THE IMPACT OF CARDIOVASCULAR DRUGS ON GLYCEMIC CONTROL: A REVIEW.

OBJECTIVE: The prevalence of diabetes mellitus (DM) is steadily rising in the U.S., both in the general population and among those with cardiovascular disease (CVD). Understanding how to treat a patient with both conditions is becoming increasingly important. With multiple therapeutic options for CVD management, some medications will invariably impact glycemia in this group of patients. The concept of "DM-friendly" management of CVD is based on a treatment approach of selecting medications that do not impair glycemic control and provide equivalent cardioprotective effects. This article reviews the glycemic effects of various classes of medications commonly used to treat CVD. METHODS: Data sources were all PubMed- and Google Scholar-referenced articles in English-language peer-reviewed journals from 1980 through April 2016. Studies selected could include observational studies or prospective clinical trials. Prospective clinical trials included in this review focused on investigating the association of the medication of interest with glycemic outcomes. Meta-analyses and systematic reviews were also included. RESULTS: The data on glycemic effects were lacking for many of the medication classes and individual medications examined. However, in our review, certain beta-blockers and renin angiotensin aldosterone system inhibitors, and select calcium channel blockers were consistently shown to have favorable glycometabolic profiles when compared with other commonly used cardiovascular therapies. CONCLUSION: Several commonly prescribed medications for the treatment of CVD, such as certain beta-blockers and renin angiotensin aldosterone system inhibiting agents, are associated with favorable glycometabolic effects. As clinicians are more often faced with the challenge of treating patients with DM and concomitant CVD, consideration of how common cardiovascular medications may affect glycemia should be incorporated into the clinical decision making process. ABBREVIATIONS: A1C = hemoglobin A1C ACE = angiotensin-converting enzyme ARB = angiotensin II receptor blocker CCB = calcium channel blocker CI = confidence interval CVD = cardiovascular disease DM = diabetes mellitus MI = myocardial infarction RR = relative risk.

IMPACT OF GLUCOSE MANAGEMENT TEAM ON OUTCOMES OF HOSPITALIZARON IN PATIENTS WITH TYPE 2 DIABETES ADMITTED TO THE MEDICAL SERVICE.

OBJECTIVE: To improve glycemic control of hospitalized patients with diabetes and hyperglycemia, many medical centers have established dedicated glucose management teams (GMTs). However, the impact of these specialized teams on clinical outcomes has not been evaluated. METHODS: We conducted a retrospective study of 440 patients with type 2 diabetes admitted to the medical service for cardiac or infection-related diagnosis. The primary endpoint was a composite outcome of several well-recognized markers of morbidity, consisting of: death during hospitalization, transfer to intensive care unit, initiation of enteral or parenteral nutrition, line infection, new in-hospital infection or infection lasting more than 20 days of hospitalization, deep venous thrombosis or pulmonary embolism, rise in plasma creatinine, and hospital re-admissions. RESULTS: Medical housestaff managed the glycemia in 79% of patients (usual care group), while the GMT managed the glycemia in 21% of patients (GMT group). The primary outcome was similar between cohorts (0.95 events per patient versus 0.99 events per patient in the GMT and usual care cohorts, respectively). For subanalysis, the subjects in both groups were stratified into those with average glycemia of <180 mg/dL versus those with glycemia >180 mg/dL. We found a significant beneficial impact of glycemic management by the GMT on the composite outcome in patients with average glycemia >180 mg/dL during their hospital stay. The number of patients who met primary outcome was significantly higher in the usual care group (40 of 83 patients, 48%) than in the GMT-treated cohort (8 of 33 patients, 25.7%) (P<.02). CONCLUSION: Our data suggest that GMTs may have an important role in managing difficult-to-control hyperglycemia in the inpatient setting. ABBREVIATIONS: BG = blood glucose GMT = glucose management team HbA1c = hemoglobin A1c ICU = intensive care unit POC = point of care T2D = type 2 diabetes.

Multiple Disease Associations in Autoimmune Polyglandular Syndrome Type II.

OBJECTIVE: Autoimmune polyglandular syndrome type II (APS II) is characterized by adrenal insufficiency (Addison's disease), autoimmune thyroid disease, and/or type 1 diabetes mellitus (DM1). Multiple other autoimmune diseases have been associated with APS II. Here we report a case of a patient with APS II who over the course of 10 years developed Addison's disease, hypothyroidism, DM1, Hashimoto's encephalopathy, vitiligo, celiac disease, seronegative arthritis, and ulcerative colitis. This is a particularly aggressive course of APS II, and this combination of autoimmune diseases has not been previously reported. METHODS: A 25-year-old female with a history of ulcerative colitis (UC), celiac disease, and DM1 presented to our institution with mental status changes. She was diagnosed with Hashimoto's encephalopathy and treated with high-dose steroids and intravenous immunoglobulin (IVIG). She recovered well from her encephalopathy but her posthospitalization course was complicated due to the development of Addison's disease, vitiligo, seronegative arthritis, and hypothyroidism. RESULTS: The current understanding of APS II and its autoimmune disease associations are briefly summarized. The association of UC and Hashimoto's encephalopathy with APS II is novel and discussed in detail. CONCLUSION: A case of a patient with APS II with a dramatic development of 8 autoimmune diseases over 10 years is described. The novel APS II developments of Hashimoto's encephalopathy and UC are discussed. This case highlights the potential complexity and severity of the clinical course of APS II.

Effect of glargine insulin delivery method (pen device versus vial/syringe) on glycemic control and patient preferences in patients with type 1 and type 2 diabetes.

OBJECTIVE: To evaluate the effects of two different glargine insulin delivery methods (pen device vs. vial/syringe) on glycemic control and patient preferences in a randomized, open-label, crossover, comparative effectiveness study. METHODS: Thirty-one patients discharged from the hospital were recruited for this study. In the hospital, all patients were treated with a basal-bolus insulin regimen. Upon discharge, 21 patients received glargine by pen device for 3 months and were then switched to vial/syringe for the next 3 months (group 1). Group 2 consisted of 10 patients discharged on vial/syringe and converted to pen device after 3 months. Hemoglobin A1c (HbA1c) was measured at enrollment and at 3 and 6 months. A questionnaire assessing patient preference was administered at 3 and 6 months. RESULTS: Groups 1 and 2 had similar baseline HbA1c (10.7 ± 2.2% and 11.2 ± 2.5%, respectively) and similar reduction in HbA1c at 3 months (7.8 ± 1.7% and 7.3 ± 1.4%, respectively; P<.001 vs. baseline). However, after crossover, the changes in HbA1c from 3 to 6 months were significantly different between groups. HbA1c increased to 8.5 ± 2.0% at 6 months in group 1 after switching to the vial/syringe but remained unchanged (7.1 ± 1.6%) in group 2 after switching to a pen device (P<.01, group 1 vs. group 2). Patient questionnaires after each phase of the trial revealed that patients found the pen device more convenient and were more likely to recommend this insulin delivery method to someone else. CONCLUSION: Patients switching to a glargine pen device achieved lower HbA1c at the 6-month follow-up. Patients in both groups overwhelmingly preferred glargine pens over vials/syringes.

Glycemic control and outcomes of hospitalization in noncritically ill patients with type 2 diabetes admitted with cardiac problems or infections.

OBJECTIVE: Although the importance of glycemic control is well established for patients with diabetes hospitalized for surgical problems, it has not been supported by clinical studies for patients with diabetes hospitalized on the medical floors. METHODS: We conducted a retrospective study of 378 patients with type 2 diabetes admitted for cardiac or infectious disease (ID) diagnosis between September 1, 2011, and August 1, 2012. Exclusion criteria included type 1 diabetes, admission to the intensive care unit (ICU), hospital stay shorter than 3 days, and daily glucocorticoid dose >20 mg of methylprednisolone. The primary composite outcome included death during hospitalization, ICU transfer, initiation of enteral or parenteral nutrition, line infection, deep vein thrombosis, pulmonary embolism, rise in plasma creatinine by 1 or >2 mg/dL, new infection, an infection lasting for more than 20 days, and readmission within 30 days and between 1 and 10 months after discharge. RESULTS: Patients were stratified by mean blood glucose (BG) level: group 1 had mean BG of <180 mg/dL (n = 286; mean BG, 142 ± 23 mg/dL), whereas group 2 had mean BG levels >181 mg/dL (n = 92; mean BG, 218 ± 34 mg/dL; P<.0001). Group 2 had a 46% higher occurrence of the primary outcome (P<.0004). The rate of unfavorable events was greater in cardiac and ID patients with worse glycemic control (group 2). CONCLUSION: Our data strongly support a positive influence of better glycemic control (average glycemia <180 mg/dL or 10 mmol/L) on outcomes of hospitalization in patients with type 2 diabetes.

Virtual Patient Simulation Offers an Objective Assessment of CME Activity by Improving Clinical Knowledge and the Levels of Competency of Healthcare Providers.

The main goal of continuing medical education (CME) is to help healthcare providers (HCP) improve their knowledge and levels of competency with an ultimate enhancement of their performance in practice. Despite the long and well-intentional history of CME, the proof of success (based on improved clinical outcomes) is difficult to obtain objectively. In the past several years, the traditional CME world has been disrupted by replacing multiple-choice questions with virtual simulation. We utilised an innovative, next-generation virtual patient simulation (VPS) platform to develop objective measures to assess the success of educational activities that can be applied to the CME. This VPS platform was used at five distinct educational events designed to assess learners' knowledge and competency in the guideline-driven management of Type 2 diabetes, hyperlipidaemia, and hypertension. A total of 432 learners (medical doctors, nurse practitioners, and clinical pharmacists) participated in these educational events of whom 149 went through two consecutive cases with a similar clinical picture and educational goals. Their ability to achieve glycaemic, lipid, and blood pressure control improved significantly as they moved from the first to the second case. The participants improved their test performance in all categories - between 5 and 38%, achieving statistically significant increases in the many goals examined. In conclusion, this study employed the pioneering application of technology to produce, collect and analyse the VPS data to evaluate objectively educational activities. This VPS platform allows not only an objective assessment of the effectiveness of the CME activity but also provides timely and helpful feedback to both learners and providers of a given educational event.

Virtual patient simulation platforms challenging traditional CME: Identification of gaps in knowledge in the management of Type 2 diabetes and Hyperlipidaemia.

As any other aspect of contemporary life, an old and established field of CME undergoes a transformation into a "digital age." Virtual patient simulation (VPS) has shown to be an interactive and efficient way of engaging healthcare professionals (HCP) in continuing medical education. VPS can identify gaps in knowledge and improve competence, using engaging, online tools. The Edocate VPS Platform has been developed by a group of physicians, education experts, and computer specialists. In this communication, we report the experience of several hundreds of HCP using the Edocate VPS application in the fields of type 2 diabetes (T2DM) and hyperlipidemia. The Edocate VPS application, displaying both simple and complex clinical situations, was presented to an international group of HCPs who had the task to perform physical exams, order lab and imaging tests, update the medical record with the right diagnoses, prescribe medications, and perform long-term follow-up through multiple visits. The HCPs received personalized, guideline-based, feedback on their actions. The analytical capabilities of the Edocate VPS platform run very deep and allow in-depth analysis of learners' competence in achieving the best outcomes, while teaching to apply a personalized approach, avoiding side effects of medications, and providing instantaneous access to the most current references in the field. The data collected from the program has shown significant gaps in knowledge and adherence to guidelines in the areas of management of T2DM and hyperlipidemia. Only about 50% of all participants achieved guideline-compatible glycemic control - namely HbA1c below 7%. Furthermore, only 41% of practicing physicians and 23% of family medicine residents achieved levels of LDL below 70 mg/dl in their virtual patients. In conclusion, the data presented in this communication strongly suggests that this novel simulation platform can enable medical organizations to create immersive VPS cases for their primary educational and CME efforts.

Multiple abnormalities of myocardial insulin signaling in a porcine model of diet-induced obesity.

Heightened cardiovascular risk among patients with systemic insulin resistance is not fully explained by the extent of atherosclerosis. It is unknown whether myocardial insulin resistance accompanies systemic insulin resistance and contributes to increased cardiovascular risk. This study utilized a porcine model of diet-induced obesity to determine if myocardial insulin resistance develops in parallel with systemic insulin resistance and investigated potential mechanisms for such changes. Micropigs (n = 16) were assigned to control (low fat, no added sugars) or intervention (25% wt/wt coconut oil and 20% high-fructose corn syrup) diet for 7 mo. Intervention diet resulted in obesity, hypertension, and dyslipidemia. Systemic insulin resistance was manifest by elevated fasting glucose and insulin, abnormal response to intravenous glucose tolerance testing, and blunted skeletal muscle phosphatidylinositol-3-kinase (PI 3-kinase) activation and protein kinase B (Akt) phosphorylation in response to insulin. In myocardium, insulin-stimulated glucose uptake, PI 3-kinase activation, and Akt phosphorylation were also blunted in the intervention diet group. These findings were explained by increased myocardial content of p85alpha (regulatory subunit of PI 3-kinase), diminished association of PI 3-kinase with insulin receptor substrate (IRS)-1 in response to insulin, and increased serine-307 phosphorylation of IRS-1. Thus, in a porcine model of diet-induced obesity that recapitulates many characteristics of insulin-resistant patients, myocardial insulin resistance develops along with systemic insulin resistance and is associated with multiple abnormalities of insulin signaling.

Transition of Patients to and from Insulin Degludec: A Clinical Challenge.

With appearance of new insulins on the market, new clinical challenges, much like unintended consequences, came into light in our daily practice. One of the most pressing issues has become an issue of switching patients to and from newer insulins in various clinical situations. A proper switch from 1 medication to another requires understanding of pharmacokinetics (PK) and pharmacodynamics (PD) of both drugs. Unfortunately, there is no research in this area and, as a result, there are no guidelines nor is there even a consensus. We present 5 clinical scenarios in which the patients were transitioned to or from insulin degludec. Because there are no data and no current consensus, we have polled 200 diabetes care providers soliciting their opinion as to how they would handle these clinical situations. Our poll of endocrinologists revealed multiple approaches as well as elements of confusion among providers. Even though all answers, summarized following each case, might be reasonable, and there might not be a single correct answer, we wish to express our opinion that is based on PK and PD of these insulins. Because there is more than 1 correct way of implementing these transitions, we urge our colleagues to institute a very close follow-up of these patients with frequent adjustments of insulin dose to avoid stacking with potential hypoglycemia.

Knockdown of JNK rescues 3T3-L1 adipocytes from insulin resistance induced by mitochondrial dysfunction.

Mitochondrial dysfunction has been linked to etiology of insulin resistance, however the mechanism remains unknown. In this study we investigated whether mitochondrial dysfunction induced by cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP) alters insulin sensitivity in 3T3-L1 adipocytes and which cellular signaling molecules might be involved. Fully differentiated 3T3-L1 adipocytes were treated with 10 microM FCCP for 1h, resulting in increased serine-307 phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation, association of p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase) with IRS-1, decreased insulin-stimulated PI 3-kinase activity and H(3)-2-deoxyglucose (2DOG) uptake. A partial (46%) knockdown of JNK1 blocked FCCP-induced serine phosphorylation of IRS-1 and restored insulin-stimulated tyrosine phosphorylation of IRS-1, association of p85alpha subunit of PI 3-kinase with IRS-1, activation of PI 3-kinase, and stimulation of 2DOG uptake. Thus, FCCP-induced mitochondrial dysfunction may cause insulin resistance that is ameliorated by reduction of JNK1 expression.

Treatment of Diabetes in Older Adults: An Endocrine Society* Clinical Practice Guideline.

OBJECTIVE: The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults. CONCLUSIONS: Diabetes, particularly type 2, is becoming more prevalent in the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects.

Effects of chronic hyperinsulinemia in insulin-resistant patients.

Selective insulin resistance influences pathogenesis and treatment of type 2 diabetes and metabolic syndrome. Downregulation of the antiatherogenic pathway and maintained activity of the proatherogenic and cancerogenic pathways lead to atherosclerosis and cancer. Exogenous insulin added to "compensatory" hyperinsulinemia might worsen the primary end points, resulting in potential increase in cardiovascular and cancer events in spite of improvement of surrogate metabolic end points. Conversely, metformin can improve primary and surrogate end points.

Pioglitazone acutely stimulates adiponectin secretion from mouse and human adipocytes via activation of the phosphatidylinositol 3'-kinase.

AIMS: Thiazolidinediones increase circulating adiponectin. We have previously demonstrated the involvement of the phosphatidylinositol 3-kinase (PI3K) signaling pathway in insulin-stimulated adiponectin secretion. We therefore investigated the effects of the thiazolidinedione pioglitazone on acute adiponectin secretion, and the involvement of the PI3K signaling pathway in this action. MAIN METHODS: We treated murine 3T3-L1 and human primary adipocytes with 1-10 uM pioglitazone for 2 h, +/-PI3K inhibition by Wortmannin (WT). Secreted adiponectin was measured by Western blot. PI3K activity following 15-minute treatments with 1-10 uM pioglitazone was measured by thin layer chromatography. Pioglitazone's effect on adiponectin synthesis and on secretion of newly synthesized adiponectin was studied in 3T3-L1 adipocytes using a pulse-chase technique. KEY FINDINGS: Pioglitazone was found to increase adiponectin secretion and PI3K activity in a dose-dependent manner from 3T3-L1 and human adipocytes. In 3T3-L1 adipocytes, 10 uM pioglitazone increased adiponectin secretion by 84+/-14% (p<0.0001) at 2 h. Similarly, in human adipocytes there was a 56+/-18% (p<0.02) increase in secretion. WT blocked the pioglitazone effect and decreased adiponectin secretion at 2 h (47% of pioglitazone treated, p<0.006). Pioglitazone increased PI3K activity in a dose-dependent manner in both 3T3-L1 (1.7 vs. 2.7-fold increase over control at 2 uM vs. 10 uM dose, p=0.02) and human adipocytes. SIGNIFICANCE: Our data show that pioglitazone acutely stimulates adiponectin secretion from both 3T3-L1 and human adipocytes. This acute effect of pioglitazone is PI3K-dependent.

Clinical Diabetes Centers of Excellence: A Model for Future Adult Diabetes Care.

Although diabetes research centers are well defined by National Institutes of Health, there is no clear definition for clinical Diabetes Centers of Excellence (DCOEs). There are multiple clinical diabetes centers across the United States, some established with philanthropic funding; however, it is not clear what defines a DCOE from a clinical perspective and what the future will be for these centers. In this Perspective we propose a framework to guide advancement for DCOEs. With the shift toward value-based purchasing and reimbursement and away from fee for service, defining the procedures for broader implementation of DCOEs as a way to improve population health and patient care experience (including quality and satisfaction) and reduce health care costs becomes critically important. It is prudent to implement new financial systems for compensating diabetes care that may not be provided by fiscally constrained private and academic medical centers. We envision that future clinical DCOEs would be composed of a well-defined infrastructure and six domains or pillars serving as the general guiding principles for developing expertise in diabetes care that can be readily demonstrated to stakeholders, including health care providers, patients, payers, and government agencies.