Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND:Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.RESULTS:During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

[Diabetes mellitus and heart failure]. / Hohe Inzidenz, schlechte Prognose. Herzinsuffizienz bei Diabetikern.

Chronic heart failure (CHF) in patients with diabetes mellitus (DM) is a condition that is frequent and has a poor prognosis. Diabetes mellitus is an independent risk factor for CHF and vice versa. CHF is found in 10-15% of the patients with DM compared to 3% in individuals without DM. Apart from CHD and hypertension, hyperglycaemia and insulin resistance are directly linked to the development of diastolic dysfunction and to CHF. According to the stepwise diagnostic procedure recommended by the ESC in its guidelines from 2005, if heart failure is suspected, the disease should first be diagnosed by ECG, X-ray, or testing for natriuretic peptide and followed by echocardiography when test results are abnormal. Treatment of CHF in patients with diabetes mellitus is the same as that for nondiabetic patients and includes the use of ACEIs, ARBSs (as an alternative to or in combination with ACEIs), BBs, diuretics (in particular loop diuretics), aldosterone inhibitors and digitalis. Most importantly, meticulous glucose control is a must in patients with diabetes mellitus and CHF to improve prognosis. Contraindications for antidiabetic drugs such as glitazones for CHF-NYHA classes I-IV and metformin for NYHA classes III-IV need to be considered in patients with CHF and diabetes mellitus.

Acarbose and metabolic control in patients with type 2 diabetes with newly initiated insulin therapy.

AIM: This study was designed to investigate the effect of acarbose in patients with type 2 diabetes with newly initiated insulin treatment who had previously been insufficiently controlled with oral antihyperglycaemic agents [haemoglobin A(1c) (HbA(1c)) >/= 8%]. METHODS: In this 20-week double-blind, placebo-controlled study, 163 patients were randomized to receive acarbose up to 100 mg three times a day or matching placebo. Both the groups were newly initiated with insulin, which was adjusted according to blood glucose values. Primary efficacy parameter was the change in HbA(1c) from baseline; changes in daily insulin doses were also assessed. RESULTS: Mean HbA(1c) was significantly reduced by acarbose compared with placebo (2.31 vs. 1.81%, p = 0.033). Insulin doses were comparable at the end of the study. There was no difference in blood glucose and triglyceride levels between the treatment groups. Postprandial serum insulin levels increased in both treatment arms owing to insulin administration but less so under acarbose. In contrast to the placebo group, an increase in body mass index was prevented for acarbose-treated patients. CONCLUSION: As adjunct administration to newly initiated insulin therapy, acarbose enhances the optimization of blood glucose control in patients with type 2 diabetes.

Chromium in metabolic and cardiovascular disease.

Chromium is an essential mineral that appears to have a beneficial role in the regulation of insulin action, metabolic syndrome, and cardiovascular disease. There is growing evidence that chromium may facilitate insulin signaling and chromium supplementation therefore may improve systemic insulin sensitivity. Tissue chromium levels of subjects with diabetes are lower than those of normal control subjects, and a correlation exists between low circulating levels of chromium and the incidence of type 2 diabetes. Controversy still exists as to the need for chromium supplementation. However, supplementation with chromium picolinate, a stable and highly bioavailable form of chromium, has been shown to reduce insulin resistance and to help reduce the risk of cardiovascular disease and type 2 diabetes. Since chromium supplementation is a safe treatment, further research is necessary to resolve the confounding data. The existing data suggest to concentrate future studies on certain forms as chromium picolinate and doses as at least 200 mcg per day.

The importance of beta-cell management in type 2 diabetes.

Despite intervention with effective oral glucose-lowering agents, most patients with type 2 diabetes will experience a gradual loss of glycaemic control. Irrespective of underlying levels of insulin resistance, the progressive failure and loss of beta-cells are ultimately responsible for the onset of frank type 2 diabetes. The mechanisms responsible for loss of beta-cell function are likely to be multifactorial, but may involve toxicity because of elevated glucose and/or lipid levels, increased secretory demand because of insulin resistance, amyloid deposition and altered levels of cytokines. Preservation of beta-cell function is now gaining recognition as a critical target in the management of type 2 diabetes. For patients with frank type 2 diabetes, preservation of beta-cell function has the potential to reduce or stabilise the progression of type 2 diabetes and to decrease the need for additional oral glucose-lowering agents and/or insulin therapy. There is a growing body of animal/preclinical evidence for improved and preserved beta-cell function with current glucose-lowering agents, such as the thiazolidinediones, metformin and the glucagon-like peptide-1 analogue, exenatide. Clinical studies incorporating indirect measures of beta-cell function also support a protective effect with some agents. A number of novel therapies that are currently under investigation may also offer beta-cell structural and functional protection, including dipeptidyl peptidase IV inhibitors and cannabinoid receptor type 1 blockers. Emerging evidence from interventional trials suggests that both intensive lifestyle changes and pharmacotherapy can delay or possibly prevent the onset of type 2 diabetes in high-risk individuals. For patients newly diagnosed with type 2 diabetes, early and aggressive intervention strategies that combine maximal glucose-lowering efficacy alongside potential beta-cell preserving properties may provide an opportunity to delay or prevent progression of the disease.

Two Caucasian families with the hepatocyte nuclear factor-1alpha mutation Tyr218Cys.

We report on the first two Caucasian families with the MODY3 HNF-1alpha mutation Tyr218Cys. Clinical and laboratory examinations are shown in detail. Patients with HNF-1alpha related MODY may develop the full spectrum of diabetic complications. Therefore, early detection of family members with MODY3 is warranted.

Oral glucose tolerance test is needed for appropriate classification of glucose regulation in patients with coronary artery disease: a report from the Euro Heart Survey on Diabetes and the Heart.

BACKGROUND: Patients with coronary artery disease (CAD) and abnormal glucose regulation (AGR) are at high risk for subsequent cardiovascular events, underlining the importance of accurate glucometabolic assessment in clinical practice. OBJECTIVE: To investigate different methods to identify glucose disturbances among patients with acute and stable coronary heart disease. METHODS: Consecutive patients referred to cardiologists were prospectively enrolled at 110 centres in 25 countries (n = 4961). Fasting plasma glucose (FPG) and glycaemia 2 h after a 75-g glucose load were requested in patients without known glucose abnormalities (n = 3362). Glucose metabolism was classified according to the World Health Organization and American Diabetes Association (ADA; 1997, 2004) criteria as normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. RESULTS: Data on FPG and 2-h post-load glycaemia were available for 1867 patients, of whom 870 (47%) had normal glucose regulation, 87 (5%) had IFG, 591 (32%) had IGT and 319 (17%) had diabetes. If classification had been based on the ADA criterion from 1997, the proportion of misclassified (underdiagnosed) patients would have been 39%. The ADA 2004 criterion would have overdiagnosed 8% and underdiagnosed 33% of the patients, resulting in a total misclassification rate of 41%. For ethical concerns and practical reasons, oral glucose tolerance test (OGTT) was not conducted in 1495 of eligible patients. These patients were more often women, had higher age and waist circumference, and were therefore more likely to have AGR than those who were included. A model based on easily available clinical and laboratory variables, including FPG, high-density lipoprotein cholesterol, age and the logarithm of glycated haemoglobin A1c, misclassified 44% of the patients, of whom 18% were overdiagnosed and 26% were underdiagnosed. CONCLUSION: An OGTT is still the most appropriate method for the clinical assessment of glucometabolic status in patients with coronary heart disease.

Rosiglitazone is effective and well-tolerated in a range of therapeutic regimens during daily practice in patients with type 2 diabetes.

Subjects (N = 22,808) with inadequately controlled type 2 diabetes mellitus (T2DM) were included in a large 6-month observational study in Germany. Rosiglitazone (RSG) was added to existing therapy in line with daily practice, with 19,962 subjects evaluated for efficacy by treatment group: RSG monotherapy (n = 1017), RSG plus metformin (MET) (n = 7160), RSG plus sulphonylurea (n = 5033), triple oral therapy (n = 4247), and the remaining subject population (n = 2505). Overall, RSG significantly reduced median HbA(1c) and fasting blood glucose by 1.3% and 50 mg/dl over 6 months (p < 0.001 for both). The proportion of subjects achieving glycaemic goals of

Once-daily insulin glargine administration in the morning compared to bedtime in combination with morning glimepiride in patients with type 2 diabetes: an assessment of treatment flexibility.

AIMS: To compare the incidence of nocturnal hypoglycemia and glycemic control following bedtime or morning insulin glargine (LANTUS; glargine) plus glimepiride. METHODS: In this 24-week, multinational, open, randomized study, 624 patients with type 2 diabetes poorly controlled on oral therapy received morning or bedtime glargine plus morning glimepiride (2, 3 or 4 mg) titrated to a target fasting blood glucose level < or = 5.5 mmol/l. RESULTS: The incidence of nocturnal hypoglycemia was equivalent between the two groups, with morning glargine non-inferior to bedtime (13.0 VS. 14.9 % of patients; between-treatment difference -1.9 %; one-sided 95 % confidence interval -100 %; 2.84 %). At endpoint, similar improvements in glycemic control were observed with morning compared to bedtime glargine: HbA1c: -1.65 +/- 1.21 VS. -1.57 +/- 1.16 %; p = 0.42; fasting blood glucose: -4.25 +/- 2.82 VS. -4.48 +/- 2.75 mmol/l; p = 0.08. The endpoint mean daily glargine dose was comparable (34.7 +/- 17.4 VS. 32.4 +/- 17.0 IU; p = 0.15), and there was no significant between-treatment difference in the change in body weight (2.1 VS. 1.8 kg; p = 0.39). CONCLUSIONS: Once-daily glargine can be administered in a flexible morning or bedtime regimen (plus morning glimepiride) to achieve good glycemic control without any difference in hypoglycemia.

[62 year-old patient with rapid progressive edema, low potassium and hypertension]. / Hypertonie, Hypokaliämie und rasch progrediente Odeme bei einem 62-jährigem Diabetiker.

A 62 year-old patient was admitted to hospital with rapid progressive edema, low potassium and hypertension. This symptoms are caused by Cushing's syndrome through ectopic paraneoplastic ACTH-production. Primary neoplasm is a small cell cancer. A Sertoli-cell-tumor of the testis was diagnosed as an additional carcinoma. Palliative chemotherapy and adrenostatic agents did not improve the clinical findings and the patient died eight weeks after admission.

Effects of nateglinide on myocardial microvascular reactivity in Type 2 diabetes mellitus--a randomized study using positron emission tomography.

AIMS: To evaluate effects of the oral antidiabetic insulinotropic agent nateglinide on myocardial blood flow (MBF) and microvascular reactivity in Type 2 diabetic patients. METHODS: Forty-seven Type 2 diabetic patients were randomly assigned 2 : 1 to nateglinide 120 mg (t.i.d., n = 33) or placebo (n = 14). At baseline and after 16 weeks of treatment, MBF was quantified using positron emission tomography with N-13 ammonia at rest, during endothelial-dependent stimulation by cold pressor test and during adenosine-mediated vasodilation. Additional blood samples were taken to assess glycaemic control and lipid profile. RESULTS: MBF at rest and during adenosine did not change during the study. The percentage of flow increase from rest during cold pressor test did not improve significantly in the nateglinide group vs. placebo (from 26.1 +/- 37.2% to 29.1 +/- 27.8% between week 0 to week 16 for nateglinide vs. 14.9 +/- 37.1% to 18.1 +/- 28.4% for placebo; P = 0.07 for nateglinide when adjusted for higher baseline values). Nateglinide decreased HbA1c by 0.4% (from 7.6 +/- 0.9% to 7.2 +/- 1.3%) compared to an increase of 0.5% in the placebo group (from 7.9 +/- 0.8% to 8.4 +/- 1.7%; P = 0.02 for nateglinide). No differences between the two groups were observed in insulin levels and lipid status. CONCLUSIONS: Nateglinide neither improved, nor impaired myocardial blood flow in Type 2 diabetic patients. Potential effects on endothelial-dependent myocardial blood flow remain to be investigated further. Positron emission tomography is a sensitive approach to assess the effects of therapeutic agents on myocardial blood flow in patients with diabetes.

Coronary calcification in long-term type 1 diabetic patients -- a study with multi slice spiral computed tomography.

The risk for cardiovascular disease in diabetes is excessive. Multislice spiral computed tomography (MSCT) is a new technique for the assessment of coronary calcification in coronary artery disease. The aim of the study was to evaluate the presence of coronary calcium in asymptomatic long-term type 1 diabetic patients. Seventy-one type 1 diabetic patients (age 48 +/- 9 y, HbA1c 7.7 +/- 1.2, BMI 24.4 +/- 2.8, duration of diabetes 26 +/- 9 y) without clinical evidence for coronary artery disease were assessed with MSCT. A volumetric score was used to calculate the coronary calcification (CC) score. Five cardiac reflex tests were performed to study patients for cardiac autonomic neuropathy. Coronary calcifications were detectable in 22 (31 %) type 1 diabetic patients (CC-score > 0, mean CC-score 174 +/- 228 [X+/-SD]). Fourty-nine (69 %) type 1 diabetic patients demonstrated no coronary calcifications (CC-score= 0). In patients with coronary calcifications, both cardiac autonomic neuropathy and retinopathy were detected more frequently than in those without (64 % vs. 29 %, p < 0.02; 59 % vs. 31 %; p < 0.02). Duration of diabetes was longer in patients with than without coronary calcification (32 +/- 10 y vs. 24 +/- 8 y, p < 0.01). Age, BMI, and HbA1c were not significantly different between patients with and without coronary calcification. The study demonstrates that nearly one third of asymptomatic long-term type 1 diabetic patients present with coronary calcifications. In the patients, there is evidence for an association between coronary calcification and both cardiac autonomic neuropathy and retinopathy. MSCT is a promising non-invasive approach to analyze early alterations of the coronary system in diabetic patients.

[Cardiovascular risk in diabetes--diagnostic and therapeutic aspects]. / Infarktmortalität erheblich unterschätzt. Die Achillesferse des Diabetikers ist das Herz.

In Germany, more than 27,000 diabetic patients suffer an acute myocardial infarction annually; in addition, the number of cardiac infarction patients with unrecognized permanent disturbances of the glucose metabolism is high. The cardiovascular mortality of diabetics in comparison with nondiabetics is four to six times higher. Through an intensification of diagnostics and therapy, it is possible to reduce the hospital mortality of diabetics with acute myocardial infarction. For each patient with myocardial infarction and for whom diabetes has not been previously diagnosed, it is recommended that the blood sugar be tested upon admission to the hospital and that an oral glucose tolerance test be conducted for the detection of a glucose metabolic disorder during the postinfarction phase. An example of a successful approach for metabolic intervention is glucose-insulin infusion to optimize the metabolic condition during the acute phase.

Gliclazide modified release: results of a 2-year study in patients with type 2 diabetes.

AIM: To evaluate the efficacy and safety of gliclazide modified release (MR), alone or combined with other oral antidiabetic drug(s) over 2 years in type 2 diabetic patients. METHODS: Two consecutive periods: (i) a 10-month, double-blind comparative study, where 800 type 2 diabetic patients were randomized either to gliclazide MR (30-120 mg) once daily or to gliclazide (80-320 mg) twice daily. All the patients were then treated with gliclazide MR for a 2-month switch period; (ii) 549 patients were subsequently enrolled in a 12-month, open-label period on gliclazide MR alone or in combination according to glycaemic control, 507 of whom completed the study. RESULTS: Glycated haemoglobin (HbA1c) significantly decreased from baseline over 2 years by -0.46 +/- 1.08% in the whole cohort of 2-year completed patients, -0.95% in the subgroup of diet-failed patients and by -0.34% in the subgroup of patients pretreated with one oral antidiabetic drug. HbA1c was reduced by -0.43 +/- 1.02% and by -0.51 +/- 1.16%, when gliclazide MR was used in monotherapy and in combination therapy, respectively. The overall incidence of symptoms suggestive of hypoglycaemia was 4.8 episodes/100 patient-year, with no severe episode. This incidence was similarly low in elderly patients and patients with impaired renal function. CONCLUSION: Gliclazide MR alone or in combination with another oral antidiabetic drug significantly improved glycaemic control in type 2 diabetic patients over 2 years with a very good safety profile, notably in the elderly and in patients with impaired renal function.

IRIS II study: the IRIS II score--assessment of a new clinical algorithm for the classification of insulin resistance in patients with Type 2 diabetes.

AIMS: With the increasing availability of new drugs for the treatment of insulin resistance in patients with Type 2 diabetes, simple methods for their identification is an important challenge. The aim of our study was to compute a new algorithm for estimating insulin resistance in a routine clinical setting. METHODS: Clinical data and blood samples were collected from 4265 Type 2 diabetic patients from 149 clinical sites. A clinical algorithm to estimate insulin resistance was developed by stepwise multiple regression analysis. The new generated score was compared with the HOMAIR-score, calculated from fasting insulin and glucose levels measured in a central laboratory. In a subgroup of 48 patients, the score was verified against a frequently sampled intravenous glucose tolerance test with subsequent modified minimal model analysis according to Bergman. RESULTS: Multiple regression analysis revealed fasting blood glucose, BMI, triglycerides and HDL as the most powerful predictors of insulin resistance which were used for further computation of the IRIS II score. A significant overall correlation was found between the HOMAIR-score and the new clinical IRIS II score (r = 0.42; P < 0.0001). Compared with HOMAIR, the new score revealed a specificity of 0.95, a sensitivity of 0.34 and a positive predictive value of 0.95. This was in good agreement with the subset analysis of the intravenous glucose tolerance test, where a sensitivity of 0.37 and a specificity of 0.85 of the IRIS II score was calculated. Patients with insulin resistance according to the IRIS II score revealed an increased odds ratio for overall vascular complications (1.28; 1.11-1.46; P < 0.001). CONCLUSIONS: The new IRIS II score can identify insulin resistance in Type 2 diabetic patients with high predictive value and high specificity.

Hospital outcome of acute myocardial infarction in patients with and without diabetes mellitus.

AIMS: To assess hospital mortality and morbidity in diabetic and non-diabetic patients with acute myocardial infarction and to compare the results between the two groups. METHODS: All patients admitted in 1999 to the intensive care unit of the Schwabing City Hospital with diagnosis of acute myocardial infarction were assessed for hospital mortality and co-morbidity. RESULTS: Three hundred and thirty patients with acute myocardial infarction were admitted. Of those, 126 (38%) were diabetic and 204 (62%) were non-diabetic patients. Mortality within 24 h after admission was 13.5% in diabetic patients and 5.4% in non-diabetic patients (P<0.01). Mortality during entire hospitalization was higher in diabetic than in non-diabetic patients (29.4% vs. 16.2%; P=0.004). Diabetic patients were resuscitated more frequently than non-diabetic patients (24% vs. 11%, P<0.01). In diabetic patients, heart rate at admission was increased (91 +/- 27 vs. 82 +/- 23/min; P<0.01) and presence of angina pectoris was reported less frequently (59% (n=72) vs. 82% (n=167); P<0.001). Preceding myocardial infarction, microalbuminuria, peripheral artery disease and arterial hypertension were more frequent in diabetic than in non-diabetic patients. Diabetic patients demonstrated higher C-reactive protein (CRP) levels than non-diabetic patients (91.4 +/- 78.2 mg/l vs. 45.2 +/- 62.4 mg/l; P<0.001). CONCLUSIONS: In diabetic patients with acute myocardial infarction, early hospital mortality is increased and signs of cardiac autonomic dysfunction and microangiopathy are detected more frequently than in non-diabetic patients. The need for advanced treatment strategies early in the course of diabetic patients with myocardial infarction is emphasized.