Robert Chilton

Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes

To determine the effects of empagliflozin on blood pressure (BP) and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes mellitus (T2DM).

SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study

Although cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. Although sodium–glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin’s metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization. In this Perspective, we will discuss possible mechanisms for these beneficial effects of empagliflozin and their implications for the care of T2DM patients.

The Cardiovascular Effects of GLP-1 Receptor Agonists

Glucagon-like peptide-1 receptor (GLP-1R) agonists have been shown to regulate blood glucose concentrations by mechanisms including enhanced insulin synthesis/secretion, suppressed glucagon secretion, slowed gastric emptying, and enhanced satiety. GLP-1 receptors have also been identified in the heart, kidneys, and blood vessels, leading to the hypothesis that GLP-1R agonists may affect cardiovascular function or cardiovascular disease (CVD). The aim of this literature review was to assemble and assess preclinical and clinical data of potential medical importance regarding the cardiovascular effects of GLP-1R agonists. Preclinical studies with the GLP-1R agonists GLP-1, exenatide, or liraglutide provided evidence that GLP-1R stimulation favorably affects endothelial function, sodium excretion, recovery from ischemic injury, and myocardial function in animals. Similar observations have been made in exploratory studies on GLP-1 infusion in normal subjects and patients with type 2 diabetes. Post hoc analyses of phase III studies of patients with type 2 diabetes treated with exenatide(bid or qw) or liraglutide(qd) showed that these GLP-1R agonists reduced blood pressure, an effect largely independent of weight loss, and that liraglutide slightly increased heart rate. Preliminary data also indicated that GLP-1R agonists reduced markers of CVD risk such as C-reactive protein and plasminogen activator inhibitor-1. Ongoing studies are examining the effects of administering GLP-1R agonists to patients at risk of CVD, postangioplasty patients, post-CABG patients, and patients with heart failure. Additional studies should provide meaningful data to determine whether GLP-1R agonists provide unique treatment benefits to patients at risk for or with established CVD.

Type 2 diabetes, cardiovascular risk, and the link to insulin resistance

BACKGROUND Patients with type 2 diabetes mellitus frequently have coexistent dyslipidemia, hypertension, and obesity, and are at risk for microvascular and macrovascular disease complications such as myocardial infarction, stroke, retinopathy, and microalbuminuria. To optimize cardiovascular health outcomes for patients with type 2 diabetes, strategies to reduce the risks of microvascular and macrovascular disease are needed in clinical practice. OBJECTIVE This article provides an overview of the cardiovascular risk profile of patients with type 2 diabetes and discusses the cardiovascular consequences of use of the thiazolidinediones (insulin-sensitizing agents) in the treatment of type 2 diabetes. METHODS A literature search of MEDLINE/PubMed was performed to identify relevant articles published from 1966 to April 2003. Search terms used were diabetes, cardiovascular disease, atherosclerosis, dyslipidemia, obesity, hypertension, blood pressure, hyperglycemia, inflammation, C-reactive protein, fibrinolysis, plasminogen activator inhibitor type-1, microalbuminuria, thiazolidinediones, safety, hepatotoxicity, and edema. Bibliographies within the identified articles were also evaluated for additional relevant articles and information. RESULTS Recommendations for cardiovascular risk reduction through preventive and therapeutic strategies that target the symptoms of insulin resistance may reduce the microvascular and macrovascular sequelae of diabetes and ameliorate the impact of other components of the metabolic syndrome, including hypertension, hyperglycemia, and obesity. In this regard, thiazolidinediones are promising therapies. CONCLUSIONS Early data suggest that, in addition to reducing hyperglycemia, pioglitazone and rosiglitazone effect changes in the dyslipidemic profile, hemodynamics, vascular inflammation, and endothelial functioning of patients with type 2 diabetes. Additional research is needed to further distinguish the cardiovascular benefits of these drugs.

Cardiovascular risk and thiazolidinediones-what do meta-analyses really tell us?

Meta‐analyses of clinical trials suggest that the use of the thiazolidinedione (TZD), rosiglitazone, in patients with type 2 diabetes mellitus may increase the risk of myocardial ischaemic events by 30–40%. Although these controversial data must be interpreted with caution, in the absence of definitive prospective cardiovascular (CV) outcomes data, they represent a prominent source of evidence concerning the CV safety of rosiglitazone. The results of meta‐analyses and a large randomized‐controlled CV outcomes trial provide strong evidence that pioglitazone does not increase the risk of coronary events. This article clarifies the clinical significance of these meta‐analytical findings alongside other sources of evidence and assesses their impact on evolving treatment guidelines and recommendations for the use of TZDs in patients with type 2 diabetes.

PROactive: time for a critical appraisal

The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) remains the only completed cardiovascular (CV) outcomes study with a thiazolidinedione. It has provided valuable information on the impact of pioglitazone on CV outcomes in a high-risk population of patients with type 2 diabetes and established macrovascular disease. The investigators in PROactive chose a challenging primary composite endpoint that included events in multiple vascular beds (cerebral, cardiac, and peripheral), as well as both disease-related and procedural endpoints. They also pre-specified a more conventional main secondary composite endpoint of all-cause mortality, myocardial infarction, and stroke. Since the results of PROactive were first presented, there has been much debate on the relative merits of the statistically non-significant 10% decrease in the primary endpoint vs. the statistically significant 16% decrease in the main secondary endpoint seen with pioglitazone. However, PROactive includes more information than just these two main endpoints and has provided an extensive safety data set, as well as new insights into the impact of pioglitazone in different patient subpopulations. In this article, we consider all the results from PROactive presented to date and offer our own appraisal of how these findings shape the CV efficacy and safety profile of pioglitazone.

Infection of an Implantable Cardioverter Defibrillator: Management Without Removal of the Device in Selected Cases

A case is presented in which an implantable Cardioverter defibrillator (ICD) became infected in the abdominal wall pocket 5 weeks following implantation. There was no evidence clinically or by computed tomographic scan suggesting mediastinal extension of the infection. The infection was treated successfully by debriding the abdominaJ wall pocket followed by a combination of pocket irrigation with antibiotic solution, parenteraJ antibiotics, and long‐term oral antibiotics. This conservative therapy was and avoided removal of the device.

Angioscopic evaluation of site-specific administration of ReoPro

Systemic administration of newer antiplatelet agents such as the GP IIb/IIIa agent ReoPro (Centocor BV Leiden, The Netherlands) has been shown to decrease the early incidence of recurrent ischemia and recurrent myocardial infarction. The currently approved protocol for administration of ReoPro involves an initial weight adjusted bolus followed by a systemic infusion over the next 12 hr. The systemic administration is proposed as the only route of administration because it is stated that the drug must be exposed to circulating platelets. An alternative approach would be to deliver ReoPro locally and allow the platelets to disaggregate only when in contact with the local arterial wall. The optimal method of monitoring the efficacy of such a strategy is to visually assess the presence of platelet rich or red blood cell rich thrombus using angioscopy. We report our initial experience in 12 patients who received local administration of ReoPro using currently approved catheters for local administration of agents into coronary arteries who were evaluated before and after intervention using intracoronary angioscopy. None of the patients received a subsequent 12-hr infusion. There was successful resolution of thrombus in 11 of 12 patients. Recurrent ischemia occurred in one patient without myocardial infarction.

Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus

Aims: To determine the effects of empagliflozin on adiposity indices among patients with type 2 diabetes mellitus. Methods: Changes in weight, waist circumference, estimated total body fat, index of central obesity and visceral adiposity index were assessed using analysis of covariance and testing of treatment by strata for age, sex and baseline waist circumference in patients with type 2 diabetes mellitus randomized to blinded treatment with empagliflozin versus placebo in clinical trials of 12 weeks (cohort 1) or 24 weeks (cohort 2) duration. Results: This study comprised 3300 patients (cohort 1, N = 823; cohort 2, N = 2477). Empagliflozin reduced weight, waist circumference and adiposity indices versus placebo in both cohorts. Adjusted mean (95% confidence interval) change from baseline in empagliflozin versus placebo was −1.7 kg (−2.1 to −1.4 kg) and −1.9 kg (−2.1 to −1.7 kg) for body weight (p < 0.001); −1.3 cm (−1.8 to −0.7 cm) and −1.3 cm (−1.7 to −1.0 cm) for waist circumference (p < 0.001); −0.2% (−0.7% to 0.3%; p = 0.45) and −0.3% (−0.7% to 0.0%; p = 0.08) for estimated total body fat; −0.007 (−0.011 to −0.004) and −0.008 (−0.010 to −0.006) for index of central obesity (p < 0.001); and −0.3 (−0.5 to 0.0; p = 0.07) and −0.4 (−0.7 to −0.1; p = 0.003) for visceral adiposity index in cohorts 1 and 2, respectively. Adipose reductions were seen across most age, sex and waist circumference subgroups. Conclusion: Empagliflozin significantly reduced weight and adiposity indices with the potential to improve cardiometabolic risk among patients with type 2 diabetes mellitus.

New options for the treatment of obesity and type 2 diabetes mellitus (narrative review).

Moderate weight loss (>5%), which has been associated with improvements in glycemic parameters in patients with dysglycemia, also reduces the presence of other comorbidities, including dyslipidemia and hypertension, culminating in a reduced risk of cardiovascular disease. Lifestyle changes are the recommended preliminary approach to weight loss, with an initial weight-loss goal of 10% of body weight achieved over 6 months at a rate of 1-2 pounds per week selected as an appropriate target to decrease the severity of obesity-related risk factors. Implementing and maintaining the lifestyle changes associated with weight loss can, however, be challenging for many patients. Therefore, additional interventions sometimes may be necessary. Bariatric surgery can also be a highly effective option for weight loss and comorbidity reduction, but surgery carries considerable risks and is still applicable only to selected patients with type 2 diabetes. Thus, attention is turning to the use of weight-loss medications, including 2 recently approved compounds: twice-daily lorcaserin and a once-daily combination of phentermine and topiramate extended-release, both shown to be safe and effective therapies in the management of obesity in patients with type 2 diabetes.