Effects of anti-diabetic treatments in type 2 diabetes and fatty liver disease.

Introduction: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are significant non-communicable diseases that often affect individuals concurrently. In individuals with both T2DM and NAFLD, there is evidence that anti-diabetic therapies may demonstrate potential combined beneficial metabolic and reduced hepatic inflammatory effects.Areas covered: A PubMed and Google Scholar search was performed to find relevant literature. Included studies focused on individuals with T2DM and NAFLD receiving anti-diabetic treatments including bariatric surgery, insulin sensitizers, incretin mimetics, and SGLT2 inhibitors. Additional articles highlight investigational treatments.Expert opinion: In individuals with T2DM and NAFLD, 5-10% weight loss or bariatric surgery if unable to lose weight or maintain weight loss are appropriate. GLP-1 receptor agonists and SGLT2 inhibitors result in weight loss, appear safe and may provide beneficial hepatic outcomes. Whether their effects are related to favorable weight changes or intrinsic hepatic effects is unclear. Thiazolidinediones have advantageous anti-hyperglycemic and hepatic effects but individuals must be monitored for weight gain and edema. Metformin and DPP-4 inhibitor beneficial hepatic effects remain debated. There are opportunities to standardize markers and imaging of NAFLD. Studies powered to evaluate the possible cardiovascular benefits of anti-diabetic therapies in individuals with T2DM and NAFLD are needed.

Biochemical follow-up of nonfunctioning benign thyroid nodules.

OBJECTIVE: For the biochemical follow-up of benign thyroid nodules, some authors recommend periodic lifelong measurement of thyroid-stimulating hormone (TSH) to assess for the development of toxic nodules over time. The purpose of this retrospective study was to assess the incidence of thyroid dysfunction over time in patients with benign thyroid nodule(s), with a normal TSH at diagnosis and to identify any factors that may predict biochemical dysfunction over time. METHODS: Medical records of patients with the diagnosis of thyroid nodule(s) between January 2011 and August 2014 were reviewed. Patients who had TSH measurement within 1 year of initial diagnostic ultrasound (US) were included. RESULTS: One-hundred fifty-seven patients identified with thyroid nodule(s) satisfied inclusion criteria. At a median follow-up of 45 (34-63) months, 13 (8.3%) patients developed thyroid dysfunction. The mean initial TSH in the group which developed subclinical hyperthyroidism (0.65 mIU/mL) was statistically different from the group that did not develop thyroid dysfunction (1.37 mIU/mL, P: 0.007). More patients with TSH <1 mIU/L developed thyroid dysfunction as compared to subjects with TSH ≥1 mIU/L (P: .022). There was no significant difference in the incidence of thyroid dysfunction on the basis of gender, race, smoking status, TPO Ab positivity and number of nodules at diagnosis. CONCLUSIONS: We recommend re-examining the current practice and clinical utility of frequent TSH monitoring in all patients with thyroid nodules, particularly if initial TSH level is ≥1 mIU/L.

The use of diazoxide in the management of spontaneous hypoglycemia in patients with ESRD.

Although diabetes remains the number one cause of renal failure nationwide, spontaneous hypoglycemia in patients with CKD has also been described in the absence of exogenous insulin or any other diabetes treatment. Decreased renal gluconeogenesis and impaired renal insulin clearance are underlying mechanisms of hypoglycemia in individuals with ESRD. Diazoxide was originally approved as an anti-hypertensive medication, but also is known to bind ATP-sensitive K channels in the beta cells of the pancreas, ultimately leading to inhibition of insulin release. We detail six cases of ESRD-associated hypoglycemia which responded to treatment with diazoxide therapy.

Pharmacoeconomic evaluation of sodium-glucose transporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

INTRODUCTION: Clinicians have many safe and effective options for the treatment of type 2 diabetes that can improve glycemic control and effect other cardio-metabolic parameters. Sodium-glucose transporter-2 inhibitors (SGLT-2) are the most recent class of therapies, have a novel mechanism of action, and provide good glycemic efficacy and a favorable cardiovascular risk profile. Cost-effectiveness data can play an important role in assessing the benefits of this class of therapy in anti-diabetes treatment regimens. Areas covered: This review summarizes all the available evidence regarding the cost-effectiveness of SGLT-2 inhibitors. For the purposes of this article, the authors have performed a systematic review of pharmacoeconomic analyses through a non-restricted literature until June 2018. Expert opinion: The available analyses demonstrate that SGLT-2 inhibitors are a more cost-effective option compared to other oral anti-diabetes therapies and insulin in the treatment of individuals with uncontrolled type 2 diabetes. Future studies should examine populations with renal and liver disease and expand data of some SGLT-2 inhibitors to patients at high cardiovascular risk and hard endpoint data.

Role of glycemic control on hospital-related outcomes in patients with diabetes mellitus undergoing renal transplantation.

OBJECTIVE: To compare length of stay (LOS) and incidence of hypoglycemic events and infections in hospitalized patients with diabetes mellitus (DM) undergoing renal transplantation, among groups of patients defined by admission glucose and mean inpatient daily glucose. METHODS: A retrospective analysis of 190 charts of patients with DM who underwent renal transplantation over a 2-year period was conducted. Patients were grouped according to admission glucose and mean inpatient daily glucose (≤140 mg/dL, 141-180 mg/dL, and >180 mg/dL). RESULTS: Admission glucose was not associated with LOS. A mean inpatient daily glucose of ≤140 mg/dL was associated with a longer LOS compared to a mean inpatient daily glucose of >180 mg/dL (p=0.03). Patients with an admission glucose of ≤140 mg/dL had approximately half the rate of hypoglycemic events compared to those with admission glucose of 141-180 mg/dL (odds ratio [OR]=2.1; p=0.02) or >180 mg/dL (OR=1.9; p=0.04). However, patients whose mean daily glucose was ≤140 mg/dL had approximately twice the rate of hypoglycemic events than those whose mean daily glucose was 141-180 mg/dL (OR=0.4; p=0.01) or >180 mg/dL (OR=0.4; p=0.004). The incidence of infections was low and was not associated with admission or mean daily glucose levels. CONCLUSION: Lower mean daily inpatient glucose levels (≤140 mg/dL) are associated with longer LOS and greater incidence of hypoglycemic episodes in diabetes patients undergoing renal transplantation. Our findings suggest that target blood glucose levels of 140-180 mg/dL may be appropriate in this specific population. Additional prospective research is needed to confirm these findings.

Frequency of Adverse Events Before, During, and After Hospital Admission.

OBJECTIVES: Adverse events (AEs) are unintended physical injuries resulting from or contributed to by medical or surgical care. We determined the frequency and type of AEs before, during, and after hospital admission. METHODS: We conducted a cohort study of 296 adult hospital patients. We used the standardized Institute for Healthcare Improvement Global Trigger Tool for Measuring Adverse Events to review the medical records of the hospital patients for occurrence, timing relative to hospital admission, severity, and preventability of AEs. We also identified the primary physiologic system affected by the AE. RESULTS: Among 296 patients, we identified 338 AEs. AEs occurred with similar frequency before (n = 148; 43.8%) and during hospital admission (n = 162; 47.9%). Fewer AEs occurred after discharge (n = 28; 8.3%). Half of all AEs (n = 169; 50.0%) were severe, whereas 47.9% (n = 162) were preventable. CONCLUSIONS: AEs occur with similar frequency before and during hospitalization and may contribute more to hospital admissions than previously recognized. These findings suggest that efforts to improve patient safety should include outpatient settings in addition to the more commonly targeted acute care settings.

Cardiovascular effects of anti-diabetes drugs.

INTRODUCTION: Cardiovascular disease remains the major contributor to morbidity and mortality in diabetes. From the need to reduce cardiovascular risk in diabetes and to ensure that such risk is not exacerbated by drug treatments, governmental regulators and drug manufacturers have focused on clinical trials evaluating cardiovascular outcomes. AREAS COVERED: Findings from mechanistic and clinical trials of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors will be reviewed. These drug classes will be compared within the context of available cardiovascular outcomes data. Clinical implications of new study regulations will be examined. EXPERT OPINION: Recent cardiovascular studies provide a more comprehensive evaluation of specific anti-diabetes therapy in individuals with high cardiovascular risk. Long-term effects of anti-hyperglycemic agents in patients with lower cardiovascular risk are still speculative. Historical data supports continued use of metformin as a first-line agent. DPP-4 inhibitors and GLP-1 receptor agonists appear to have neutral effects on cardiovascular outcomes. The significantly decreased cardiovascular risk associated with empagliflozin SGLT-2 inhibitor therapy is impressive and may change how practitioners prescribe add-on therapy to metformin.

Concentrated insulins: the new basal insulins.

INTRODUCTION: Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. AREAS COVERED: This review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. CONCLUSION: Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration.

Thyroid Swelling and Thyroiditis in the Setting of Recent hCG Injections and Fine Needle Aspiration.

A 60-year-old woman presented with a neck mass and underwent fine needle aspiration of a left thyroid nodule. During this time, she had been injected with hCG for weight loss. Soon after, she developed rapid diffuse thyroid growth with pain. She was ultimately diagnosed with thyrotoxicosis due to postaspiration subacute thyroiditis and subsequently became hypothyroid. This condition is rare in the nonpregnant state in noncystic nodules with a smaller needle gauge approach. The incidence of thyroid nodule discovery and evaluation is increasing. As more procedures are undertaken, understanding of potential complications is important. This case highlights potential complications of thyroid fine needle aspiration including diffuse thyroid swelling and thyroiditis. The role of hCG injections is speculated to have potentially stimulated thyroid follicular epithelium via cross-reactivity with the TSH receptor and contributed to the acute inflammatory response after fine needle aspiration.

Cushing disease: highlighting the importance of early diagnosis for both de novo and recurrent disease in light of evolving treatment patterns.

OBJECTIVE: To highlight and summarize current literature on Cushing disease (CD)-related morbidity and mortality, focusing on residual complications after "cure" and the changing role of pharmacologic therapy in CD. METHODS: Current journal articles on the consequences of untreated or undertreated CD, CD recurrence, and recent trends in CD treatment were collected from PubMed searches and analyzed in combination in view of the authors' clinical experience. RESULTS: Timely recognition and treatment of de novo and recurrent CD remains a singular clinical challenge. Chronic excess cortisol exposure leads to potentially irreversible sequelae and death, stressing the importance of early diagnosis and treatment. Disease relapse after primary pituitary adenomectomy is prevalent and recurrence may manifest decades after initial surgery. Increased risk for mortality and hypercortisolism-related complications in postsurgical CD patients may indicate persistent subclinical disease and further underscores the need for cautious, ongoing observation and testing. Potential long-term pharmacologic treatment options (e.g., pasireotide, mifepristone) have recently emerged that may provide biochemical and symptomatic remission for those with refractory CD, or those for whom surgery is contraindicated. CONCLUSION: Delays in CD diagnosis, management, and follow-up are common and lead to increased adverse metabolic complications and mortality. Rapid recognition and treatment as well as vigilant monitoring are therefore essential. After surgical treatment, some patients may suffer from persistent subclinical CD that remains difficult to detect with routine testing. Although long-term pharmacologic treatment has historically been limited by adverse reactions or escape from response, new treatments may offer more options for patients with refractory disease.

The cardiovascular effects of insulin.

INTRODUCTION: Cardiovascular disease remains one of the leading causes of morbidity and mortality in diabetes mellitus. A causal link between insulin, atherosclerosis and cardiovascular risk has been investigated at the basic science level and studied in large clinical trials. AREAS COVERED: The cardiovascular actions of insulin and its role at the level of the endothelium will be reviewed. Cardiovascular outcomes in several large diabetes trials where insulin management was prominent will be summarized. EXPERT OPINION: The vascular actions of insulin are complex and mediated primarily via nitric oxide and endothelin-1. It appears that insulin resistance, rather than hyperinsulinemia itself, increases cardiovascular risk. In fact, hyperinsulinemia in the setting of normal beta cell function protects obese and insulin-resistant individuals from type 2 diabetes. Large clinical trials have supported that insulin management is not associated with increased adverse outcomes. A multifactorial approach targeting modifiable risk factors, including smoking cessation, blood pressure and lipid management, reduces cardiovascular risk. Therapy goals should be individualized and hypoglycemia, especially in individuals receiving insulin management, should be strictly avoided.

Empagliflozin, a sodium glucose co-transporter 2 inhibitor, in the treatment of type 1 diabetes.

INTRODUCTION: Available anti-hyperglycemic therapy in type 1 diabetes (T1DM) is currently restricted to insulin, pramlintide, and pancreas or islet cell transplantation. The imperfect replication of normal insulin secretion and glucose control has been a driver for development of other anti-hyperglycemic agents for this population. Empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is currently under investigation as an add-on therapy to insulin in T1DM. AREAS COVERED: Within the drug evaluation, the authors describe the mechanism of action of SGLT2 inhibitors and preliminary results from studies investigating treatment in rodent models and in individuals with T1DM. EXPERT OPINION: Studies on adjunct therapeutic effects of empagliflozin in individuals with T1DM are limited, but initial reports show favorable effects on reducing HbA1c, body weight, total daily insulin dose and hypoglycemic events. Intriguingly, this drug may confer a degree of renal protection by reducing glomerular hyperfiltration that can arise in the diabetic state. Currently, the primary concern seems to be the presence of ketone levels indicating an under-insulinized state. Long-term effects can only be inferred from studies in type 2 diabetes mellitus at this time. Empagliflozin represents a novel non-insulin-mediated therapy that warrants further investigation.

Vildagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes.

INTRODUCTION: Vildagliptin is a dipeptidyl peptidase-4 inhibitor targeting the incretin system to improve glycemic control in type 2 diabetes. AREAS COVERED: This review focuses on the pharmacokinetics, drug interactions and use of oral vildagliptin in special populations. Clinical efficacy and vildagliptin's role in the spectrum of therapeutics available are briefly addressed. EXPERT OPINION: Vildagliptin is an effective and well-tolerated oral dipeptidyl peptidase-4 inhibitor. It is dosed orally and can be used safely as monotherapy or in combination with other oral anti-hyperglycemic agents and insulin. It is rapidly absorbed and can be taken without regard to food. It is metabolized by hydrolysis and renally cleared. It has low potential for drug interactions and is well tolerated in elderly patients. Body mass index and gender have no significant pharmacokinetic impact. There is no significant interaction with CYP enzymes. There is a low risk for hypoglycemia and weight gain. Dose adjustment is recommended for renal impairment. Prescribing vildagliptin in the setting of liver dysfunction is not recommended, although pharmacokinetics is minimally (if at all) affected. A variety of patients with type 2 diabetes may benefit from treatment with vildagliptin. Therapy should be individualized but the paucity of data in populations with advanced renal failure and hepatic dysfunction may limit the use in these patients.

Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus.

INTRODUCTION: Canagliflozin is an orally administered sodium glucose cotransporter 2 inhibitor proposed for the treatment of type 2 diabetes. Canagliflozin improves glycemic control in an insulin-independent fashion through inhibition of glucose reuptake in the kidney. AREAS COVERED: This article reviews the available data on the pharmacodynamics, the pharmacokinetics and metabolism, and the efficacy and safety of canagliflozin. Relevant articles were identified via PubMed using the search term canagliflozin with no date restriction. The authors also discuss the abstracts from canagliflozin studies presented at large diabetes conferences. EXPERT OPINION: Canagliflozin offers a relatively modest reduction in HbA1c, FPG, and PPG. It has a low incidence of hypoglycemia and a reduction in body weight. Dose adjustment may be recommended in the elderly, those on loop diuretics, and those with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2) if there are concerns or symptoms of volume-related side effects. Issues remain with observed increases in low-density lipoprotein cholesterol (LDL-C) and the odds of heart attack and stroke. Canagliflozin offers a novel mechanism of action, a modest glycemic control, and a favorable side-effect profile. It was approved by the US Food and Drug Administration in April 2013 and is undergoing evaluation by the European Medicines Agency.