FIB-4 as a screening and disease monitoring method in pre-fibrotic stages of metabolic dysfunction-associated fatty liver disease (MASLD).

AIMS: Guidelines emphasize screening high-risk patients for metabolic dysfunction-associated steatotic liver disease (MASLD) with a calculated FIB-4 score for therapy to reverse fibrosis. We aimed to determine whether FIB-4 can effectively screen and monitor changes in steatohepatitis (MASH). METHODS: Data were retrieved from the NIDDK-CR R4R central repository, of the CRN/PIVENS (pioglitazone vs vitamin E vs placebo) trial of adult patients without diabetes mellitus and with MASLD. RESULTS: 220 patients with MASLD had alanine transaminase (ALT), aspartate aminotransferase (AST) and platelet count, to calculate FIB-4, and repeat liver biopsies for histological MASLD activity scores (NAS). Compared to NAS score of 2, Fib-4 was higher at NAS 5) (p = 0.03), and NAS score of 6 (p = 0.02). FIB-4 correlated with cellular ballooning (r = 0.309, p < 0.001). Levels of ALT (ANOVA, p = 0.016) and AST (ANOVA p = 0.0008) were associated with NAS. NAS improved with pioglitazone by 39 %, p < 0.001 and with vitamin E by 36 %, p < 0.001. Pioglitazone and vitamin E both improved histological sub-scores for steatosis, and inflammation, without statistical changes in fibrosis grade. Changes in FIB-4 correlated with changes in NAS (r = 0.237, p < 0.001). CONCLUSIONS: In this post hoc analysis, changes in FIB-4 were associated with changes of steatohepatitis. Medication known to treat steatohepatitis, may be considered, before the onset of advanced fibrosis.

The Changing Landscape of Treatment for Cystic Fibrosis Related Diabetes.

Objective: Patients with Cystic Fibrosis related diabetes [CFRD] are treated with insulin and high calorie diets to maintain body mass. The combined CFTR modulator elexacaftor/tezacaftor/ivacaftor [ETI] decreases pulmonary exacerbations and improves nutritional status. We reviewed the effects of ETI on BMI, HbA1c and diabetes regimen in patients with CFRD over a period of three years. Methods: Data of previously CFTR-modulator-naïve patients with CFRD and pancreatic insufficiency on ETI therapy were retrieved from an electronic health record database. Patients were followed for a mean duration of 2.7 ± 0.8 years after ETI initiation. Data pertaining to weight, BMI, HbA1c and diabetes regimen were collected at 6 months, 12 months, 2 years and at 3 years post-ETI initiation. Patients were then dichotomized based on their baseline BMI into a low BMI group and an "at target" BMI group. The effects of ETI on changes in weight, BMI, A1c and diabetes regimen were compared in both groups over a period of three years. Results: Twenty-seven patients with CFRD (15 men/12 women), age 30.6 ± 11.5 (SD) years, BMI 22.4 ± 4.0 kg/m2, were included. Fifteen patients had low BMI (<22 kg/m2 for women, <23 kg/m2 for men) and 12 patients had at target BMI (≥22 kg/m2for women, ≥BMI 23 kg/m2 for men). Patients with low BMI had an increase in their BMI from 19.5 ± 1.7 to 21.4 ± 2.2 kg/m2 at one year (p = 0.002), and 21.8 ± 1.8 kg/m2 at three years (p = 0.004) after ETI initiation. Four patients (out of 15) in the low BMI group had achieved normal BMI by the end of study follow up. There was no change in weight in the at target BMI group. HbA1c and basal insulin requirements did not change in either group. Five patients started non-insulin therapies. Conclusion: BMI increased after ETI therapy in CFRD patients with low BMI, but not in those with at target BMI. The use of non-insulin therapies is increasing in CFRD and should be evaluated in future studies.

Stroke Prevention by Antihyperglycemic Drugs in Type 2 Diabetes Mellitus.

OBJECTIVES: The American Heart Association/American Stroke Association and the American Association of Clinical Endocrinology provided guidelines for patients with transient ischemic attacks or strokes (TIA/stroke) and diabetes mellitus with the use of glucose-lowering agents (GLA) effective in preventing major adverse cardiovascular events (MACE). This review evaluated GLA for specific differences in TIA/stroke prevention. METHODS: Previous reviews and meta-analyses were evaluated for outcomes of MACE, cardiovascular death (CVD), hospitalization for heart failure, and TIA/stroke. The GLA were glucagon-like peptide 1-receptor agonists (GLP-1RA, 6-trials, n = 46 541), sodium-glucose transport 2 inhibitors (SGLT2i, 5-trials, n = 46 959), insulin-providing regimens (IP, 4-trials, n = 26 223), and thiazolidinediones (TZD, 1-trial, n = 5238). RESULTS: There were reductions in MACE for each class. Relative risk (rr) reductions for TIA/stroke were found with GLP-1RA (rr = 0.840, 95% CI: 0.759, 0.936, P =.001) but not with SGLT2i, IP, or TZD. Cardiovascular deaths were decreased with GLP-1RA (rr = 0.873, CI: 0.804, 0.947, P =.001) and SGLT2i (rr = 0.835, CI: 0.706, 0.987, P =.034), but not with TZD or IP. Hospitalizations for heart failure were decreased only with SGLT2i (rr = 0.699, CI: 0.626, 0.781, P <.001). Increased CVD correlated with aggressive lowering of A1c (r = -0.611, P =.012) and showed a trend with the relative risk of hypoglycemia (r = 0.447, P =.08). For GLP-1RA, there was no increase in hypoglycemia and a direct correlation with a decreased rr for stroke with decreases in A1c (r = 0.917, P =.010). CONCLUSION: Improvements in A1c with GLP-1RA were associated with stroke prevention in patients with diabetes and with TIA or stroke. Reductions in cardiovascular mortality include therapy with GLP-1RA and SGLT2i. Aggressive lowering of A1c, however, was associated with increased CVD.

Euglycemic diabetic ketoacidosis: The paradox of delayed correction of acidosis.

OBJECTIVE: The effectiveness of standard treatment for diabetic ketoacidosis (DKA) in "euglycemic DKA" (EuDKA, blood glucose (BG) ≤ 250 mg/dL) was evaluated with respect to the time to correction of BG ≤ 200 mg/dL, anion gap (AG)≤12 mmol/L, and serum bicarbonate [HCO3] ≥18 mmol/L. METHODS: Data were retrieved from an electronic health record (EPIC) for "diabetic ketoacidosis." Patients were categorized by initial BG as EuDKA, middle range DKA (MrDKA, >250 < 600 mg/dL) and hyperosmolar DKA (HyperDKA ≥600 mg/dL). RESULTS: There were 56 patients (27men, 29women; age 45.8 ± 15.6 (SD) years. The initial 8-h insulin infusion rate (0.05 ± 0.02, 0.09 ± 0.03, 0.14 ± 0.05units/kg/h, p < 0.001) and the time to correction of BG (3.4 ± 1.9, 6.1 ± 2.9 and 9.6 ± 3.9 h, p < 0.001), differed for EuDKA, MrDKA and HyperDKA. There were no differences in the time to correction of AG or [HCO3]. The earlier time to correction of BG in EuDKA resulted in paradoxical longer lag times for correction of [HCO3] (p = 0.003) and AG (p = 0.048). Changes in BG, AG and [HCO3] correlated with insulin infusion rates of 0.08-0.1units/kg/h whereas in EuDKA the insulin infusion rate was 0.05 ± 0.02 units/kg/h. CONCLUSION: In EuDKA, correlation analyses suggest that higher glucose and insulin infusion rates than what would be projected for the level of blood glucose are required to reverse ketoacidosis. Prospective trials are required to optimize the levels of glucose and insulin infusions in EuDKA.

Reconsideration of "Albumin corrected total calcium" Determinations: Potential errors in the Clinical management of disorders of calcium metabolism.

BACKGROUND: The formula, referenced in major textbooks, for albumin corrected calcium [Calcium(alb)] may not accurately depict ionized calcium [ICa]. We evaluated the accuracy of unadjusted calcium [Calcium(Unadjusted)] and [Calcium(alb)], and developed a protocol for local laboratory adjustment of calcium for albumin. METHODS: Laboratory data were obtained from an electronic health record. Assessments were accuracy, false positive, and false negative rates. Clinical reliability was defined in "error zones" for calcium [Ca]: Zone A = Ca(normal), ICa(low); Zone B = Ca(low), ICa(normal); and Zone C = Ca(normal), ICa(high), Zone D = Ca(high), ICa(normal). RESULTS: A linear regression from 468 laboratory tests was used to derive a formula for "revised corrected calcium" [Calcium (revised)] over a range of albumin concentrations where, [Calcium (revised)] = plasma calcium (mg/dl) + [(4- Albumin (g/d)L)]*(plasma calcium (mg/dl)*0.052)]. [Calcium(alb]] vs [Calcium(Unadjusted)] decreased zone B errors 12%, [95%CI;8-15%], vs 44% [95%CI;37-50%], p < 0.001. However, [Calcium(alb]] vs [Calcium(Unadjusted)] increased zone A error (60%,[95%CI;42-78%], vs 7% [95%CI;1-13%], p < 0.001). [Calcium (revised)] decreased zone A errors (15%, [95%CI;6-24%]) vs [Calcium(alb) ] (60% [95%CI;42-78%], p < 0.001) and Zone D errors from 9% [95%CI;6-12%] to 2% [95%CI;1:5%, p < 0.001]. CONCLUSIONS: [Calcium(alb)] is unreliable in hypo- or hypercalcemia. We provide a protocol for locally derived correction of calcium for albumin.

Glucagon-like peptide 1-receptor agonists and A1c: Good for the heart but less so for the eyes?

BACKGROUND AND AIMS: Glucagon-like peptide1-receptor agonists (GLP1-RA) decrease major adverse cardiovascular events (MACE) in people with type 2 diabetes mellitus and cardiovascular disease (CVD). Caution is recommended for semaglutide and dulaglutide with risk of exacerbating diabetic retinopathy (DR). Analyses were performed to determine if worsening of DR was dependent on drug class or fall in A1c. RESEARCH DESIGN AND METHODS: Meta-analyses and meta-regressions (MR) were performed on the 7 major cardiovascular outcome trial (CVOTs) (n = 56004 patients) of GLP1-RA. A second analysis of 11 studies (n = 11894 subjects) with semaglutide documenting DR followed. RESULTS: Six of the CVOTs evaluated DR. For the GLP1-RA class, there was no increase in the relative rate (rr) for retinopathy (rr = 1.09,95%CI; 0.925,1.289, p = 0.30), with only an increase with parenteral semaglutide (rr = 1.73; 1.10:2.71, p = 0.02). MR showed that decreases in A1c correlated with decreases in MACE (log rr = 0.364∗(Δ A1c), p = 0.014), but increases in DR (log rr= (-0.67∗(ΔA1c), p = 0.076). The change in DR was predominantly found for subcutaneous semaglutide given for >1 year (rr = 1.559,1.068,2.276, p = 0.022) and with decreases in A1c > 1.0% (rr = 1.59; 1.092,2.316, p = 0.016). For the class of GLP1-RA, the rate difference (rd) for worsening retinopathy was = 0.001 (and number needed to harm [NNH] = 1000) compared with rd for MACE = -0.013 (number needed to treat [NNT] = 77). The computation for semaglutide was NNH = 77 and NNT = 43. CONCLUSIONS: This meta-analysis may assist in decisions balancing the relative risk (of existing retinopathy) versus benefits (to existing CVD). There should be close collaboration with ophthalmology to grade the baseline degree of retinopathy when initiating and following patients.

Fatty acids as a direct regulator of aldosterone hypersecretion.

Primary hyperaldosteronism is a major cause of secondary hypertension and carries additional cardiovascular risks beyond that of the elevated blood pressure. Primary hyperaldosteronism is more prevalent in obese people, and weight loss reduces aldosterone levels. It needs to be determined whether obesity related factors directly contribute to the pathogenesis of primary hyperaldosteronism. Here we show that the non-esterified fatty acids (NEFA) palmitic acid, and to a lesser extent, linoleic acid significantly stimulated aldosterone production and steroid enzyme induction in adrenocortical HAC15 cells of human origin. Palmitic acid, linoleic acid, and to a much lesser extent, oleic acid induced the expression of aldosterone synthase. Induction of the Steroidogenic Acute Regulatory Protein (StAR) was modest. Increased aldosterone secretion was independent of fatty acid beta-oxidation in the mitochondria but may involve free fatty acid receptor 1 (FFAR1/GPR40) and endoplasmic reticulum (ER) stress. Palmitic acid and linoleic acid induced the expression of C/EBP Homologous Protein (CHOP), a marker of ER stress, correlating with their ability to induce aldosterone synthase gene expression. Palmitic acid, but not linoleic acid decreased mitochondrial potentials and induced uncoupling protein 2 (UCP2). Palmitic acid enhanced, while docosahexaenoic acid (DHA) suppressed aldosterone response to angiotensin II (Ang-II). Our study provides evidence that NEFAs modulate aldosterone production, and further suggests that hyperaldosteronism shares similar pathogenesis with other obesity-related disorders such as metabolic syndrome.

Meta-analysis of trials in non-alcoholic fatty liver disease with therapeutic interventions for metabolic syndrome.

AIMS: Non-alcoholic fatty liver disease [NAFLD] is associated with metabolic syndrome [MS]. Current guidelines restrict therapy for NAFLD, other than weight loss, in early non-fibrotic disease. It was postulated that intervention with therapies for MS may improve liver fat content. METHODS: A systematic evaluation of Cochrane and PubMed databases was performed for NAFLD or NASH if they were: 1) interventions for metabolic syndrome or diabetes mellitus 2) randomized controlled trials [RCT], with 3) primary outcomes of liver fat content [LFC] (by magnetic resonance spectroscopy [MRS] or liver biopsy (Nonalcoholic Fatty Liver Disease Activity Score [NAS]). RESULTS: There were 30 RCT (in 24 publications) of 2409 subjects. LFC decreased with pioglitazone (MRS, -8.0 ± 1.0 %, p < 0.001), diet and exercise (-7.8 ± 1.7 %, p < 0.001) and omega-3 fatty acids (-6.0 ± 2.5 %, p = 0.02). Decreases in NAS scores were significant for pioglitazone (-1.4 ± 0.4 units, p < 0.001) and D&E (-1.0 ± 0.1 units, p < 0.001). Weight loss correlated with improvement in LFC (p < 0.001) and NAS (p < 0.001). Lowered serum triglycerides correlated with final LFC (p < 0.001) and NAS scores (p < 0.001). CONCLUSIONS: Therapies of MS with weight loss, antiglycemic and triglyceride lowering medicines improved LFC and NAS scores. Further studies are necessary to demonstrate if these therapies would pre-emptively limit progression of disease.

Meta-Analysis of Clinical Fracture Risk Reduction of Antiosteoporosis Drugs: Direct and Indirect Comparisons and Meta-Regressions.

OBJECTIVE: Antiosteoporotic drug (AOD) trials have variabilities in duration and fracture risks. This study evaluated AOD's versus controls regarding reduction in relative rates and rate differences in vertebral and hip fractures and comparative costs. METHODS: Primary randomized controlled trials of antiosteoporotic drugs in postmenopausal women with documentation of vertebral fracture rates or hip fracture rates were extracted from meta-analyses and PubMed through February 2021. Direct and indirect meta-analyses and meta-regressions analyzed the fracture reductions. RESULTS: There were 24 randomized controlled trials of drug versus placebo (73 862 women) and 10 randomized controlled trials of drug versus drug. The reductions in the relative rates of vertebral fractures were significant for antiresorptive (alendronate, risedronate, zoledronate, denosumab, and raloxifene) and anabolic (teriparatide, abaloparatide, and romosozumab) drugs. Denosumab, teriparatide, and abaloparatide were more effective in reducing vertebral fracture rates than oral bisphosphates (all P < .05) but were not more effective in reducing vertebral fracture rates than zoledronate. The reductions in hip fracture rates were significant for alendronate, denosumab, and zoledronate (all P < .05), without significant differences among drugs. Anabolic drugs did not show significant hip fracture rate reduction. Meta-regression of rate differences enabled the calculation of costs per vertebral fracture prevented, which were estimated at >$100 000 for anabolic drugs and between $2289 and $28 947 for antiresorptive drugs. Many direct drug versus drug trials were underpowered to demonstrate benefits of one drug over another. CONCLUSION: This study suggests goal-directed, cost-effective therapies relative to patient risk for vertebral and hip fractures. Anabolic drugs are better at preventing vertebral fractures than oral bisphosphonates. Anabolic drugs are not superior to zoledronate or denosumab and are substantially more expensive. When comparing drugs that prevented hip fractures, there was no statistical benefit of any drug.

Outcomes for continuous subcutaneous insulin infusion users in young adults from lower socioeconomic backgrounds.

OBJECTIVE: Diabetes technology is available and its efficacy and safety have been demonstrated; however, there is little evidence as to how this technology is being utilized and its effectiveness in vulnerable populations. This study evaluated differences in outcomes for young adults in the United States (U.S.) from lower socioeconomic (SES) backgrounds with type 1 diabetes (T1D) managed on continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI) or fixed-dose insulin (FDI). RESEARCH DESIGN METHODS AND PARTICIPANTS: Utilizing the Optum® de-identified Electronic Health Record data set between 2008 and 2018 to perform a retrospective, cohort study, we identified 805 subjects with T1D aged 18-30 years with Medicaid. We evaluated median difference in HbA1c between CSII and MDI/FDI users for 24 months. Predictors of diabetic ketoacidosis (DKA)-associated hospitalizations by CSII use were evaluated using logistic regression. RESULTS: CSII users showed statistically significant lower median HbA1c values at 24 months of follow-up compared to individuals on MDI/FDI. Non-white individuals were at lower odds of receiving treatment with CSII. Subjects on CSII were not more likely to be hospitalized for DKA compared to subjects treated with MDI/FDI. Older subjects were at lower odds of being hospitalized for DKA. Males and subjects followed by Endocrinologists were at higher odds of being hospitalized for DKA. CONCLUSIONS: Young adults with T1D from lower SES backgrounds show improved glycaemic control when in CSII compared to MDI/FDI without increases in hospitalizations for DKA.

Nephrotic range proteinuria associated with focal segmental glomerulosclerosis reversed with pioglitazone therapy in a patient with Dunnigan type lipodystrophy.

Familial partiallipodystrophy (FPLD)is a rare disorder associated withsevere insulin resistance, hypertriglyceridemia, lowserumHDLcholesterol and proteinuricrenaldisease. Although proteinuric renal disease is not common among in patients with partial lipodystrophy, we report a patient with Dunnigan type FPLD complicated by nephrotic syndrome which resolved following treatment with thePPARγagonist pioglitazone, CPAP, diet, and exercise.

Etomidate, Adrenal Insufficiency and Mortality Associated With Severity of Illness: A Meta-Analysis.

PURPOSE: Etomidate causes adrenal insufficiency. Yet in critically ill patients, it is controversial whether it increases mortality rates above that of comparator anesthetic induction agents. We postulated that etomidate would increase relative mortality rates correspondingly to the severity of illness as defined by SAPS or APACHE scores. MATERIALS AND METHODS: A literature search was performed on Pub Med, SCOPUS, and Cochrane Reviews for human studies, regardless of language, between 1983 and February 2020. The search strategy used keywords, "etomidate," "adrenal insufficiency," "glucocorticoid," and "intensive care." Both authors reviewed electronic data search titles, abstracts and extracted data, which were checked by the other reviewer. Primary outcome was 28-day survival. Secondary outcome was adrenal insufficiency. RESULTS: There were 29 trials of etomidate versus comparators in 8584 patients. Etomidate was associated with adrenal insufficiency (risk ratio (rr) = 1·54, 95% CI; 1·42, 1·67, p < 0.001) and increased overall relative mortality rates (rr = 1.09, CI;1.04,1.16, p = 0.001). Meta-regression showed that with etomidate there was a continuous progressive relative risk of mortality associated with increasing severity of illness (predefined in each article by standard critical illness scores). In those patients who had a predicted mortality rate > the median for this analysis (predicted mortality 44%) the relative mortality rate (rr) = 1.20, Ci;1.12,1.29, p < 0.001, the absolute risk difference (rd) = 0.08, CI;0.05,0.11, p < 0.0001 and the number needed to harm (1/rd) was 12.5. In those with a calculated predicted mortality <44% there was no increase in relative mortality rate. CONCLUSIONS: Whereas etomidate causes adrenal insufficiency, it was not shown to increase mortality in many analyzed here in ICU settings. However, etomidate associated relative mortality rates increased progressively and correlated with the severity of critical illness scores. Intensivists should anticipate the need for glucocorticoid supplementation after etomidate in those with severe critical illness and in those with acute deterioration of vital signs.

Glucagon-like Peptide-1 Receptor Agonists versus Sodium-Glucose Cotransporter Inhibitors for Treatment of T2DM.

CONTEXT: Cardiovascular outcome trials (CVOT) of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated reduction of major adverse cardiovascular events (MACE), cardiovascular deaths (CVD), and renal outcomes. OBJECTIVE: Assist in the prescribing decision regarding severity of illness and risk for adverse events. DESIGN: Meta-analysis of the major CVOT and previous meta-analyses. MAIN OUTCOME MEASURES: Six trials of GLP-1 RA (51 762 subjects) and 4 trials of SGLT2i (33 457 subjects) showed both drug classes reduced MACE and CVD versus controls, with neither class preferred (comparison GLP1-RA vs SGLT2i: relative rate [rr] MACE 1.09, 95% confidence interval [CI] 0.97, 1.22, P = ns; rr CVD 1.04, 95% CI 0.87, 1.24, P = ns). Hospitalization for heart failure (HHF) improved with SGLT2i (rr 0.68, CI 0.61, 0.76, P < 0.001) but not with GLP-1 RA, (rr 0.93, CI 0.86,1.03, P = ns). Meta-regression suggested benefits of the SGLT2i on CVD and HHF were accentuated with the underlying rate of MACE in the cohort (i.e., >10 events/1000pt*year). GLP-1 RA and SGLT2i showed reduction in renal outcomes (GLP-1 RA rr 0.83, CI 0.75, 0.91, p ≤ 0.001, SGLT2i rr 0.67, CI 0.57, 0.79, P < 0.001) without a preferential difference (GLP-1 RA vs SGLT2i, rr 1.24, CI 0.95, 1.61, P = ns; relative difference (rd) 0.005, CI -0.011, 0.021, P = ns). Serious adverse events for SGLT2i were mycotic genital infections in women (number needed to harm [NNH] = 13 and diabetic ketoacidosis NNH = 595. Gastrointestinal intolerance was the serious adverse event in the GLP1-RA class (NNH = 35). CONCLUSION: GLP-1 RA and SGLT2i classes showed similar reduction in MACE, CVD, and renal outcomes. SGLT2i have advantages over GLP-1 RA in reduction in HHF.

Intravenous Insulin Versus Conservative Management in Hypertriglyceridemia-Associated Acute Pancreatitis.

CONTEXT AND OBJECTIVE: Hypertriglyceridemia is implicated in ~5% of cases of acute pancreatitis. It is assumed that intravenous insulin is effective in lowering triglyceride (TG) concentrations in hypertriglyceridemia-associated acute pancreatitis (HAAP). However, the efficacy of intravenous insulin versus conservative management alone is not known. DESIGN AND SETTING: Charts of 106 patients who were admitted with HAAP and had TG concentrations >1000 mg/dL at admission were reviewed. Patients who received intravenous insulin for at least 8 hours were included in the intravenous insulin group, while the rest were considered to have received conservative management. We compared the change in TG concentrations from baseline in the 2 groups. RESULTS: Fifty-one patients received intravenous insulin while 55 patients were managed conservatively. Baseline TG concentrations were higher in the intravenous insulin group (median [25th, 75th percentile] 3307 [2106, 4425] mg/dL vs 2304 [1416, 2720] mg/dL; P < 0.001). The TG concentrations declined rapidly in both groups, reaching below 1000 mg/dL by day 3 and < 500 mg/dL by day 4. TG concentrations in the intravenous insulin group had decreased by 69% and 85% on days 2 and 4, respectively. The fall in the conservative management group was 63% and 79%, which was not statistically different than the change in the intravenous insulin group. CONCLUSION: Our results show that intravenous insulin did not result in a more rapid fall in TG compared with conservative treatment in patients with HAAP. Fasting and intravenous fluids were effective in lowering TG concentrations rapidly, with no further contribution from insulin.

Insulin infusion responses in diabetic ketoacidosis alone and with a mixed hypochloremic alkalosis.

AIMS: Although diabetic ketoacidosis (DKA) commonly presents as a pure diabetic ketoacidosis (PDKA), up to 30% of cases may be associated with a mixed hypochloremic metabolic alkalosis (HMA). It is unknown whether there is a difference in treatment outcomes between these two entities. We evaluated an insulin infusion protocol (IIP), previously validated for hyperglycemia management in ICU's, for the management of PDKA and HMA. MATERIALS AND METHODS: A retrospective case series/cohort study of 41 DKA admissions was further characterized as having PDKA or HMA. HMA was defined in those having an elevated delta-delta gradient (ΔAG-ΔHCO3) ≥ 5 mmol/L and base excess chloride (BECl) > 2.7 mmol/L. The main outcome measures were times to recovery of glucose levels to ≤250 mg/dL and of anion gap to ≤12 mmol/L. RESULTS: The initial serum glucose was 553 ±â€¯265 mg/dL, serum bicarbonate of 8.8 ±â€¯5.1 mmol/L, and venous pH 7.13 ±â€¯0.2). Recovery of glucose occurred in 5 h: 25 min (±3 h:39min), and for anion gap in 11 h:25 min (±6 h:56min). HMA compared with PDKA had a delayed recovery of serum glucose (7 h: 23min ±â€¯3 h: 35min vs. 4 h: 31min ±â€¯3:h:21min, p = 0.017), which was due to the higher initial level of glucose (p = 0.02) rather than level of BECl (p = 0.17). There was no difference in time to anion gap closure between the PDKA and HMA. CONCLUSIONS: Correction of hyperglycemia and acidosis in PDKA as well as in HMA was managed through the IIP. The simultaneous fluid and electrolyte management corrected the hypochloremic alkalosis.

Pheochromocytoma as a reversible cause of cardiomyopathy: Analysis and review of the literature.

CONTEXT: Pheochromocytoma and paraganglioma are rare neuroendocrine tumors which overproduce catecholamines and arise from the adrenal gland or extra-adrenal chromaffin cells of the sympathetic and parasympathetic ganglia (1). Excessive catecholamine-induced stimulation of cardiac myocytes leads to damage which manifests in several forms ranging from Takotsubo to dilated cardiomyopathy. Diagnosis of pheochromocytoma-related cardiomyopathies is often delayed due to the atypical presentation associated with many cases. OBJECTIVE: Limited data exists on the presentation and outcomes of the various forms of pheochromocytoma-induced cardiomyopathies. We performed a literature review to assess the association of pheochromocytoma and cardiomyopathy to aide in further understanding this clinical entity. DESIGN: 163 cases from 150 articles published between 1991 and November 2016 were included from a PubMed search. RESULTS: There were 163 occurrences of pheochromocytoma and cardiomyopathy (63 dilated cardiomyopathy, 38 Takotsubo cardiomyopathy, 30 inverted Takotsubo cardiomyopathy, 10 HOCM, 8 myocarditis, and 14 unspecified cardiomyopathy). Many patients lacked classic signs or symptoms of pheochromocytoma with hypertension as a presenting symptom in 65% and the triad of headache, palpitations, and diaphoresis only in 4%. Resection of the pheochromocytoma led to improvement of the cardiomyopathy in 96% while lack of resection was associated with death or cardiac transplantation in 44%. CONCLUSION: Pheochromocytoma should be considered in the evaluation of non-ischemic, non-valvular cardiomyopathy even in the absence of symptoms of catecholamine excess. Our study highlights the importance of early suspicion and diagnosis of pheochromocytoma in cases of idiopathic heart failure as early resection may prevent progression to irreversible myocardial remodeling and death.

CLINICAL EVALUATION OF COST EFFICACY OF DRUGS FOR TREATMENT OF OSTEOPOROSIS: A META-ANALYSIS.

OBJECTIVE: To assess the cost efficacy of available regimens for therapy of osteoporosis as defined as the cost time's number need to treat to prevent one fracture. METHODS: Existing meta-analyses were supplemented through electronic databases SCOPUS and PubMed between 2013 (a date overlapping the latest meta-analyses) and March 2016. Primary references included all randomized controlled trials of anti-osteoporotic drugs versus comparators using search terms "osteoporosis," "random," and "trial." RESULTS: There were 43 evaluable randomized, double-blind, placebo-controlled trials in 71,809 postmenopausal women comparing fracture frequency. Trials were similar in recruitment age (mean ± SD, 67.3 ± 8.1 years) and follow-up duration (25.5 ± 12.6 months). Cost comparisons were evaluated for a treatment strategy assuming generic alendronate as first-line therapy. Denosumab and teriparatide showed benefits in vertebral fracture reduction over alendronate at incremental costs respectively of $46,000 and $455,000 per fracture prevented. Zoledronate, recently released as a generic, would be either less expensive or comparable in cost. None of the alternate medicines were statistically better in preventing hip fractures. Teriparatide was more effective in preventing nonvertebral fractures at an incremental cost of $1,555,000. CONCLUSION: The most cost-effective initial therapy of postmenopausal osteoporosis is generic oral alendronate or generic parenteral zoledronate. There is no statistically significant difference in efficacy of available drugs to prevent hip fractures. There are limited data to suggest switching drugs after sustaining an osteoporotic fracture while on oral alendronate therapy, although generic zoledronate may be considered on the basis of side effects or questions of medication adherence. ABBREVIATIONS: ALN = alendronate; DEN = denosumab; IBN = ibandronate; NNT = number needed to treat; OR = odds ratio; RCT = randomized controlled trial; RIS = risedronate; RLN = raloxifene; TER = teriparatide; ZOL = zoledronate.

A unified Hyperglycemia and Diabetic ketoacidosis (DKA) insulin infusion protocol based on an Excel algorithm and implemented via Electronic Medical Record (EMR) in Intensive Care Units.

BACKGROUND: To assess the efficacy of a unified hyperglycemia and diabetic ketoacidosis (DKA) insulin infusion protocol (IIP), based on an Excel algorithm and implemented as an electronic order set, in achieving glycemic targets and minimizing hypoglycemia. METHODS: An IIP was instituted in medical and surgical intensive care units for post-cardiac surgery (PCS) and other stress hyperglycemia (SH), diabetes hyperglycemia (DH), and DKA. The IIP initiated therapeutic insulin rates at elevated blood glucose (BG), and decreased insulin when target range was achieved. A convenience sample (n=62) was studied; 20 PCS, 15 with DH, 9 with SH, 8 with diabetes on vasopressors, 7 with diabetes on glucocorticoids and 3 with DKA were assessed. RESULTS: The protocol maintained BG at 144±24.7mg/dL for PCS and 167±36mg/dL for patients with diabetes mellitus. It maintained acceptable target range (ATR) (100mg/dL-180mg/dL) 89% of the time for PCS and 67% of the time for patients with diabetes mellitus. There were no measurements of BG<70mg/dL. The protocol lowered the BG at a similar rate and time period in those with diabetes, DKA and those with or without vasopressors or glucocorticoids. To determine long-term efficacy, a retrospective review of Point of Care (POC) RALS (Remote Automated Data System) BG data 2 years post implementation demonstrated fewer episodes of hypoglycemia<70mg/dL and hyperglycemia>240mg/dL and more BG values within ATR. CONCLUSIONS: This IIP maintained ATR without hypoglycemia for patients in the ICU setting without requiring complex nursing calculations.

Circulating cytokines as determinants of weight loss-induced improvements in insulin sensitivity.

Dietary calorie restriction and exercise promote weight loss and may have additive effects for improving insulin sensitivity, independent of weight loss. It is not known if these effects are attributable to changes in circulating cytokines. We evaluated the hypothesis that modest, matched weight loss induced by calorie restriction and exercise have additive effects on circulating cytokines and these changes correlate with improvements in insulin sensitivity. Overweight and sedentary women and men (n = 52, 45-65 years) were randomized to undergo 7 % weight loss by using 3-6 months of calorie restriction, exercise, or a combination of both calorie restriction and exercise. Concentrations of cytokines and hormones were measured in fasting and oral glucose tolerance test blood samples. Insulin sensitivity was estimated based on oral glucose tolerance test for glucose and insulin. With all groups combined, fasting leptin (p < 0.0001) and high molecular weight adiponectin (p = 0.04) decreased and pentraxin-3 increased (p < 0.0001), in a manner that correlated with improvements in insulin sensitivity (all p ≤ 0.0002). These changes, combined with decreases in glucose-dependent insulinotropic polypeptide from the oral glucose tolerance test, explained 63 % of the variance (p < 0.0001) in insulin sensitivity improvements. Exercise and calorie restriction had additive effects on leptin, with a similar trend for high molecular weight adiponectin. Monocyte chemoattractant protein-1 and C-reactive protein concentrations did not change. Calorie restriction and exercise had opposite effects on soluble tumor necrosis factor receptor-1. Modest weight loss in overweight adults decreases serum leptin and high molecular weight adiponectin, and increases pentraxin-3 concentrations in a manner that correlates with increased insulin sensitivity. Exercise has additive effects to those induced by calorie restriction for reductions in leptin and possibly adiponectin. These changes may contribute to the additive effects of calorie restriction and exercise for improving insulin sensitivity.