Reviews

Diabetes is associated with a considerable increase in the risk of premature development of atherosclerosis especially coronary heart disease (CHD). In the Framingham study it was documented that the incidence of cardiovascular disease in diabetic men was twice that among non-diabetic men, and in diabetic women it was about three times. The absolute risk of cardiovascular death has been found to be much higher for diabetic than non-diabetic people in the Multiple Risk Factor Intervention Trial, irrespective of the presence of other risk factors. The cause of increased risk of CHD in diabetic has been proposed to be multifactorial, e.g. hypertension, obesity, smoking and dyslipidemia.

Theoretically there are reasons to believe that hyperglycemia is associated with premature atherosclerosis. Hyperglycemia is associated with increased advanced glycation end-products (AGE) and AGE has been traditionally linked to cross-linking of collagen of the arterial wall. AGE modified LDL which are cleared slowly by hepatocytes. Epidemiological studies, like the large cross-sectional WHO multinational study on the contrary has that neither the degree of glycemia nor the duration of diabetes are related to risk of CHD. The large prospective Whitehall study also showed a non-linear relation between glycemia and CHD. The Tecumseh study and London cohort of the WHO Multinational Study also confirmed the lack of association between degree of hyperglycemia and the coronary risk. Only a handful of studies have examined the effect of improved glycemic control on cardiovascular events. In the DCCT trial, intensive therapy as compared to conventional therapy decreased the level of hyperglycemia and microvascular complications to a significant degree, but reduced the risk of CHD events which was not statistically significant. In the large United Kingdom Prospective Diabetes Study (UKPDS) trial which studies about 5000 diabetic patient for a period of 10 years, intensive glycemic control has reduced the risk of myocardial infarction, compared to the standard treatment, by 16% which however failed to reach any statistical significance.

Reaven in 1988, described a syndrome called ‘Syndrome X', which was later called insulin resistance syndrome, comprising of glucose intolerance, hypertension, dyslipidemia and compensatory hyperinsulinemia. So, rather than CHD being a complication of diabetes, it is more likely that diabetes develops in individuals who already possesses the characteristics which increase the risk of CHD in addition to the risk of developing diabetes. This assumes special significance, as Indians have noted to have high rates of diabetes and impaired glucose tolerance (IGT). Central obesity and insulin resistance has been implicated as the etiology for diabetes and CHD in Indians. In a recent study in native Indian population it was found that there is clustering of cardiovascular risk factors in urban Asian Indian, especially central obesity, dyslipidemia and glucose intolerance.

A population based study has documented that in hypertriglyceridemia and low HDL cholesterol state, insulin resistance is as common as in type 2 diabetes mellitus, whereas it is less frequent in hypercholestrolemia. In the multivariate analysis, the fasting hyperinsulinemia has been related to low HDL concentration and increased triglyceride concentration. Hyperinsulinemia was not related to increased LDL or total cholesterol.

Classic Lipid Abnormalities:

The lipid abnormalities associated with diabetes are better termed as 'dyslipoproteinemia' or ‘dyslipidemia', rather than ‘hyperlipoproteinemias' or ‘hyperlipidemia', because in diabetes there may be changes in the both the quantity or quality of the lipoproteins. The most frequent of quantitative dyslipidemia in type 2 diabetes is increased triglyceride. The UKPDS study has shown that the hypertriglyceridemia of diabetes are already prevalent at the time of diagnosis. The hypertriglyceridemia of diabetes is also influenced by the presence of other factors, which are unrelated to hyperglycemia or insulin resistance, e.g. presence or absence of nephropathy, obesity, hypothroidism, the frequent occurrence of genetically determined lipoprotein disorders (families combined hyperlipidemia or familial hypertriglyceridemia), alcohol and estrogen usage, etc. Multiple evidences in the recent literature from different countries established the role of triglyceride as an independent risk factor in the causation of CHD. In a recently published meta-analysis involving seventeen population based prospective studies have established triglyceride as an independent risk factor for CHD even after adjustment for HDL-cholesterol.

The other quantitative dyslipidemia associated with type 2 diabetes which was noted earlier is low HDL cholesterol concentration. UKPDS study also noted low HDL is prevalent in diabetes population, which is especially prominent in diabetic females. The future risk for CHD death in the study, was found to be four fold higher in diabetes with low HDL cholesterol than in diabetics without it.

The similarity of plasma total cholesterol levels in those with and those without diabetes may erroneously lead one to conclude that cholesterol has no coronary risk effect in diabetics. The Multiple Risk Factor Intervention Trial data has shown that at any given serum cholesterol concentration, those with diabetes had a risk of CHD mortality between two and four times greater than the risk without diabetes. There may be several reasons for this. First, the level of cholesterol in serum reflects the level of all lipoproteins, not just LDL. Thus an elevation of serum cholesterol may, in part, indicate an increase in the triglyceride-rich lipoproteins. Second, there may be many nonlipoprotein atherogenic factors e.g. advanced glycation end products, that might increase the risk. Third, LDL may be modified in a way that would make any given amount more atherogenic such as glycation, oxidation of LDL particles or a shift towards the smaller and denser particles.

Plasma LDL comprises of multiple discrete subclasses differing in size, density and chemical composition. A common, heritable phenotype characterized by the predominance of small, dense LDL particles is associated with increased concentration of plasma triglyceride, reduced levels of HDL and increased risk of CHD in comparison with subjects with larger LDL. It was that normolipidemic men with diabetes has two fold increase in the percentage of individuals with the small dense LDL compared with normolipidemic men without diabetes. In a prospective study on the role of small LDL, a known risk factor for CHD, has found that subjects with predominance of small LDL had a greater than twofold increased risk for developing type 2 diabetes mellitus over a follow-up period of 3.5 years. Diabetes subjects have been found to have LDL more glycated, and thus more susceptible to oxidation than in nondiabetic subjects. Oxidized LDL is believed to be more atherogenic than nonmodified LDL. Increased oxidized LDL has been found in diabetic subjects.

Lipoprotein(a) [Lp(a)] is an atherogenic particle that structurally resembles a LDL particle but contains a molecule apolipoprotein(a) attached to apolipoprotein B-100 by a disulphide bond. And it has been shown to be independent risk factor for CHD in non-diabetic subjects. Whether Lp(a) is elevated in type 2 diabetes is controversial with some studies showing higher levels, while other studies showing higher levels, while other studies show no difference, and some studies showing even lower Lp(a) levels, in type 2 diabetic subjects. So the consensus is, diabetic state does not have any impact on Lp(a) concentration, though diabetic patients with CHD have been found to have higher Lp(a) concentration than diabetic patients without CHD.

Altered lipoprotein metabolism in diabetes

Insulin by activating lipoprotein lipase clears triglyceride components of chylomicrons and VLDL from the circulation. The release of non-esterified fatty acid (NEFA) is increased in diabetes. In liver, the NEFA is converted to triglycerides.

In presence of insulin deficiency or resistance there is tendency to form low HDL, formation due to decreased triglyceride clearance. Glycation of HDL apolipoprotein A-I and A-II appears to accelerate HDL catabolism and then there may be rapid clearance of HDL particles in diabetes before they have circulated long enough to acquire sufficient cholesterol to become HDL.

Treatment

Primary Prevention and Secondary Prevention

Primary prevention is prevention in subjects who never had experienced any morbid event e.g. myocardial infarction, whereas secondary prevention is the prevention of disease progression in patients who already had sustained a morbid event. Since diabetic subjects have very high rates of subclinical atherosclerosis, the relevance of such public health classification as primary and secondary prevention becomes uncertain. The high case fatality rate and the high proportion of sudden death in diabetic subjects with the first CHD event may make primary prevention even more important. Secondary prevention studies have received most attention because of both the extraordinary increases in the risk of CHD in the overall population conferred by a prior myocardial infraction and because the number of large, well-designed secondary prevention trials. Though treatment of diabetic dyslipidemia has been studied in many trials, but no studies have specifically studied the effects of HDL raising modalities. Most of the trials were designed to lower LDL cholesterol and triglycerides and measure the effects.