Class effects of SGLT2 inhibitors on cardiorenal outcomes.

BACKGROUND: To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes. RESULTS: The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m2 for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA-REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30-300, 11.0% UACR > 300 mg/g). CONCLUSIONS: Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.

Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review.

In this systematic review, we sought to summarize the 3 recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials (Dapagliflozin Effect on CardiovasculAR Events (DECLARE-TIMI 58), Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, and Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)) and to explore the potential causes for their different results. We found that the major adverse cardiovascular event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14% for DECLARE-TIMI 58, CANVAS, and EMPA-REG OUTCOME, respectively. DECLARETIMI 58 had the fewest cardiorenal events (across treatment and control arms) and EMPA-REG OUTCOME the most. DECLARE-TIMI 58 used alternative inclusion criterion for baseline renal function (creatinine clearance ≧ 60 mL/min) compared to the other trials (estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 bodysurface area). Therefore, the DECLARE-TIMI 58 study cohort had higher eGFR (mean eGFR 85.2 mL/min/1.73 m2 compared to 76.5 and 74 in CANVAS and EMPAREG OUTCOME, respectively); this may have caused the difference in results. Additionally contributing to the high event rate in EMPA-REG OUTCOME was the requirement of prior confirmed cardiovascular disease (CVD), resulting in 99.2% of patients with CVD compared to only 65.6% and 40.6% in CANVAS and DECLARE-TIMI 58, respectively (which did not require CVD). In conclusion, there is a need for large-scale studies of SGLT2i with matching inclusion/exclusion criteria and appropriate endpoints to ensure a truly direct comparison of the drugs.

Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data.

Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM.

Initiating and intensifying insulin therapy for type 2 diabetes: why, when, and how.

With the exception of insulin, all diabetes medications have limited glucose-lowering capacity. Therefore, as type 2 diabetes progresses, insulin is often needed to achieve near-normal glycemic targets and avoid complications. Concerns about the initiation of insulin by both clinicians and patients play a major role in poor glycemic control. This article discusses current guidelines for treating type 2 diabetes, exploring when and how insulin therapy should be initiated and intensified, and how barriers to insulin use may be overcome. Advances include the development of novel long-acting, premixed, and rapid-acting insulin analogues and delivery devices. These agents have near-physiological time-action profiles that allow safer, flexible, and more convenient dosing. Many patients find using an insulin pen device easier, more convenient, and more discreet than using a vial and syringe. Nurses and medical assistants can be trained to understand the glucose-lowering capacities and limitations of each class of diabetes medications, including recognizing when insulin therapy is necessary. In addition, by showing patients how easy insulin pens are to use, clinic staff can help empower, educate, and encourage patients with type 2 diabetes to optimize their glycemic control with insulin once oral antidiabetic agents alone have become inadequate.

Impact of Subclinical Hypothyroidism on Cardiometabolic Biomarkers in Women.

CONTEXT: Whether subclinical hypothyroidism (SCH) is associated with cardiometabolic abnormalities is uncertain. OBJECTIVE: To examine diverse cardiometabolic biomarkers across euthyroid, SCH, and overt hypothyroidism (HT) in women free of cardiovascular disease (CVD). DESIGN: Cross-sectional adjusted associations for lipids, lipoprotein subclasses, lipoprotein insulin resistance score, inflammatory, coagulation, and glycemic biomarkers by ANCOVA for thyroid categories or TSH quintiles on a Women's Health Study subcohort. SETTING: Outpatient. PATIENTS OR OTHER PARTICIPANTS: Randomly sampled 3,914 middle-aged and older women for thyroid function analysis (thyroid-stimulating hormone [TSH], free T4), of whom 3,321 were not on lipid lowering therapy. INTERVENTION: None. MAIN OUTCOME MEASURE: Associations of SCH and HT with cardiometabolic markers. RESULTS: Going from euthyroid to HT, the lipoprotein subclasse profiles were indicative of insulin resistance [respective values and p for trend]: larger VLDL size (nm)[51.5 (95%CI51.2, 51.8) to 52.9 (51.8, 54.1) p=0.001]; higher LDL particles concentration (nmol/L)[1283 (95%CI1267, 1299) to 1358 (1298, 1418) p=0.004] and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid 49.2 (95%CI 48.3, 50.2) to SCH 52.1 (95%CI 50.1, 54.0), and HT 52.1 (95%CI 48.6, 55.6), p for trend 0.008. Of the other biomarkers, SCH and HT were associated with higher hs-CRP and HbA1c. For increasing TSH quintiles results were overall similar. CONCLUSIONS: In apparently healthy women, SCH cardiometabolic profiles indicated worsening insulin resistance and higher CVD risk markers compared with euthyroid individuals, despite similar LDL and total cholesterol. These findings suggest that cardiometabolic risk may increase early in the progression towards SCH and OH.

Hypertriglyceridemia: the importance of identifying patients at risk.

This review aims to explain risk factors, consequences, and management strategies recommended for patients with hypertriglyceridemia. A search of PubMed was performed: 'Hypertriglyceridemia'[Majr], limited to English-language and published in the 5 years up to April 2016. Abstracts of the 680 results were screened for inclusion. Reference lists of publications included were also screened for inclusion. Approximately 25% of the United States population has elevated (≥150 mg/dL) triglycerides (TG) putting them at an increased risk of cardiovascular disease, non-alcoholic fatty liver disease, and pancreatitis. Risk factors for hypertriglyceridemia include genetics, lifestyle and diet, renal disease, endocrine disorders, and certain medications. Guidelines recommend that all patients with hypertriglyceridemia are advised on lifestyle modification to reduce TG to <150 mg/dL; a reduction in body weight of 5-10% can reduce TG by approximately 20%. For patients with TG <400 mg/dL, the primary goal is to reduce low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol, with most guidelines recommending statin therapy. When TG is ≥500 mg/dL the primary goal is to reduce TG levels to lower the risk of pancreatitis. Statin therapy (if LDL-C is elevated) in combination with a fibrate, or long-chain omega-3 fatty acid may be required. The Food and Drug Administration withdrew approval for niacin and some fibrates in combination with statins in April 2016 citing unfavorable benefit-risk profiles. With the increasing incidence of associated conditions (e.g. obesity, metabolic syndrome, and type 2 diabetes mellitus), it is likely that primary care physicians will encounter more patients with hypertriglyceridemia.

Coronary heart disease in men.

Elimination of key risk factors such as dyslipidemia and hypertension is important for reducing cardiovascular events later in life. A medical history, physical examination, and laboratory determination of lipid and glycosylated hemoglobin levels provide a good assessment of cardiovascular risk. A statin is first-line therapy for reducing LDL-C, which is the primary lipid target in most patients. High-dose statin therapy may be required to reach desired target levels. The choice of initial antihypertensive therapy is based on patient comorbidities and drug side effects; however, most patients require combination antihypertensive therapy to reach goal. The combination of this multifactorial risk approach along with smoking cessation and modification of other risk factors should complement current and future cardiovascular care for men.

Lipoprotein associated phospholipase A(2): role in atherosclerosis and utility as a biomarker for cardiovascular risk.

Atherosclerosis and its clinical manifestations are widely prevalent throughout the world. Atherogenesis is highly complex and modulated by numerous genetic and environmental risk factors. A large body of basic scientific and clinical research supports the conclusion that inflammation plays a significant role in atherogenesis along the entire continuum of its progression. Inflammation adversely impacts intravascular lipid handling and metabolism, resulting in the development of macrophage foam cell, fatty streak, and atheromatous plaque formation. Given the enormous human and economic cost of myocardial infarction, ischemic stroke, peripheral arterial disease and amputation, and premature death and disability, considerable effort is being committed to refining our ability to correctly identify patients at heightened risk for atherosclerotic vascular disease and acute cardiovascular events so that they can be treated earlier and more aggressively. Serum markers of inflammation have emerged as an important component of risk factor burden. Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) potentiates intravascular inflammation and atherosclerosis. A variety of epidemiologic studies support the utility of Lp-PLA(2) measurements for estimating and further refining cardiovascular disease risk. Drug therapies to inhibit Lp-PLA(2) are in development and show considerable promise, including darapladib, a specific molecular inhibitor of the enzyme. In addition to substantially inhibiting Lp-PLA(2) activity, darapladib reduces progression of the necrotic core volume of human coronary artery atheromatous plaque. The growing body of evidence points to an important role and utility for Lp-PLA(2) testing in preventive and personalized clinical medicine.

Distinguishing among incretin-based therapies. Glucose-lowering effects of incretin-based therapies.

Extensive experience from randomized clinical trials demonstrates the efficacy of GLP-1 agonists and DPP-4 inhibitors as monotherapy and in combination with metformin and other agents, although reductions in FPG and PPG, and consequently A1C, are greater with GLP-1 agonists than with DPP-4 inhibitors. This difference may result from the pharmacologic levels of GLP-1 activity that are achieved with the GLP-1 agonists and their direct action on the GLP-1 receptor. The GLP-1 agonists have attributes that would make either of them an appropriate choice in the management of all 3 patients in our case studies, while either DPP-4 inhibitor would be an appropriate choice for Case 1. Differences in dosing, administration, safety, and tolerability should be considered.

Distinguishing among incretin-based therapies. Patient education and self-management.

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies.

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies.

The multifactorial nature of the pathogenesis of T2DM provides an opportunity to combine treatments that act upon different mechanisms. In addition to improving insulin resistance and pancreatic ß-cell dysfunction, the GLP-1 agonists and DPP-4 inhibitors improve the impaired incretin response, as well as increase insulin secretion and reduce glucagon secretion, both in a glucose-dependent manner. As a result of these multiple actions, the GLP-1 agonists and DPP-4 inhibitors lower both fasting and postprandial glucose levels. The effects of GLP-1 agonists tend to be greater, probably because they produce pharmacologic levels of GLP-1 compared to physiologic levels with the DPP-4 inhibitors. Another difference is that unlike the DPP-4 inhibitors, the GLP-1 agonists also slow gastric emptying and promote satiety.

Distinguishing among incretin-based therapies. Introduction.

The "treat to target" approach is to quickly achieve the target glycosylated hemoglobin (AIC) goal of <7% in most people, and then intensify or change therapy as needed to maintain glycemic control. Results of an online survey demonstrate uncertainty regarding the clinical differences between glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase (DPP)-4 inhibitors. The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options.

Clinical practice in type 2 diabetes: After metformin and lifestyle, then what?

According to the most recent data from the Centers for Disease Control, nearly 24 million Americans have type 2 diabetes mellitus (T2DM); of these, 6 million individuals with T2DM remain undiagnosed. At least 57 million more American adults are at high risk for developing T2DM by virtue of having impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both, which constitute prediabetes. Treating T2DM remains challenging, despite the availability of effective therapies. Recent data indicate that slightly more than half of the patients (~56%) with T2DM are achieving the American Diabetes Association (ADA) glycosylated hemoglobin (HbA1C) goal of <7%. A major contributing factor to the inability to maintain glycemic control in patients with T2DM is its progressive nature. There is a continuum from normoglycemia to IGT/IFG (prediabetes) to diabetes, and from uncomplicated diabetes to more difficult-to-control diabetes and diabetes with complications. This continuum has implications for treatment strategies and for the need to continually modify these strategies as the disease progresses. Understanding where the patient is on the continuum of disease may help identify mechanisms of action that can be targeted and aid in therapeutic decision-making. For example, early in the disease process, T2DM is characterized by insulin resistance and hyperinsulinemia. As such, agents that target insulin sensitivity and insulin resistance may be especially useful early in the disease process. Although the 2 main defects of T2DM are insulin resistance and pancreatic beta-cell dysfunction/failure, other aspects of its pathophysiology may be targeted to specific metabolic pathways and effects.

How to implement incretin therapy.

The roles of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are rapidly evolving, despite limited recommendations on their use in current guidelines. This evolution is based on data from the large number of clinical trials demonstrating the clinical efficacy and favorable safety profile of these agents in individuals with type 2 diabetes mellitus (T2DM). This article focuses on factors to consider when implementing the GLP-1 receptor agonists and DPP-4 inhibitors as monotherapy or in combination with other agents in the treatment of T2DM.