Disease progress

Early detection is crucial
Effective screening and early detection of both the metabolic syndrome and diabetes makes it possible to slow the progress, prevent complications or even avoid that diabetes develops. For diagnosis of diabetes accompanied by typical symptoms single blood glucose determination currently establishes the diagnosis.

For diagnosis of earlier stages of diabetes or of the metabolic syndrome determination of glucose levels fasting or after an oral glucose load may, however, be misleading. It has been found that the use of HbA1c predicts the likelihood of having impaired glucose tolerance in high-risk patients, who have normal fasting glucose levels. The use of fasting glucose levels in combination with HbA1c may therefore in the future become be a reasonable approach also for screening subjects at risk. One may say that HbA1c is a confirmation of the mean glucose control. An HbA1c of 6% indicates that the mean glucose level is about 9 mmol/L. A determination of HbA1c each third month is generally recommended. Of importance is also mode of treatment that should aim at reducing the fluctuations as much as possible.

HbA1c can also be used for screening and diagnosis of the metabolic syndrome and diabetes.

Late complications of diabetes
Diabetes is associated with a range of late complications. Diabetic patients have a 2.5- to 5-fold increased risk of having increased coronary artery calcification score, and myocardial infarctions are common. Patients with diabetes have the same risk of myocardial infarction, as do non-diabetic patients with a history of infarction. For women, data indicate substantially elevated risk of cardiovascular disease even before the clinical diagnosis of Type 2 diabetes. A causal association between blood glucose and the development of microvascular disease causing retinopathy, nephropathy, stroke and neuropsychiatric symptoms has also been demonstrated in many studies of type 1 diabetics The association between HbA1c and late complications has been shown in several large longitudinal studies.

Good glycemic control is crucial for prevention of complications. In the large Diabetes Control and Complications Trial (DCCT), patients with Type 1 diabetes were randomised to receive either conventional insulin therapy, or an intensive insulin regimen consisting of multiple daily injections, or an insulin pump to maintain near-normal glycemia. The mean HbA1c values over the nine-year study period were 7.2% with intensive therapy and 9.1% in the conventional group, showing that strict glycemic control ameliorates long-term glucose values. More important, late complications were rarer in the group with lower HbA1c treated intensively.

In the United Kingdom Prospective Diabetes Study (UKPDS), a study of over 4,000 patients with newly diagnosed Type 2 diabetes, treated with different regimens, a 1% reduction of HbA1c was associated with a 35% reduction in macrovascular endpoints, 18% reduction in myocardial infarction, and 17% reduction in all-cause mortality. Also in this study there was a correlation between HbA1c values obtained and the rate of complications. Over the 10-year study period, the average HbA1c was 7.0% in the intensively treated group compared with 7.9% in the conventional group. The benefit of intensive treatment appeared to be independent of type of treatment.

Another aspect is the relationship between glycemic control and diabetes-related costs. Most of the costs of diabetes in suffering, lost years and in health care come from its complications. Lost working capacity is another costly consequence of diabetes.
An American study of 1,642 diabetic patients recently found that no less than 42% of them had some form of work inability: 19% had significant work disability, 12% were unemployed, 7% had been absent from their work at least 5 days during the previous month, and 4% reported severe difficulty with work tasks.

Recent data from a large American retrospective database analysis suggest that Type 2 diabetics, who stayed continuously at the target HbA1c level of 7% or less, incurred lower diabetes-related costs than patients with higher levels over a 1-year follow-up. A study of the global burden of the disease, published by the WHO, the World Bank and Harvard University showed data from 1990, where diabetes and its complications were estimated to account for 2.8 million deaths, compared to 6.2 million of cardiovascular disease and 4.4 of cerebrovascular disease. Given the steep increase of diabetes incidence, the number is likely to be much higher already.

Primary and secondary prevention of these complications by an optimal glycemic monitoring, where HbA1c is a very valuable tool, may become very efficient in reducing late complications and associated cost. Tight glycemic control requires a motivated and educated patient in addition to appropriate treatment, and vigilant monitoring. The patient may become more motivated to comply with treatment and life style changes by being aware of the association between HbA1c and complications/life expectancy. A recent Swedish study showed that HbA1c was the most important factor associated with coping strategies for patients with Type 2 diabetes.

What are the mechanisms behind the late complications?
The chief mechanism behind the glucose-mediated vascular damage is proposed to be hyperglycemia-induced oxidative stress, a stress that fluctuates with glycemic burden. Studies correlating the magnitude of oxidative stress with fluctuating levels of glycemia support the hypothesis that glucose variability, considered in combination with HbA1c may be a more reliable marker of blood glucose control and risk for long-term complications than HbA1c alone.

A large number of studies have also found an association between the new risk factor for vascular and other diseases, homocysteine, and late complications in diabetics. Homocysteine levels are often increased in later stages of diabetes, in particular in the presence complications and in Type 2 diabetics. Hyperhomocysteinemia is related to vascular disease, neurological disorders, retinopathy, dementia, depression, pregnancy complications, foetal malformations, and osteoporosis. These conditions are all over represented among diabetic patients. Several potential biochemical mechanisms, many of them oxidative, by which a disturbed homocysteine metabolism may result in these conditions, have been found. How impaired glucose regulation affects the homocysteine metabolism is, however, not clear, even though renal impairment may reduce homocysteine clearance. Additional mechanisms are likely to contribute. Oral antidiabetic drugs from the biguanide group that reduce the absorption of vitamin B12, a vitamin implicated in the homocysteine metabolism, may contribute to increased homocysteine levels. Obesity, smoking and sedentary lifestyle, common in persons with the metabolic syndrome and diabetics, are also associated with increased homocysteine levels. In addition to effective glycemic control, monitoring of homocysteine levels by homocysteine-lowering vitamins may be a strategy to further reduce late complications.