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Within the USA, between 1980 and 2005, the prevalence of diagnosed diabetes has increased in all age groups, with the age group 65-74 years having the highest prevalence. The treatment of type 2 diabetes mellitus (T2DM) in elderly people is made more difficult than in their younger counterparts, primarily owing to the impact of co-morbidities, complications and hypoglycaemia as well as technical difficulties with insulin injections. Accordingly, the treatment approach for elderly patients with T2DM may need to be modified to accommodate co-morbidities and illnesses associated with ageing. Risks associated with insulin therapy, particularly hypoglycaemia, have traditionally limited the use of insulin in this patient population. Insulin glargine is associated with a low risk of hypoglycaemia compared with neutral protamine Hagedorn insulin, for example, and could thus provide a treatment of choice for healthcare providers when considering the increasing prevalence of diabetes in the elderly population. A regimen based on insulin glargine plus oral agents provides clinicians with a tool to help meet therapeutic targets in this population without increasing risk of hypoglycaemia.

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OBJECTIVE: The purpose of this study was to compare the effect of two insulin therapies with respect to long-term complications in type 2 diabetes patients using the Diabetes Mellitus Model (DMM). The therapies under investigation were insulin glargine combined with the oral antidiabetic agents, glimepiride and metformin, (BOT = basal supported oral treatment) and premixed insulin (CT = conventional therapy). METHODS: The DMM predicts complications over a 10-year period using data from published studies. Particular interest is placed on the influence of HbA1c levels related to time. The simulations are based on 10,000 virtual patients taking BOT and CT and the clinical data are based on the results of the LAPTOP study (Lantus + Amaryl + metformin versus premixed insulin in patients with type 2 diabetes mellitus after failing oral treatment pathways) comparing BOT and CT for 24 weeks. The simulations were performed in patients aged 60 A+/- 9 years with type 2 diabetes in which the duration of disease had a baseline of 9 A+/- 7 years. Sensitivity analyses were carried out by changing the response rate of those on BOT, the age of patients and duration of diabetes. RESULTS: The overall relative risk reductions obtained with BOT versus CT for the base case are, 11% for the nervous and vascular systems, 7% for the renal system, 5% for ophthalmic disorders, 3% for the cardiovascular system and mortality and 6% for any kind of event after 10 years. The advantages of BOT were robust to all the changes in the sensitivity analyses. When compared with the base case, the best therapeutic effects were obtained in younger patients who had been diabetic for a shorter period. CONCLUSIONS: Using the DMM data from the LAPTOP study, simulations based on both therapies showed that the BOT regimen provides better glycemic control and reduction in HbA1c thereby leading to a reduction in the long-term complications of diabetes and mortality.

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INTRODUCTION: It has been suggested that atherosclerotic vascular disease is a chronic inflammatory process. The aim of this study was to investigate the importance of C-reactive protein (CRP) as a cardiovascular risk marker and predictor of death, as well as its relation to other factors of the metabolic syndrome in a cohort of type 2 diabetic patients at high risk of severe macrovascular complications. MATERIAL AND METHODS: 592 patients, aged 55 to 74 years (311 men, 281 women), with signs and symptoms of circulation deficits were examined by duplex ultrasound for suspected cerebrovascular and peripheral arterial disease and followed over a period of 5 years. At baseline, 292 patients of the total group had type 2 diabetes (49.3%). Ischemic heart disease was present in 40.2%, internal carotid stenosis in 21.9% and peripheral arterial disease in 39.7% of the subjects. RESULTS: During the observation period, 104 patients had died, 72 (69.2%) due to cardiovascular causes. Non-fatal myocardial infarction occurred in 39 patients (7.4%), non-fatal stroke in 70 patients (13.3%) and amputations because of gangrene were unavoidable in 24 patients (4.6%). In Cox regression analysis, CRP was the strongest predictor of death and cardiovascular death in the total cohort (RR 3.7 [95% CI 1.86-7.50] and 5.4 [2.13-13.76]), as well as in the type 2 diabetic subgroup (RR 3.3 [1.27-8.70] and 5.4 [1.44-20.0]). In contrast neither the traditional cardiovascular risk factors nor the data of diabetic metabolic control were able to improve prediction. CRP was correlated positively with plasma levels of triglycerides (r=0.19, p=0.002), C-peptide (r=0.21, p=0.004), postprandial glucose (r=0.17, p=0.009), albuminuria (r=0.16, p=0.020), and inversely with HDL cholesterol (r=-0.20, p=0.002) in type 2 diabetic patients. CONCLUSIONS: CRP seems to be a better predictor of death and cardiovascular events than traditional risk factors or parameters of metabolic control in type 2 diabetic patients at high risk for cardiovascular endpoints. Additionally, CRP is associated with several facets of the metabolic syndrome.

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AIM: The Bremen Diabetes Study is an observation study to characterise type 2 diabetic patients at high risk for death and cardiovascular complications by routine metabolic and cardiovascular tests. The aim of the present analysis was to evaluate the prediction of QTc interval prolongation and/or heart rate for cardiovascular mortality in comparison to traditional cardiovascular risk factors. METHODS: We followed 475 type 2 diabetic patients (age 55 - 75 years; 304 women, 171 men) from a defined residential area, seen in our clinic primarily for metabolic control. Patients with coexisting micro- or macroangiopathic complications were not excluded. Outcome data were obtained for 423 subjects. QT intervals were measured in a 12 lead ECG and corrected for heart rate with Fridericia's equation [QTc = QT/RR1/3]. RESULTS: During the 5 year observation period 57 patients (13.5 %) died due to cardiovascular causes. In multivariate analysis we found that QTc interval prolongation (p = 0.0008), elevated heart rate (p = 0.0001), serum creatinine (p = 0.0260), smoking (p = 0.0056) and peripheral arterial disease (p = 0.0127) at baseline were independent predictors for cardiovascular death. The odds ratio was 2.7 (95 % CI 1.07 - 4.11) for QTc interval prolongation (> 421 ms) and 3.3 (95 % CI 1.33 - 8.19) for elevated heart rate (> 75/min). CONCLUSION: Easily established ECG criteria such as prolonged QTc time and elevated heart rate obviously are powerful predictors of cardiovascular death in type 2 diabetic patients and are possibly superior to the traditional cardiovascular risk factors. As heart rate itself is an independent risk indicator, QTc time should be calculated by a formula (e.g. Fridericia's equation) that more accurately corrects QT for heart rate than the widely used Bazett's formula.

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AIMS/HYPOTHESIS: Islet autoantibodies precede the clinical onset of Type I (insulin-dependent) diabetes mellitus. The cumulative development of such autoantibodies in infants followed from birth and in particular infants with high-risk HLA genotypes is poorly defined, but such information is essential to design trials to prevent islet autoimmunity. METHODS: HLA genotypes were determined in offspring of parents with Type I diabetes who were followed from birth for at least 2 years (median follow-up: 3.1 years) and who were characterised for the expression of insulin, GAD65, IA-2 and islet cell autoantibodies at birth, 9 months, 2 and 5 years of age. RESULTS: The HLA genotypes DRB1*03/04(DQB1*57non-Asp) and DRB1*04/04(DQB1*57non-Asp) were present in 7.1% and 5.0% of offspring of parents with Type I diabetes. The frequency of both genotypes was increased in offspring who developed islet autoantibodies within the first 2 years of life (27.3% vs 5.5%, odds ratio 6.3 [p = 0.002] and 22.7% vs 4.2%, odds ratio 6.6 [p = 0.003]) and half of all offspring who developed antibodies had these genotypes. Other genotypes were not associated with an increase in risk. By life-table analysis, the cumulative risk of developing islet autoantibodies by the age of 2 years was 20% (95% CI 9.4,30.6) for offspring carrying either the DRB1*03104(DQB1*57non-Asp) or the DRB1*04/04(DQB1*57non-Asp) genotype compared with 2.7% (95% CI 1.2,4.2) for offspring without these genotypes (p < 0.0001). CONCLUSION/INTERPRETATION: These data show that early appearance of islet autoantibodies is remarkably frequent for DR3/4 heterozygous and DR4/4 homozygous offspring and indicate that primary prevention could be considered once available in an offspring cohort selected for these genotypes.

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Non-insulin-dependent diabetes mellitus is a major health problem in developed countries. The descriptive epidemiology of this disease and its cardiovascular complications are reviewed, and insulin resistance is identified as a common risk factor for both of them. The requirements for cost-effective programs to modify insulin resistance to prevent this disorder and its cardiovascular complications are discussed.

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Cardiovascular diseases are the major cause of morbidity and mortality in the diabetic patient. Acute myocardial infarction carries twice the mortality of that in the general population. Although in the thrombolytic era, in-hospital survival for both diabetic and non-diabetic patients have improved considerably, the overall case fatality rate due to out-of-hospital death is still more than 50%. Screening relates particularly to the systematic search for cardiovascular risk factors and asymptomatic atherosclerosis. The individual risk cannot exactly be described by the level of risk factors alone. Today, diagnosis of preclinical cardiovascular disease can identify the high risk patient for severe cardiovascular events. The presence of asymptomatic or 'preclinical' cardiovascular disease such as left ventricular hypertrophy, peripheral arterial vessel disease, carotid atherosclerosis, autonomic neuropathy, and renal dysfunction carries a markedly increased risk for symptomatic morbidity as well as cardiovascular mortality. The unfavorable connection between autonomic neuropathy and coronary heart disease risk has just recently been reported. Therefore, diabetic patients with existing cardiovascular disease should be investigated and managed as vigorously as is warranted by existing evidence.

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OBJECTIVE: To evaluate the association of antibodies to glutamic acid decarboxylase (GAD-ab) and diabetic complications (neuropathy, retinopathy, and nephropathy) in patients with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: We examined the prevalence of GAD-ab (immunoprecipitation assay) and islet cell antibodies (ICAs) (indirect immunofluorescence) in a representative sample of IDDM patients (n = 146) with different disease duration (2-52 years, median 13.2 years). Of all patients characterized for the existence of diabetic complications, 56 of 146 had peripheral neuropathy, 24 of 142 had autonomic neuropathy, 67 of 141 had retinopathy, and 39 of 146 had nephropathy. RESULTS: GAD-ab (> 2 SD) were detected more frequently than ICA (> 5 Juvenile Diabetes Foundation units) in IDDM patients of different disease duration (GAD-ab+ 37% [54 of 146] vs. ICA+ 22% [32 of 146], P = 0.011; diabetes duration less than median: GAD-ab+ 47% vs. ICA+ 23%, P = 0.0046; diabetes duration greater than median: GAD-ab+ 27% vs. ICA+ 22%, P > 0.05). For GAD-ab and for ICA, respectively, no difference was observed in frequency of positivity or titers between patients with or without diabetic complications. CONCLUSIONS: Both GAD-ab and, to a lesser extent, ICA persist for a long time in several individuals. This persistence is not related to diabetic neuropathy or any other diabetic complication.

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Several epidemiologic and clinical studies over the past years have shown that insulin resistance and hyperinsulinemia are related to dyslipidemia, hypertension, android obesity and non-insulin-dependent diabetes mellitus (NIDDM). The insulin-resistance syndrome is thus closely associated with a cluster of potent cardiovascular risk factors, thereby explaining the 3-4 times higher incidence of cardiovascular disease in NIDDM. Recent observations point to the fact that insulin resistance is genetically determined and can be diagnosed a long time before the clinical manifestation of diabetes mellitus in the prediabetic stage (stage of hyperinsulinemia, hypertension and hyperlipidemia). Hence, it is not surprising that many NIDDM subjects suffer from cardiovascular complications already at the time diabetes is diagnosed. The pathogenetic mechanism of insulin resistance/hyperinsulinemia as cardiovascular risk factor is considered to be a direct atherogenic action of insulin on vessel wall cells and an indirect effect on upper body obesity, blood pressure, lipids and hemostasis.

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Numerous surveys have shown that in industrial countries diabetic subjects develop hypertension more frequently than non-diabetic persons. In fact, three typical hypertension forms in these patients can be discerned: essential, renal, and isolated systolic hypertension. In type 2-diabetes (NIDDM) hypertension can be seen in close association with obesity, glucose intolerance, lipid changes, and insulin resistance within the framework of the metabolic syndrome. The increased incidence of hypertension in type 1-diabetes (IDDM) is a result of development of diabetic nephropathy. In the elderly type 2-diabetics particularly frequently isolated systolic hypertension is present which reflects increased arterial stiffness and loss of vascular distensibility. In hypertension progression of both macrovascular disease and microangiopathy is increased whereby interaction of hyperglycemia and hypertension seems to be the main risk factor. In most hypertensive diabetic patients drugs will be necessary to lower blood pressure in a therapeutical range. There are several effective substances available which should be prescribed individually according to the needs and accompanying conditions in these patients.

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Clinical and epidemiological findings over the last few years are increasingly pointing to a metabolic syndrome comprising major cardiovascular risk factors, which frequently characterizes type II diabetes and its preliminary stages. More recent studies have shown that insulin resistance is genetically determined and can be detected in a pre-diabetic stage long before diabetes mellitus becomes manifest. It is thus not surprising that a large percentage of patients with type II diabetes already have clear signs of arteriosclerosis at the time the diagnosis is made. The results of the Schwabing study II indicate a "point of no return" for the development of cardiovascular disease, which makes early and vigorous intervention involving all facets of the metabolic syndrome a matter of urgency.

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Several hormones such as 1,25-dihydroxy-vitamin D3 (1,25-(OH)2D3), alpha-MSH, or ACTH have been found to interact extensively with the immune system. In view of the immune-mediated nature of Type 1 (insulin-dependent) diabetes mellitus, 49 recently diagnosed diabetic patients were investigated in terms of serum 1,25-(OH)2D3-levels, 25-hydroxyvitamin D3(25-(OH)D3), alpha-MSH and ACTH, and compared with 42 healthy controls. A marked decrease of 1,25-(OH)2D3-levels was found at onset of Type 1 (insulin-dependent) diabetes compared to normal controls (39 +/- 2 vs 55 +/- 4 pg/ml, p less than 0.01). Grouping patients according to season (winter or summer) of diabetes onset and blood sampling, it was demonstrated that the decrease of 1,25-(OH)2D3 was primarily present during summer and due to a loss of the seasonal rhythm of this hormone observed in healthy controls (summer: patients vs controls 41 +/- 2 vs 63 +/- 4 pg/ml, p less than 0.001; winter: 37 +/- 3 vs 33 +/- 3 pg/ml, n.s.). Serum concentrations of 25-(OH)D3 were closely correlated with those of 1,25-(OH)2D3, both in controls (r = 0.55, p less than 0.002) and diabetic patients (r = 0.41, p less than 0.05), yielding a similar loss of seasonal variation also of this vitamin D3 metabolite in Type 1 (insulin-dependent) diabetic patients. No difference was found in the mean and median values of alpha-MSH and ACTH between IDDM patients and controls, although patients exhibited much higher variation of alpha-MSH levels than did controls.(ABSTRACT TRUNCATED AT 250 WORDS)

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In a randomized cross-over study the antihypertensive effects of nifedipine and the combination of co-dergocrine and nifedipine (Pontuc) respectively as well as the influence of both preparations on the glucose metabolism was tested in 22 hypertensive patients with diabetes type II over a period of 4 weeks. During treatment with the combination a significantly more pronounced blood pressure reduction was achieved compared to monotherapy with nifedipine, whereas the heart rate was significantly increased only by nifedipine. Both drugs--nifedipine and co-dergocrine/nifedipine--did not change the concentrations of glucose in the blood or urine or of HbA1.

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The antihypertensive and metabolic effects of the new long-acting angiotensin converting enzyme (ACE) inhibitor, ramipril (Hoe 498), were assessed in 21 patients with non-insulin-dependent diabetes mellitus (NIDDM) over a 12-week treatment period. In an average dose of 5 mg given once daily, ramipril effectively reduced the elevated blood pressure. In 74% of the cases systolic and diastolic blood pressure was normalised during monotherapy. Mean blood glucose and glycosylated hemoglobin (HbAI) values showed a slight but significant (p less than 0.05) decrease at the end of the ramipril treatment period (glucose: 8.5 +/- 1.4 mmol/l vs 8.0 +/- 0.9 mmol/l; HbAI: 10.0 +/- 1.3% vs 9.7 +/- 1.1%). C-peptide levels did not change. Since there was also a small reduction of body weight during treatment, the observed hypoglycemic response could not be fully ascribed to ramipril. Also, a reduction in total cholesterol and an increase of HDL cholesterol could be documented during treatment with ramipril. The reduction in body weight could also be made partly responsible for this positive effect on lipid metabolism. No serious side effects were reported during the entire study period. Due to these beneficial effects, ramipril can be recommended as first-line drug in the management of hypertensive subjects with NIDDM.

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