Heart Disease in Early type 2 Diabetes

Abstract: The steadily increasing prevalence of diabetes constitutes a major health problem. By the year 2025, the prevalence of diabetes is estimated to be as high as 5.4 %. This is to be compared with reports from Swedish coronary care units, which suggest that as many as 66 % of the patients admitted in fact have previously undiagnosed diabetes or pre-diabetes (impaired glucose tolerance) 1. Cardiovascular disease is also the major contributor to mortality in the diabetic population. Screening for micro-vascular complications has been routine for decades, but no similar practice for early detection and treatment of cardiac complications has been conducted. This is especially notable, since treatment at different stages of heart dysfunction, even symptomatic, has proved to reduce cardiovascular complications 2-4. Routine echocardiography (UCG) assessment would be considered optimal for such conduct, but is not always possible due to lack of accessibility and high costs. The measurement of the natriuretic peptides (NP) has been suggested as a tool to identify patients who could benefit from further risk evaluation by UCG. There are, however, inconsistent results regarding which of these NP (N-terminal brain natriuretic peptide (Nt-proBNP), brain natriuretic peptide (BNP) and/or N-terminal atrial natriuretic peptide (Nt-proANP)) would best serve this purpose. This inconsistency might be due differences in renal-dependent clearance for the different NP: s. In paper I, in a head to head comparison of Nt-proBNP, BNP and Nt-proANP and their relation to UCG signs of structural heart disease and renal function, we found that after adjustment for renal function with cystatin C, Nt-proBNP in particular showed good age-independent correlations to UCG signs of structural heart disease. In paper II, we used Nt-proBNP, paired with cystatin C, to assess whether asymptomatic heart disease is more common in patients with type-2 diabetes compared to controls, where neither group has known cardiac disease. The study showed that patients with type-2 diabetes had significantly higher Nt-proBNP values than control subjects (P<0.001) and, notably, that 61.3 % of the patients with diabetes had Nt-proBNP values above the recommended value for Nt-proBNP, indicating the presence of previously unknown heart disease and a need for further risk stratification with UCG examination. Hypertension is present in as many as 70 % of patients with type-2 diabetes, thus being considerably more common than in the non-diabetic population. The reason for the increased prevalence of hypertension in type-2 diabetes is, however, unknown. One hypothesis is that hyperinsulinemia, secondary to peripheral insulin resistance, induces salt retention in the kidney, which in turn might lead to salt sensitive hypertension. Since earlier studies had shown that Nt-proANP correlated strongly to salt sensitivity, in paper III, we aimed to assess if patients with type-2 diabetes had elevated levels of Nt-proANP in the plasma. Surprisingly, we saw that salt sensitivity, as estimated by Nt-proANP, was significantly less common in patients with type-2 diabetes compared to controls and concluded that other pathophysiological mechanisms than salt sensitivity might explain the increased prevalence of hypertension in type 2 diabetes. Even if hypertension and arteriosclerosis are important factors behind the development of heart disease in patients with diabetes, the mechanisms are probably more complex. Increased insulin resistance has been shown to have negative cardiac effects. Bearing this in mind, it would be rational that an insulin-sensitising drug would have favourable effects on cardiac performance. The Thiazolidinedions (TZD) are drugs that increase insulin sensitivity. In paper IV we studied the glycaemic and non-glycaemic effects of the TZD pioglitazone, as an additional treatment to metformin and sulfonylurea in patients with type-2 diabetes. The addition of pioglitazone treatment improved glycaemic control and peripheral insulin resistance, but caused elevated levels of Nt-proBNP, arguing for haemodynamical stress. This was most likely due to a sub clinical fluid retention in all patients treated, suggesting that patients eligible for TZD should be evaluated from their heart function and not from the fluid retention per se.