved before irreversible
end-organ damage has occurred, reduces the incidence of
microvascular disease, neurologic dysfunction, and cardiovascular
disease in patients with type 1 diabetes. Additional data from the
DCCT support the importance of beginning intensive therapy as early
as possible after the diagnosis of type 1 diabetes:
Slide 38
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
Slide 39
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.
Slide 40
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.
Slide 41
Increasing the intensity of glycemic control to achieve
A1C