ONSET OF VASCULAR COMPLICATIONS IN TYPE 2 DIABETES:
CONTINUUM OR THRESHOLD
Adela Rovira, MD., Endocrinology Department, Fundación Jiménez Díaz. Madrid. Spain.
The main cause of death in people with type 2 diabetes is cardiovascular disease. In the last years multiple
therapeutic strategies have been implemented in order to reduce this burden. However, we are alerted of the fact
that when the vascular damage is established it is very difficult to avoid its progress.
The mechanisms of the vascular damage in diabetes are complex. In people with type 2 diabetes multiple
vascular risk factors are present as it is age, hyperglycemia, high blood pressure, atherogenic lipid profile,
prothombotic state and central obesity. During the last decades, several studies have lightened the relationship
between hyperglycemia and cardiovascular complications. But, among the vascular risk factors that are
susceptible of being pharmacologically treated, hyperglycemia is in fact the most difficult to control. Furthermore,
most studies performed in subjects with type 2 diabetes, have failed to prove that glucose control, by means of an
intensified treatment, may reduce the cardiovascular morbidity and mortality.
The dilemma about whether lowering glucose may lead to a proportional reduction in cardiovascular
complications has been recently approached by the publication of the 10-year post-trial follow-up of the United
Kingdom Prospective Diabetes Study. This post-trial study has shown that a 10 years of intensive glucose control,
from the starting point of the disease, reduces 10 years later the mortality related with diabetes (17%), myocardial
infarct (15%) and death for any cause (13%) (1).This important finding points up the importance of getting a good
glucose control from the beginning of the disease and cardiovascular complications have not been developed yet.
In the same direction, the results of the DCCT post-study follow-up over 11 years (EDIC Study), demonstrated
that a randomly assigned, tight glycemic control (mean HbA1c close to 7% over the first 7-10 years) effectively
reduces cardiac and other macrovascular disease manifestations from 98 events in 52 patients to 46 events in 31
patients, that means a decrease of 42%. The risk for myocardial infarct and stroke, as well as the mortality risk
from cardiovascular disease, was reduced by 57%. On statistical grounds, the reduction of HbA1c was by far the
most important factor behind the reduction of cardiovascular disease with a 21% reduction for each per cent
decrease of HbA1c (2).
Although the relationship between hyperglycemia and vascular disease is well established, it remains unclear
above which glucose threshold the vascular damage starts. Accumulating evidence supports a continuous
relationship between glycemia and cardiovascular disease progression. In fact, it has been shown that even at
glucose levels below the diabetes diagnostic threshold there is an increase of cardiovascular mortality. A large
meta-regression analysis of data from 95,783 subjects has shown that the relative risk for cardiovascular mortality
was 1.33 at a fasting glucose of 110 mg/dl compared with 75 mg/dl, and 1.58 at a 2-h post load glucose levels of
140 vs 110 mg/dl (3).
Therefore, it seems that 2 h post load glucose is a more important risk factor for subsequent cardiovascular
morbidity and mortality than fasting glucose. In population follow-up studies as the Whitehall, the Honolulu Heart
Programme, the Paris Prospective or the Helsinki Policemen, subjects with glucose intolerance or in the higher
quintile of a 2-h post load glucose concentrations had an almost twofold increase of cardiovascular disease (4).
As a matter of fact, the Chicago Heart Study of approximately 12 000 men without a history of diabetes showed
that white men with asymptomatic hyperglycemia (1 h glucose >=200 mg/dl) had an increase risk of
cardiovascular mortality compared with men with lower post-load glucose (<160 mg/dl) (5). The study performed
in Mauritius, Fiji and Nauru Islands (6) showed that people with isolated 2 h post-load glucose >= 200 mg/dl,
doubled their cardiovascular mortality compared with non-diabetic persons, whereas there was no significant
increase in mortality related to isolated fasting hyperglycemia (FPG >= 126 mg/dl and 2 h post-load plasma
glucose < 200 mg/dl).
One of the most convincing evidence for a relationship between abnormal glucose tolerance and an increase in
cardiovascular risk has been provided by the DECODE study, in which data from more than 10 prospective
European cohort studies including more than 22 000 subjects were analyzed. In this, death rates from any cause,
cardiovascular, and coronary artery disease, were higher in diabetic subjects diagnosed by the 2 h post-load
plasma glucose than in those not meeting this criterion. Increased mortality was also observed in subjects with
impaired glucose tolerance, whereas there was no difference in mortality between subjects with impaired and
normal fasting glucose. The relationship between 2 h post-load plasma glucose and mortality was linear, but such
a relation was not seen with FPG. Multivariate analysis showed that high 2 h post-load plasma glucose predicted
mortality from all causes, cardiovascular disease, and coronary artery disease, after adjusting for other major
cardiovascular risk factors, but high fasting glucose alone did not (7,8).
Although several prospective studies have unequivocally confirmed that post-load hyperglycemia increases
cardiovascular morbidity and mortality, it still remains to be demonstrated that lowering 2 h post-load plasma
glucose will reduce this risk. A secondary endpoint analysis of the STOP-NIDDM (Stop TO Prevent Non-InsulinDependent Diabetes Mellitus) revealed statistically significant reductions in cardiovascular disease event rates in
impaired glucose tolerant subjects receiving Acarbose compared to placebo. But the power in this analysis is low
due a very small number of events (9). Additional support is obtained from a meta-analysis of seven long-term
studies using acarbose in type 2 diabetic subjects. The risk for myocardial infarct was significantly lower in
patients receiving acarbose compared with those on placebo (10).
The importance of postprandial glucose has been addressed in The Diabetes Intervention Study, recruiting newly
diagnosed type 2 diabetic subjects. This prospective11-year population-based study of 1,139 newly diagnosed
diabetic patients, has demonstrated that baseline post-prandial hyperglycemia (blood glucose measured 1 h after
breakfast) had a greater impact on cardiovascular disease and all cause mortality than baseline fasting blood
glucose (11).
Conclusions:
It seems that there is not a specific threshold of glucose from which macrovascular damage would be initiated,
but a continuum glucose levels which could begin below those currently used for diagnosis of diabetes.
Prediabetic states, specially impaired glucose tolerance, is associated with increased risk of vascular
complications.
Primary screening for type 2 diabetes should be done by a risk score, and if possible, it should be followed by an
oral glucose tolerance test in people with high score values. High risk individuals can be a target for proper
management, not only for diabetes prevention but also for cardiovascular disease prevention.
A special attention has to be paid to post-prandial glucose levels in people with diabetes. Guidelines on this issue
have emerged in recent years from different Scientific Societies, recommending specific targets for post-prandial
glucose.
References
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