Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm - 2020 Executive Summary.

The treatment of lipid disorders begins with lifestyle therapy to improve nutrition, physical activity, weight, and other factors that affect lipids. Secondary causes of lipid disorders should be addressed, and pharmacologic therapy initiated based on a patient's risk for atherosclerotic cardiovascular disease (ASCVD). Patients at extreme ASCVD risk should be treated with high-intensity statin therapy to achieve a goal low-density lipoprotein cholesterol (LDL-C) of <55 mg/dL, and those at very high ASCVD risk should be treated to achieve LDL-C <70 mg/dL. Treatment for moderate and high ASCVD risk patients may begin with a moderate-intensity statin to achieve an LDL-C <100 mg/dL, while the LDL-C goal is <130 mg/dL for those at low risk. In all cases, treatment should be intensified, including the addition of other LDL-C-lowering agents (i.e., proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, colesevelam, or bempedoic acid) as needed to achieve treatment goals. When targeting triglyceride levels, the desirable goal is <150 mg/dL. Statin therapy should be combined with a fibrate, prescription-grade omega-3 fatty acid, and/or niacin to reduce triglycerides in all patients with triglycerides ≥500 mg/dL, and icosapent ethyl should be added to a statin in any patient with established ASCVD or diabetes with ≥2 ASCVD risk factors and triglycerides between 135 and 499 mg/dL to prevent ASCVD events. Management of additional risk factors such as elevated lipoprotein(a) and statin intolerance is also described.

JCL Roundtable. Obesity, Diabetes, and Liver Disease in Relation to Cardiovascular Risk.

Metabolic risk for cardiovascular and other systems includes much more than just LDL cholesterol. This JCL Roundtable brings together 3 experts to address new opportunities to reduce the risks posed by obesity, diabetes, and fatty liver disease. Successful nutritional approaches to weight loss are diverse and need to be matched with individual preferences. Topiramate plus extended-release phentermine has been shown to promote meaningful weight loss in randomized trials, but the patented drug combination is expensive. Clinical experience suggests that generic topiramate and phentermine may also be effective. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown favorable tolerability and efficacy for cardiovascular disease in randomized trials, an achievement without precedent among earlier diabetes medications. These 2 drug classes differ in their effects. GLP-1 RAs decrease atherosclerotic cardiovascular events and also decrease hemoglobin A1c, body weight, blood pressure, and possibly diabetic renal disease. SGLT2 inhibitors are effective in reducing heart failure events even among nondiabetic patients. They also decrease progression of diabetic renal disease. The presence of nonalcoholic fatty liver disease signifies risk for atherosclerotic cardiovascular disease as well as cirrhosis and serious hepatic decompensation, including hepatocellular carcinoma. The key to identifying cirrhosis risk is to assess pre-emptively liver fibrosis, which can be predicted initially with blood test risk scores (e.g., FIB-4 index) and more definitively by transient elastography and other imaging techniques and/or liver biopsy. Some medications approved for the treatment of type 2 diabetes may reduce liver fat (SGLT2 inhibitors, insulin) or even reverse steatohepatitis in paired liver biopsy studies (GLP-1 RAs or pioglitazone) Overall the field of preventive metabolic medicine is expanding. Clinical lipidologists should become familiar with recent advances.

Hypothyroidism Prevalence in the United States: A Retrospective Study Combining National Health and Nutrition Examination Survey and Claims Data, 2009-2019.

Previous estimates determined prevalence of hypothyroidism (HT) to be 4.6% of the US population. This study aimed to update estimates of HT prevalence in the United States by retrospective analysis of 2 datasets. Data on HT type (overt or subclinical HT) and treatment were collected from the 2009-2010 and 2011-2012 National Health and Nutrition Examination Survey (NHANES) cycles. From the Optum administrative claims database, medical and pharmacy claims were collected between January 1, 2012, and December 31, 2019. Patients were defined as having HT if, per given year, they had >1 prescription for HT treatment, >1 claim indicating an HT diagnosis, or thyroid-stimulating hormone levels >4.0 mIU/L (NHANES arm). For both studies, treatment was defined as any evidence of synthetic or natural thyroid hormone replacement, identified by pharmacy claims or patient surveys. Data are reported as percentage of patients with HT and treatments received. Between 2009 and 2012, HT prevalence remained around 9.6% of the US population. The administrative claims dataset showed that HT prevalence grew from 9.5% in 2012 to 11.7% in 2019 and that >78% of patients received thyroxine (T4) monotherapy. Similarly, the NHANES dataset showed that T4 replacement therapy was the most common treatment for HT. From 2012-2019, patients with untreated HT grew from 11.8% to 14.4%. The prevalence of HT in the United States has steadily increased since 2009. Likewise, the percentage of hypothyroid-diagnosed patients not receiving treatment also increased, suggesting that the increased prevalence may be due to increased cases of subclinical HT.

Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity.

Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.

Thiazolidinediones and risk for atherosclerosis: pleiotropic effects of PPar gamma agonism.

Despite advances in the development of anti-hyperglycaemic drugs and a greater focus on cardiovascular risk modification for patients with diabetes, cardiovascular disease remains the most common complication of type 2 diabetes. Since their initial availability in 1997, the thiazolidinediones have become one of the most commonly prescribed classes of medications for type 2 diabetes. In addition to glucose control, the thiazolidinediones have a number of pleiotropic effects on myriad traditional and non-traditional risk factors for cardiovascular disease, and hold promise with regard to modification of cardiovascular risk. In a recently reported large-scale clinical trial, pioglitazone was associated with improved cardiovascular outcomes in patients with type 2 diabetes and prevalent atherosclerotic disease. In this review, we summarise the experimental, preclinical and clinical data regarding the effects of the thiazolidinediones on cardiovascular risk factors and clinical outcomes.

Insulin Pump Malfunction During Hospitalization: Two Case Reports.

BACKGROUND: Insulin pump malfunctions and failures continue to occur; however, more severe malfunctions such as the "runaway pump" phenomenon are rarely reported. This article describes two cases of pump malfunction in which pump users appear to have received an unsolicited bolus of insulin resulting in severe episodes of hypoglycemia during hospitalization. MATERIALS AND METHODS: Both cases of insulin pump malfunction occurred in the inpatient setting at a large academic medical center in the United States. An analysis of the corresponding insulin pump downloads was performed. The Food and Drug Administration's (FDA's) Manufacturer and User Facility Device Experience (MAUDE) database was searched for similar cases involving Medtronic (Northridge, CA) insulin pumps using the terms "pump," "infusion," "insulin AND malfunction AND Medtronic." RESULTS: The two cases described show remarkable similarities, each demonstrating a severe hypoglycemic event preceded by an infusion site change followed by an alarm. In both cases a rapid spraying of insulin was reported. The insulin pump downloads validated much of the patients' and medical staff's descriptions of events. The FDA's MAUDE database search revealed 425 cases meeting our search term criteria. All cases were reviewed. Seven cases were identified involving independent movement of the reservoir piston. CONCLUSIONS: The cases detailed are the first to describe an insulin pump malfunction of this nature in the hospital setting involving unsolicited insulin boluses leading to severe hypoglycemia. The cases are particularly compelling in that they were witnessed by medical personnel. Providers and patients should receive instruction education on the recognition and management of insulin pump malfunction.

Thiazolidinediones, peripheral oedema and congestive heart failure: what is the evidence?

Cardiovascular disease is the most common complication of type 2 diabetes mellitus (type 2 DM), accounting for approximately 80% of deaths. While atherosclerotic vascular disease accounts for much of the cardiovascular morbidity and mortality among diabetic patients, congestive heart failure (CHF) is another key complication associated with diabetes, with an incidence three to five times greater in diabetic patients than in those without diabetes. One of the most promising developments in the treatment of type 2 DM has been the introduction of the thiazolidinedione (TZD) class of drugs, which appear to have pleiotropic effects beyond glycaemic control. Enthusiasm has been tempered, however, by concerns for safety in patients with CHF, given reports of worsening heart failure symptoms and peripheral oedema. With the growing epidemic of type 2 DM and the increasing use of TZDs, such concern has important therapeutic implications for a population of patients with a high prevalence of often subclinical systolic and diastolic dysfunction. This review provides an overview of the currently available data regarding the effects of TZDs on fluid retention and cardiac function. Particular emphasis is placed on the mechanisms of development of peripheral oedema and its significance in patients with impaired left ventricular function. TZDs are well known to cause an expansion in plasma volume; there has also been concern that TZDs may have direct toxic effects on the myocardium, leading to impaired cardiac function. Studies to date do not support this hypothesis and in fact there is growing evidence from animal models and human trials that treatment with TZDs actually improves cardiac function. There are also preclinical data to suggest TZDs may protect the myocardium in the setting of ischaemic insult or the toxic effects of myocardial lipid deposition. Ongoing clinical trials examining the use of these agents in patients at risk for heart failure will probably provide further insight into the aggregate cardiovascular effects of this promising class of medications.

The role of thyroid hormone therapy in acutely ill cardiac patients.

The presence of a 'low T3 syndrome' in the setting of nonthyroidal illness has long been recognized as the 'euthyroid sick syndrome', with the recommendation to observe and not treat with thyroid hormone replacement therapy. That approach has recently been challenged in the setting of critical cardiac illness. Research demonstrating that thyroid hormone therapy may improve hemodynamic parameters has rekindled interest in the use of thyroid hormone therapy in critical illness. Continued improvements in survival after critical cardiac illness provokes the question of whether thyroid hormone therapy would provide further incremental benefit.

Free fatty acids and type 2 diabetes mellitus.

Acute elevation of plasma free fatty acids (FFAs) is necessary for insulin secretion. Sustained elevation, however, leads to apoptosis of pancreatic beta-cells and is a major risk factor for cardiovascular disease and sudden death in patients with insulin resistance or a family history of diabetes mellitus, as well as in individuals with normal glucose tolerance. Data suggest that reduction of FFA plasma levels may reduce the incidence of cardiovascular disease in these at-risk patients. Thiazolidinediones have been shown not only to improve insulin sensitivity but also to reduce FFA plasma levels. Consequently, endothelial function is maintained, vascular smooth muscle cell proliferation and migration are minimized, elevated blood pressure and microalbuminuria are reduced, and high-density lipoprotein and low-density lipoprotein cholesterol particle sizes are improved.

The need for reappraisal of type 2 diabetes mellitus management.

Type 2 diabetes is a multiorgan disease that results from the combination of insulin resistance and a beta-cell secretory defect. Because the complications associated with this disease are so significant, the importance of lowering glycosylated hemoglobin levels to within the normal range cannot be overemphasized. Thiazolidinediones (TZDs) modulate lipid metabolism, improve insulin sensitivity, exert numerous nonglycemic effects on the vasculature and lipid metabolism, and may improve many risk factors associated with the metabolic syndrome. Data from the UK Prospective Diabetes Study showed that conventional methods of managing type 2 diabetes, including sulfonylureas and biguanides, do not provide long-term glycemic control. Consequently, new treatment paradigms stressing earlier use of TZDs may lead to more durable glycemic control, facilitating the reduction of complications in patients with type 2 diabetes.

Constructing an algorithm for managing type 2 diabetes. Focus on role of the thiazolidinediones.

With the understanding of type 2 diabetes mellitus constantly evolving, and with the introduction of many new agents during the past few years, it is often difficult to keep up to date with the management of type 2 diabetes. This article reviews the pathophysiology of type 2 diabetes, oral pharmacologic treatment, and proposed diabetes treatment algorithms, which aim to guide clinicians in the use of thiazolidinediones (TZDs) earlier in the course of diabetes. This is important because studies indicate that sulfonylureas, biguanides, and insulin do not protect the beta cell and cannot provide sustainable glycemic control. The basis for TZD use earlier in diabetes is 2-fold: to preserve beta-cell function while maintaining appropriate glycemic control for a longer duration than is usually attained through monotherapy with a secretagogue or biguanide, and to prevent or reverse the insulin resistance phenomenon of reduced insulin utilization that appears even prior to the clinical diagnosis of diabetes. Notably, decreasing insulin resistance also may reduce the incidence of adverse atherosclerotic consequences.

The metabolic syndrome: evolving evidence that thiazolidinediones provide rational therapy.

The metabolic syndrome, also known as the dysmetabolic syndrome, syndrome X or the insulin resistance syndrome, refers to the clustering of cardiovascular disease risk factors that are present in many individuals who are at increased risk for both cardiovascular events and type 2 diabetes. Prediabetic subjects typically exhibit an atherogenic pattern of cardiovascular risks that is associated with hyperinsulinaemia. Thus, identification of components of the metabolic syndrome is important if patients are to be treated early enough to prevent cardiovascular events and other complications related to diabetes. Therapies targeted to specific components of the metabolic syndrome such as improving glycaemic control, managing dyslipidaemia and reducing the prothrombotic state should help to minimize cardiovascular risk, particularly if initiated early. Traditional pharmacologic agents used to manage the individual components of the metabolic syndrome do not typically impact the other components. The thiazolidinediones, a new class of agents that improve insulin resistance, have the ability, in addition to their glucose-lowering effects, to exert several powerful anti-atherogenic properties, including anti-inflammatory effects in the vascular endothelium, redistribution of visceral fat and reduction of insulin resistance, hyperinsulinaemia and hyperproinsulinaemia. This makes the thiazolidinediones ideal candidates for the early treatment of many components associated with the metabolic syndrome.