Biomedical subjects
Publications and source records attributed to Eberhard Standl.
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BACKGROUND: Type 2 diabetes mellitus is associated with increased cardiovascular risk. One laboratory marker for cardiovascular risk assessment is high-sensitivity C-reactive protein (hsCRP). METHODS: This cross-sectional study attempted to analyze the association of hsCRP levels with insulin resistance, beta-cell dysfunction and macrovascular disease in 4270 non-insulin-treated patients with type 2 diabetes [2146 male, 2124 female; mean age +/-SD, 63.9+/-11.1 years; body mass index (BMI) 30.1+/-5.5 kg/m(2); disease duration 5.4+/-5.6 years; hemoglobin A(1c) (HbA(1c)) 6.8+/-1.3%]. It consisted of a single morning visit with collection of a fasting blood sample. Observational parameters included several clinical scores and laboratory biomarkers. RESULTS: Stratification into cardiovascular risk groups according to hsCRP levels revealed that 934 patients had low risk (hsCRP <1 mg/L), 1369 patients had intermediate risk (hsCRP 1-3 mg/L), 1352 patients had high risk (hsCRP >3-10 mg/L), and 610 patients had unspecific hsCRP elevation (>10 mg/L). Increased hsCRP levels were associated with other indicators of diabetes-related cardiovascular risk (homeostatic model assessment, intact proinsulin, insulin, BMI, beta-cell dysfunction, all p<0.001), but showed no correlation with disease duration or glucose control. The majority of the patients were treated with diet (34.1%; hsCRP levels 2.85+/-2.39 mg/L) or metformin monotherapy (21.1%; 2.95+/-2.50 mg/L hsCRP). The highest hsCRP levels were observed in patients treated with sulfonylurea (17.0%; 3.00+/-2.43 mg/L). CONCLUSIONS: Our results indicate that hsCRP may be used as a cardiovascular risk marker in patients with type 2 diabetes mellitus and should be evaluated in further prospective studies.
BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.
BACKGROUND: The cross-sectional IRIS-II study tried to assess the prevalence of insulin resistance and macrovascular disease in orally treated patients with Type 2 diabetes. METHODS: In total, 4,270 patients were enrolled into the study (2,146 male, 2,124 female; mean +/- SD age 63.9 +/- 11.1 years; body mass index 30.1 +/- 5.5 kg/m2; duration of disease 5.4 +/- 5.6 years; hemoglobin A1c 6.8 +/- 1.3%). The study consisted of a single morning visit with completion of a standardized questionnaire and collection of a fasting blood sample. RESULTS: The mean intact proinsulin value was 11.4 +/- 12.4 pmol/L (normal range < 10 pmol/L). Homeostasis model assessment resulted in 1,147 insulin-sensitive patients (26.9%) and 3,123 patients (73.1%) with insulin resistance. Of the latter patients 1,465 (34.3% of all patients) had also elevated intact proinsulin values, while 1,658 (38.8%) had no proinsulin elevation. In contrast, 1,042 (24.4%) of the insulin-sensitive patients had normal intact proinsulin, and only 105 (2.4%) had elevated intact proinsulin concentrations (chi2 test P < 0.0001). A specificity of 93.2% (sensitivity 46.9%) was calculated for elevated intact proinsulin as an indirect marker for insulin resistance. Of the 1,451 patients treated with sulfonylurea 52% had elevated intact proinsulin values and increased prevalence of cardiovascular complications (odds ratio 1.45). CONCLUSION: Type 2 patients with elevated fasting intact proinsulin values can be regarded as being insulin resistant. The results confirm that fasting intact proinsulin is a suitable measure for beta-cell dysfunction and insulin resistance in type 2 diabetes and may be used to support therapeutic decisions.
Although graft and patient survival after solid organ transplantation have improved markedly in recent years, transplant recipients continue to experience an increased prevalence of cardiovascular disease (CVD) compared with the general population. A number of factors are known to impact on the increased risk of CVD in this population, including hypertension, dyslipidemia and diabetes mellitus. Of these factors, new-onset diabetes after transplantation has been identified as one of the most important, being associated with reduced graft function and patient survival, and increased risk of graft loss. In 2003, International Consensus Guidelines on New-onset Diabetes after Transplantation were published, which aimed to establish a precise definition and diagnosis of the condition and recommend management strategies to reduce its occurrence and impact. These updated 2004 guidelines, developed in consultation with the International Diabetes Federation (IDF), extend the recommendations of the previous guidelines and encompass new-onset diabetes after kidney, liver and heart transplantation. It is hoped that adoption of these management approaches pre- and post-transplant will reduce individuals' risk of developing new-onset diabetes after transplantation as well as ameliorating the long-term impact of this serious complication.
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BACKGROUND AND AIM: There is scintigraphic evidence that insulin improves cardiac autonomic innervation in diabetic patients. The aim of the study was to assess the effects of insulin therapy on parameters of cardiac reflex tests in type 2 diabetic patients. PATIENTS AND METHODS: 30 type 2 diabetic patients with an HbA(1c) of > 7.5% under oral antidiabetic agents were included into the 4-month follow-up. Insulin therapy was performed according to standardized clinical guidelines. Parameters of five cardiac reflex tests were assessed to study cardiac autonomic function: Coefficient of variation (CV) of heart rate variation (HRV) at rest and during deep breathing, HRV in response to standing (max./min. 30:15-ratio), Valsalva ratio, systolic blood pressure response (> 1 test abnormal = cardiac autonomic neuropathy [CAN]). QT(QTc)-interval was also assessed in the patients. RESULTS: At 4-months follow-up, mean insulin dosage in the patients was 25 +/- 8 IU/day. HbA(1c) was decreased from 9,2 +/- 0,7 to 7.2 +/- 0.6 % (p < 0.001). Three parameters of cardiac autonomic function were significantly improved: CV of HRV at rest 2.79 +/- 0.84 versus 2.96 +/- 0.85 (p < 0,001), CV of HRV during deep breathing 4.15 +/- 1.46 versus 4.38 +/- 1.68 (p = 0.002), 30:15 ratio 1.06 +/- 0.05 versus 1.09 +/- 0.04 (p < 0.05). Length of QTc- Interval changed significantly from 417 +/- 12 ms at month 0 to 398 +/- 11 ms at month 4 (p<0.05). CONCLUSIONS: The study demonstrates that insulin therapy with regular insulin optimizes cardiac autonomic function in type 2 diabetes mellitus. It emphasizes the value of cardiac reflex tests with regard to follow-up of cardiac autonomic function in diabetes.
Atherogenesis is characterized by a chronic process, which commences years before diabetes mellitus becomes overt. Each step of the pathogenetic cascade is accompanied by inflammation. The degree of inflammation is a key determinant for the process of atherogenesis. C-reactive protein is elevated by inflammatory processes, correlates with the atherosclerotic prognosis and is therefore an important marker of inflammation. It denotes early cardiovascular damages and is elevated in acute coronary syndromes. Cardiovascular risk is excessively elevated in diabetic patients and inflammatory mechanisms are predominant in this group. Preventive interventions and therapeutic strategies based on pathophysiological processes are necessary. The importance of treatment of inflammation increases. Glitazones have been demonstrated to act via antiinflammatory effects. They do not only improve glucose utilisation, but also have pleiotropic effects, which target the increased cardiovascular risks in diabetic patients.
AIM: The objective behind the Euro Heart Survey on diabetes and the heart was to study the prevalence of abnormal glucose regulation in adult patients with coronary artery disease (CAD). METHODS AND RESULTS: The survey engaged 110 centres in 25 countries recruiting 4196 patients referred to a cardiologist due to CAD out of whom 2107 were admitted on an acute basis and 2854 had an elective consultation. Patient data were collected via a web-based case record form. An oral glucose tolerance test (OGTT) was used for the characterisation of the glucose metabolism. Thirty-one per cent of the patients had diabetes. An OGTT was performed on the 1920 patients without known diabetes, of whom 923 had acute and 997 had a stable manifestation of CAD, respectively. In patients with acute CAD, 36% had impaired glucose regulation and 22% newly detected diabetes. In the stable group these proportions were 37% and 14%. CONCLUSION: This survey demonstrates that normal glucose regulation is less common than abnormal glucose regulation in patients with CAD. OGTT easily discloses the glucometabolic state and should be a routine procedure. The knowledge of glucometabolic state among these patients should influence their future management because it has great potential to improve the outcome.
BACKGROUND: This trial compared the long-term safety and efficacy of the basal insulin preparations, insulin detemir and NPH insulin, in basal-bolus therapy for patients with type 1 diabetes. METHODS: This multinational open, parallel-group trial randomized patients to receive insulin detemir or NPH insulin twice daily in addition to mealtime human soluble insulin. Doses were titrated towards predefined glycemic targets. After an initial 6-month treatment period, patients were invited to participate in a 6-month extension period. A total of 289 from 421 elected to continue in the trial, of which 252 completed. RESULTS: Glycemic control as assessed by hemoglobin A1c (insulin detemir, 7.88%; NPH insulin, 7.78%; difference not significant) and fasting plasma glucose (insulin detemir, 10.1 mmol/L; NPH insulin, 9.84 mmol/L; difference not significant) was similar in both treatment groups at end point, with hemoglobin A1c little changed from baseline and fasting plasma glucose slightly decreased. There was some evidence for a risk reduction for hypoglycemia in association with insulin detemir, although this was not statistically significant (relative risk overall hypoglycemia, 0.71, P = 0.139; relative risk nocturnal hypoglycemia, 0.71, P = 0.067), and hypoglycemic events were fewer in each of the 12 months. There was a significant treatment difference with regard to weight outcome; NPH insulin was associated with weight gain (1.4 kg), but there was no mean weight gain (-0.3 kg) in the insulin detemir cohort (baseline-adjusted between-group difference at 12 months, 1.66 kg, P = 0.002). There were no obvious between-group differences in other safety parameters. CONCLUSIONS: Glycemic control is maintained with insulin detemir during long-term treatment. At equivalent glycemic control to NPH insulin, insulin detemir is associated with a lack of weight gain and a trend towards a reduced risk of nocturnal hypoglycemia when used in basal-bolus therapy with mealtime soluble human insulin.
OBJECTIVE: This study was performed to compare the specificity and sensitivity of intact proinsulin, adiponectin, and their ratio (proinsulin/adiponectin) in the prediction of insulin resistance as assessed by the homeostasis model assessment (HOMA) score (> or =2 = resistant). RESEARCH DESIGN AND METHODS: Using a cross-sectional approach, 500 orally treated patients with type 2 diabetes (272 women, 238 men; mean +/- SD age, 64.8 +/- 11.6 years; hemoglobin A1c, 7.0 +/- 1.5%; disease duration, 5.8 +/- 6.1 years) were investigated. Various cutoffs for body mass index-adjusted adiponectin and proinsulin/adiponectin were compared with the established cutoff value of 10 pmol/L for fasting proinsulin. RESULTS: Fasting proinsulin correlated more closely with the HOMA score (r = 0.560, P < 0.001) than fasting adiponectin (r = -0.204, P < 0.001) or proinsulin/adiponectin (r = 0.355, P < 0.001). For proinsulin, specificity and sensitivity for insulin resistance in correlation to the HOMA score results were 96% and 70%, respectively. At a comparable specificity level to proinsulin, adiponectin did not reach a comparable sensitivity (14%), while the proinsulin/adiponectin ratio almost reached the same sensitivity (65%). Overall, patients with elevated proinsulin had a higher prevalence of micro- and macrovascular disease [odds ratio 1.47 (adiponectin, 1.08; proinsulin/ adiponectin, 1.48) and 1.34 (adiponectin, 1.32; proinsulin/adiponectin, 1.27), respectively]. CONCLUSIONS: Elevation of fasting intact proinsulin seems to be the more specific marker for insulin resistance and increased cardiovascular risk than suppression of fasting adiponectin. Formation of the ratio does not lead to a further increase in the predictive value.
OBJECTIVE: To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment. RESEARCH DESIGN AND METHODS: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year. Placebo (n=51) or LAF237 (50 mg once daily, n=56) was added to ongoing metformin treatment (1,500-3,000 mg/day). HbA1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week 12, and week 52. RESULTS: In patients randomized to LAF237, baseline HbA1c averaged 7.7 +/- 0.1% and decreased at week 12 (Delta=-0.6 +/- 0.1%), whereas HbA1c did not change from a baseline of 7.9 +/- 0.1% in patients given placebo (between-group difference in DeltaHbA1c=-0.7 +/- 0.1%, P <0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 +/- 0.4 mmol/l (P <0.0001) and 1.2 +/- 0.4 mmol/l (P=0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences in change in mean prandial glucose, insulin, and FPG were -2.4 +/- 0.6 mmol/l (P=0.0001), 40 +/- 16 pmol/l (P=0.0153), and -1.1 +/- 0.5 mmol/l (P=0.0312), respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n=42) but increased in participants given placebo (n=29). The between-group difference in DeltaHbA1c after 1 year was -1.1 +/- 0.2% (P <0.0001). CONCLUSIONS: Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin monotherapy in type 2 diabetes.
OBJECTIVE: The myocardial infarction (MI) registry of the Academic Schwabing Hospital, Munich, investigates the hospital course of diabetic and nondiabetic patients with acute MI. The aim of this study was to improve quality care management and to compare hospital mortality and therapeutic approaches (i.e., PTCA, stenting, GPIIb/IIIa receptor antagonists, glucose-insulin infusion). RESEARCH DESIGN AND METHODS: Data of diabetic patients and nondiabetic patients were analyzed. All diabetic and nondiabetic subjects who were admitted in 1999 and 2001 were included: 1999, 126 (38%) diabetic and 204 (62%) nondiabetic patients; 2001, 91 (31%) diabetic and 205 (59%) nondiabetic patients. RESULTS: In 1999, coronary angiography (P < 0.01), percutaneous transluminal coronary angioplasty (PTCA) (P < 0.001), and stenting (P < 0.001) were performed less frequently in diabetic than in nondiabetic patients. During this period, total hospital mortality (29 vs. 16%, P < 0.01) and mortality within 24 h after admission (14 vs. 5%, P = 0.01) were higher in diabetic than in nondiabetic patients. In 2001, frequencies of coronary angiography, PTCA, and stenting were increased in diabetic patients (P < 0.001 vs. 1999), and the interventions were comparable with those performed in nondiabetic patients. Furthermore, glucose-insulin infusion was administered in 46% of diabetic subjects. In 2001, total hospital mortality decreased to 17% in diabetic subjects (P = 0.028 vs. 1999) and mortality within 24 h after admission declined to 4% (P = 0.027 vs. 1999). Logistic regression analysis revealed that an increase in the number of therapeutic approaches (also when adjusted for clinical variables) is associated with a reduction in mortality of diabetic patients with acute MI (adjusted odds ratio 0.14, P < 0.0001). CONCLUSIONS: Intensification of multiple advanced therapeutic strategies in diabetic patients with acute MI enables a substantial reduction in hospital mortality. The enforcement leads to rates of hospital mortality that are comparable to those of nondiabetic patients.
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In diabetic patients, a number of studies have suggested an impairment of vascular reactivity in response to vasodilatory stimuli. The pattern of dysregulation at the coronary microcirculatory level, however, has not been clearly defined. Thus, it was the aim of this study to characterise coronary microvascular function non-invasively in a homogeneous group of asymptomatic type 2 diabetic patients. In 46 patients with type 2 diabetes, myocardial blood flow (MBF) was quantified at baseline, in response to cold pressor test (CPT) and during adenosine-mediated vasodilation using positron emission tomography and nitrogen-13 ammonia. None of the patients had been treated with insulin, and none had symptoms of cardiac disease. Decreased MBF during CPT, indicating microvascular dysregulation, was observed in 16 patients (CPT-), while 30 patients demonstrated increased MBF during CPT (CPT+). Response to CPT was mildly, but significantly correlated with response to adenosine ( r=0.44, P=0.0035). There was no difference in HbA1c, serum lipid levels or serum endothelial markers between the groups. Microvascular dysregulation in the CPT- group was associated with elevated baseline MBF ( P<0.0001), reduced baseline vascular resistance ( P=0.0026) and an abnormal increase in resistance during CPT ( P=0.0002). In conclusion, coronary microvascular dysregulation is present in approximately one-third of asymptomatic, non-insulin-treated type 2 diabetic patients. Elevated baseline blood flow and reduced microvascular resistance at rest are characteristics of this dysregulation. These data suggest a state of activation of endothelial-dependent vasodilation at baseline which appears to limit the flow response to stress conditions.