Is There Evidence That Oral Hypoglycemic Agents Reduce Cardiovascular Morbidity/Mortality? Yes

Athough type 2 diabetes is a heterogeneous condition encompassing multiple metabolic and vascular alterations, it can be easily described as a disease characterized by chronic hyperglycemia and increased cardiovascular (CV) risk. Hyperglycemia is the diagnostic criterion for diabetes, the target for antidiabetic therapy, and, together with A1C, the marker of glycemic control. Progressive worsening of glycemic control has been described in type 2 diabetic patients irrespective of initial form of treatment, leading the U.K. Prospective Diabetes Study (UKPDS) investigators to describe such changes as the “natural history” of the disease ( 1). Still, maintaining good glycemic control is crucial, since it is associated with marked reduction in the risk of developing retinopathy, nephropathy, and neuropathy in both type 1 ( 2) and type 2 diabetic patients ( 1). But it is CV disease that worsens long-term prognosis in type 2 diabetes ( 3), to the point that diabetes has been proposed as a CV risk equivalent owed to the observation that 10-year risk for major coronary events approximates the risk in CHD in patients without diabetes with previous CV events ( 4), increased case fatality rate after myocardial infarction, and worse overall prognosis after CHD ( 5). In diabetic patients, even after correction for known CV risk factors, the incidence of myocardial infarction or stroke is two- to threefold higher than in the nondiabetic population, with a twofold increase in risk of death ( 6), suggesting that some feature of diabetes must confer excessive propensity toward CV disease. Can this feature be hyperglycemia? No better issue can be chosen for debate. From an epidemiological point of view, there is evidence that the risk of CV mortality increases with the increase of plasma glucose concentrations ( 7) and A1C values ( 8). Moreover, multiple atherogenic mechanisms have been identified that can be activated by hyperglycemia ( 9)

Myocardial Infarction as a Presentation of Clinical In-Stent Restenosis

Abstract Background In-stent restenosis is considered to be a gradual and progressive condition and there is scant data on myocardial infarction (MI) as a clinical presentation. Methods and Results Of 2,462 consecutive patients who underwent percutaneous coronary intervention between June 2001 and December 2002, clinical in-stent restenosis occurred in 212 (8.6%), who were classified into 3 groups: ST elevation MI (STEMI), non-ST elevation MI (NSTEMI) and non-MI. Of the 212 patients presenting with clinical in-stent restenosis, 22 (10.4%) had MI (creatine kinase (CK) ≥2 × baseline with elevated CKMB). The remaining 190 (89.6%) patients had stable angina or evidence of ischemia by stress test without elevation of cardiac enzymes. Median interval between previous intervention and presentation for clinical in-stent restenosis was shorter for patients with MI than for non-MI patients (STEMI, 90 days; NSTEMI, 79 days; non-MI, 125 days; p=0.07). Diffuse in-stent restenosis was more frequent in MI patients than in non-MI patients (72.7% vs 56.3%; p<0.005). Renal failure was more prevalent in patients with MI than in those without MI (31.8% vs 6.3%, p=0.001). Compared with the non-MI group, patients with MI were more likely to have acute coronary syndromes at the time of index procedure (81.8% vs 56.8%, p=0.02). Conclusion Clinical in-stent restenosis can frequently present as MI and such patients are more likely to have an aggressive angiographic pattern of restenosis. Renal failure and acute coronary syndromes at the initial procedure are associated with MI. (Circ J 2006; 70: 1026 - 1029

Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: a randomised, controlled trial on thiazolidinedione-induced vascular leakage

Contains fulltext : 88447.pdf (publisher's version ) (Closed access)AIMS/HYPOTHESIS: The mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedione-induced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy. METHODS: We conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (or=2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume. RESULTS: Thirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (DeltaTERalb: rosiglitazone +2.43 +/- 0.45%/h, placebo -0.11 +/- 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation. CONCLUSIONS/INTERPRETATION: Rosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00422955. FUNDING: GlaxoSmithKline.1 september 201

The additional value of first pass myocardial perfusion imaging during peak dose of dobutamine stress cardiac MRI for the detection of myocardial ischemia

Purpose of this study was to assess the additional value of first pass myocardial perfusion imaging during peak dose of dobutamine stress Cardiac-MR (CMR). Dobutamine Stress CMR was performed in 115 patients with an inconclusive diagnosis of myocardial ischemia on a 1.5 T system (Magnetom Avanto, Siemens Medical Systems). Three short-axis cine and grid series were acquired during rest and at increasing doses of dobutamine (maximum 40 μg/kg/min). On peak dose dobutamine followed immediately by a first pass myocardial perfusion imaging sequence. Images were graded according to the sixteen-segment model, on a four point scale. Ninety-seven patients showed no New (Induced) Wall Motion Abnormalities (NWMA). Perfusion imaging showed absence of perfusion deficits in 67 of these patients (69%). Perfusion deficits attributable to known previous myocardial infarction were found in 30 patients (31%). Eighteen patients had NWMA, indicative for myocardial ischemia, of which 14 (78%) could be confirmed by a corresponding perfusion deficit. Four patients (22%) with NWMA did not have perfusion deficits. In these four patients NWMA were caused by a Left Bundle Branch Block (LBBB). They were free from cardiac events during the follow-up period (median 13.5 months; range 6–20). Addition of first-pass myocardial perfusion imaging during peak-dose dobutamine stress CMR can help to decide whether a NWMA is caused by myocardial ischemia or is due to an (inducible) LBBB, hereby preventing a false positive wall motion interpretation

Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure: A Consensus Statement from the American Heart Association and American Diabetes Association

"Diabetes is a chronic, progressively worsening disease associated with a variety of microvascular and macrovascular complications. Cardiovascular disease (CVD) is the main cause of death in these patients.1,2 During the past decade, numerous drugs have been introduced for the treatment of type 2 diabetes that, used in monotherapy or in combination therapy, are effective in lowering blood glucose to achieve glycemic goals and in reducing diabetes-related end-organ disease. Two such drugs, rosiglitazone and pioglitazone, belong to the class called thiazolidinediones (TZDs).3 Troglitazone, the first agent of this class to be approved, was effective in controlling glycemia but was removed from the market because of serious liver toxicity. Both rosiglitazone and pioglitazone are indicated either as monotherapy or in combination with a sulfonylurea, metformin, or insulin when diet, exercise, and a single agent do not result in adequate glycemic control4 (package insert Avandia [rosiglitazone maleate; GlaxoSmithKline] and Actos5 [pioglitazone hydrochloride; Takeda Pharmaceuticals]). In addition to lowering blood glucose, both drugs may benefit cardiovascular parameters, such as lipids, blood pressure, inflammatory biomarkers, endothelial function, and fibrinolytic status.6,7 These beneficial effects of TZDs on glycemia and cardiovascular risk factors have made them attractive agents in patients with type 2 diabetes who are at high risk for CVD. There is a growing recognition, however, that edema can occur in patients treated with either drug. Because people with diabetes are at increased risk for CVD and many have preexisting heart disease, the edema that sometimes accompanies the use of a TZD can be cause for concern, as it may be a harbinger or sign of congestive heart failure (CHF). An analysis of Medicare beneficiaries hospitalized with the diagnosis of diabetes and CHF indicated that the number of these patients discharged on TZDs had increased from 7.2% to 16.2% over a 3-year period.8 As the number of patients taking these drugs to control glycemia increases, practitioners should be aware of the safety profile of TZDs in patients with and without underlying heart disease.

Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure: A consensus statement from the American Heart Association and American Diabetes Association

"Diabetes is a chronic, progressively worsening disease associated with a variety of microvascular and macrovascular complications. Cardiovascular disease (CVD) is the main cause of death in these patients (1,2). During the past decade, numerous drugs have been introduced for the treatment of type 2 diabetes that, used in monotherapy or in combination therapy, are effective in lowering blood glucose to achieve glycemic goals and in reducing diabetes-related end-organ disease. Two such drugs, rosiglitazone and pioglitazone, belong to the class called thiazolidinediones (TZDs) (3). Troglitazone, the first agent of this class to be approved, was effective in controlling glycemia but was removed from the market because of serious liver toxicity. Both rosiglitazone and pioglitazone are indicated either as monotherapy or in combination with a sulfonylurea, metformin, or insulin when diet, exercise, and a single agent do not result in adequate glycemic control (4) (package insert Avandia [rosiglitazone maleate; GlaxoSmithKline] and Actos (5) [pioglitazone hydrochloride; Takeda Pharmaceuticals]). In addition to lowering blood glucose, both drugs may benefit cardiovascular parameters, such as lipids, blood pressure, inflammatory biomarkers, endothelial function, and fibrinolytic status (6,7). These beneficial effects of TZDs on glycemia and cardiovascular risk factors have made them attractive agents in patients with type 2 diabetes who are at high risk for CVD. There is a growing recognition, however, that edema can occur in patients treated with either drug. Because people with diabetes are at increased risk for CVD and many have preexisting heart disease, the edema that sometimes accompanies the use of a TZD can be cause for concern, as it may be a harbinger or sign of congestive heart failure (CHF). An analysis of Medicare beneficiaries hospitalized with the diagnosis of diabetes and CHF indicated that the number of these patients discharged on TZDs had increased from 7.2% to 16.2% over a 3-year period (8). As the number of patients taking these drugs to control glycemia increases, practitioners should be aware of the safety profile of TZDs in patients with and without underlying heart disease.

Transcriptome Alteration in the Diabetic Heart by Rosiglitazone: Implications for Cardiovascular Mortality

BACKGROUND: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse. METHODS AND FINDINGS: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes. CONCLUSIONS: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment