DIABETIC KETOACIDOSIS ASSOCIATED WITH ALPELISIB TREATMENT OF METASTATIC BREAST CANCER.

OBJECTIVE: Alpelisib-induced diabetic ketoacidosis (DKA) is a rare, but life-threatening, adverse event. There have been only 2 reported cases in the literature. We describe such a case, with emphasis on the importance of screening and achieving adequate glycemic control prior to and after initiation of therapy. METHODS: A 49-year-old woman, known to have advanced breast cancer, presented with a 3-day history of nausea, vomiting, and diffuse abdominal pain. She had started alpelisib at 300 mg/day 2 months prior to presentation, after failing other options. She was diagnosed with DKA using her clinical and laboratory features, leading to treatment with hydration and intravenous insulin therapy. RESULTS: Laboratory data showed high anion gap metabolic acidosis, hyperglycemia, and ketonemia with negative GAD-65 antibodies, leading to the diagnosis of alpelisib-associated DKA. Alpelisib was held, and she was treated with intravenous insulin and hydration. When DKA and hyperglycemia resolved, alpelisib was resumed at a lower dose (200 mg/day) and her blood glucose was managed using a regimen combining insulin and metformin. CONCLUSION: Phosphatidylinositol-3 kinase signaling is important for the metabolic actions of insulin, and alpelisib has been associated with severe hyperglycemia. Metformin is the first-line treatment, however when DKA is the presenting syndrome, insulin needs to be considered. Blood glucose and hemoglobin A1c should be checked prior to treatment initiation and monitored closely after drug initiation. DKA, albeit rare, must be considered in an acutely ill, alpelisib-treated patients presenting with metabolic acidosis, and if drug discontinuation is not an option, insulin treatment may be required to control glycemia.

SPONTANEOUS CEREBROSPINAL FLUID LEAK AFTER INITIATION OF DOPAMINE AGONIST THERAPY IN MACROPROLACTINOMAS: TWO CASE REPORTS AND A LITERATURE REVIEW.

OBJECTIVE: To describe 2 spontaneous cerebrospinal fluid (CSF) leaks complicating treatment of macroprolactinoma (MPRL) with dopamine agonist (DA) therapy. METHODS: We present the 2 cases of spontaneous, DA-related CSF leaks. Prolactin levels were used to assess hyperprolactinemia. Beta-2 transferrin was tested in rhinorrhea fluid, and magnetic resonance imaging was used to assess the sella. RESULTS: Case 1 was a 45-year-old woman with a history of MPRL, recently started on bromocriptine at 15 mg/day, presented with clear rhinorrhea, headache, and nuchal rigidity. Magnetic resonance imaging showed a large sellar lesion extending into the cavernous sinuses, posterior sphenoid sinuses, and suprasellar cistern. Computed tomography revealed areas concerning for bony erosion, likely representing leak sites, and the rhinorrhea fluid was positive for beta-2 transferrin, confirming the CSF source. Empiric antibiotics for meningitis were given and she underwent urgent neuroendoscopic, transsphenoidal CSF leak repair and debulking of the pituitary mass. Case 2 was a 55-year-old man with a 10-year history of untreated MPRL who was started on bromocriptine at 5 mg/day 2 weeks prior to admission. He presented with clear rhinorrhea and a metallic taste in his mouth, worse with the Valsalva maneuver. Imaging confirmed clinical suspicion and he was taken for surgery. A high-flow CSF leak was encountered once the tumor was debulked. This was repaired with an abdominal fat pad graft. Both patients developed diabetes insipidus and required postoperative adjuvant DA therapy. CONCLUSION: Spontaneous CSF leaks can complicate medical therapy of large MPRL with underlying skull defects, typically within weeks of initiation of DA. This should prompt clinicians to educate patients about the symptoms of potential CSF rhinorrhea and encourage them to promptly report them.

Serum pigment epithelium-derived factor: Relationships with cardiovascular events, renal dysfunction, and mortality in the Veterans Affairs Diabetes Trial (VADT) cohort.

BACKGROUND: To determine if serum pigment epithelium-derived factor (PEDF) levels predict cardiovascular events, renal dysfunction and mortality in the Veterans Affairs Diabetes Study (VADT). METHODS: PEDF was evaluated in relation to subsequent cardiovascular outcomes, mortality, and renal dysfunction (defined as urinary albumin creatinine ratio (ACR) ≥300 mg/g), or chronic kidney disease (CKD) stages 3 (eGFR<60 ml/min) or 4 (eGFR<60 and <30 ml/min respectively). PEDF was measured by ELISA on sera from 881 participants collected a median (range) of 1.7 (0-5.0) years post-baseline, and later, from 832 participants 4.0 (1.5-6.9) years post-baseline. RESULTS: In 743 participants, PEDF was measured at both time-points. PEDF increased over time from (mean ±â€¯SD) 10.5 ±â€¯4.03 to 11.0 ±â€¯4.86 ng/ml (paired t-test p = 0.0092). Lower eGFR (p < 0.01), higher serum creatinine (p < 0.01) and urinary ACR (p < 0.01) were associated with increasing PEDF. Multivariate event time models included either one or two follow-up windows (i.e., between first and second PEDF measures; and, when available, from second PEDF measure until study-end). PEDF tertiles were not associated with cardiovascular events, but were significantly associated with all-cause mortality [HR = 2.00 (1.03, 3.89) comparing first to third tertile] in models adjusted for age, minority status, VADT treatment arm and prior cardiovascular event status. Higher PEDF levels also associated with development of kidney dysfunction with adjusted HRs (95% CI comparing third to first PEDF tertiles: 2.74 (1.71, 4.39) for stage 3 CKD; and 3.84 (95% CI: 1.17, 12.5) for stage 4 CKD. CONCLUSIONS: Over 2-years, higher serum PEDF levels predicted advanced nephropathy in patients with type 2 diabetes.

Epidemiology of Dysglycemia in Pregnant Oklahoma American Indian Women.

CONTEXT: Minority communities are disproportionately affected by diabetes, and minority women are at an increased risk for glucose intolerance (dysglycemia) during pregnancy. OBJECTIVES: In pregnant American Indian women, the objectives of the study were to use current criteria to estimate the prevalence of first-trimester (Tr1) dysglycemia and second-trimester (Tr2) incidence of gestational diabetes mellitus (GDM) and to explore new candidate measures and identify associated clinical factors. DESIGN: This was a prospective cohort study. In Tr1 we performed a 75-g, 2-hour oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) to determine the following: fasting insulin; homeostasis model assessment of insulin resistance; serum 1,5-anhydroglucitol; noninvasive skin autofluorescence (SCOUT). We defined dysglycemia by American Diabetes Association and Endocrine Society criteria and as HbA1c of 5.7% or greater. In Tr2 in an available subset, we performed a repeat OGTT and SCOUT. PARTICIPANTS: Pregnant American Indian women (n = 244 at Tr1; n = 114 at Tr2) participated in the study. OUTCOMES: The prevalence of dysglycemia at Tr1 and incidence of GDM at Tr2 were measured. RESULTS: At Tr1, one woman had overt diabetes; 36 (15%) had impaired glucose tolerance (American Diabetes Association criteria and/or abnormal HbA1c) and 59 (24%) had GDM-Tr1 (Endocrine Society criteria). Overall, 74 (30%) had some form of dysglycemia. Associated factors were body mass index, hypertension, waist/hip circumferences, SCOUT score, fasting insulin, and homeostasis model assessment of insulin resistance. At Tr2, 114 of the Tr1 cohort underwent a repeat OGTT and SCOUT, and 26 (23%) had GDM. GDM-Tr2 was associated with increased SCOUT scores (P = .029) and Tr1 body mass index, waist/hip circumferences, diastolic blood pressure, fasting insulin, and triglyceride levels. Overall, dysglycemia at Tr1 and/or Tr2 affected 38% of the women. CONCLUSIONS: Dysglycemia at some point during pregnancy was common among American Indian women. It was associated with features of insulin resistance and may confer long-term health risks for mother and child.

Clinical correlates of serum pigment epithelium-derived factor in type 2 diabetes patients.

AIM: To determine if serum pigment epithelium-derived factor (PEDF) levels in Type 2 diabetes are related to vascular risk factors and renal function. METHODS: PEDF was quantified by ELISA in a cross-sectional study of 857 male Veterans Affairs Diabetes Trial (VADT) subjects, and associations with cardiovascular risk factors and renal function were determined. In a subset (n=246) in whom serum was obtained early in the VADT (2.0±0.3 years post-randomization), PEDF was related to longitudinal changes in renal function over 3.1 years. RESULTS: Cross-sectional study: In multivariate regression models, PEDF was positively associated with serum triglycerides, waist-to-hip ratio, serum creatinine, use of ACE inhibitors or angiotensin receptor blockers, and use of lipid-lowering agents; it was negatively associated with HDL-C (all p<0.05). Longitudinal study: PEDF was not associated with changes in renal function over 3.1 years (p>0.09). CONCLUSIONS: Serum PEDF in Type 2 diabetic men was cross-sectionally associated with dyslipidemia, body habitus, use of common drugs for blood pressure and dyslipidemia, and indices of renal function; however, PEDF was not associated with renal decline over 3.1years.

Apolipoprotein-defined and NMR lipoprotein subclasses in the veterans affairs diabetes trial.

AIMS: The VADT was a randomized clinical trial designed to assess the effect of intensive vs. standard glucose management on cardiovascular events in Type 2 diabetes. At the end of the study, intensive management failed to improve outcomes. We performed plasma lipoprotein subclass analyses to yield new information on the effects of study randomization on cardiovascular risk. METHODS: This is a cross-sectional study of a subset of the VADT (740 men: 368 intensive; 372 standard), conducted at least six months (mean±SD: 2.1±0.8years) post-randomization. Conventional lipids, apolipoprotein-defined (ADLS) lipoprotein subclasses, ApoCIII, ApoE, and Nuclear Magnetic Resonance (NMR) lipoprotein subclasses were determined. RESULTS: In intensive vs. standard groups, conventional lipids and ADLS did not differ significantly. However, with intensive treatment, NMR-determined large and medium VLDL subclasses and VLDL diameter were lower, LDL diameter was higher, medium HDL was higher, and small HDL was lower (all p<0.05). Also, ApoCIII levels were lower (p<0.01). CONCLUSIONS: In a subset of diabetic men from the VADT, intensive glucose management did not affect conventional lipids or ADLS, but had some beneficial effects on particle characteristics as defined by NMR and on ApoCIII.

Serum carotenoids and fat-soluble vitamins in women with type 1 diabetes and preeclampsia: a longitudinal study.

OBJECTIVE: Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest. RESEARCH DESIGN AND METHODS: Maternal serum carotenoids (α- and ß-carotene, lycopene, and lutein) and vitamins A, D, and E (α- and γ-tocopherols) were measured at first (12.2 ± 1.9 weeks [mean ± SD], visit 1), second (21.6 ± 1.5 weeks, visit 2), and third (31.5 ± 1.7 weeks, visit 3) trimesters of pregnancy in 23 women with type 1 diabetes who subsequently developed PE (DM PE+) and 24 women with type 1 diabetes, matched for age, diabetes duration, HbA(1c), and parity, who did not develop PE (DM PE-). Data were analyzed without and with adjustment for baseline differences in BMI, HDL cholesterol, and prandial status. RESULTS: In unadjusted analysis, in DM PE+ versus DM PE-, α-carotene and ß-carotene were 45 and 53% lower, respectively, at visit 3 (P < 0.05), before PE onset. In adjusted analyses, the difference in ß-carotene at visit 3 remained significant. Most participants were vitamin D deficient (<20 ng/mL), and vitamin D levels were lower in DM PE+ versus DM PE- throughout the pregnancy, although this did not reach statistical significance. CONCLUSIONS: In pregnant women with type 1 diabetes, low serum α- and ß-carotene were associated with subsequent development of PE, and vitamin D deficiency may also be implicated.

Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis.

INTRODUCTION: The use of low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes is recommended by existing guidelines, but definitive evidence supporting its efficacy is lacking. The authors undertook a meta-analysis of published trials to determine the effect of low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes. METHODS: Randomized controlled trials comparing low-dose aspirin versus placebo or no treatment in patients with diabetes (either exclusively or as a subgroup) with no previous history of cardiovascular disease were identified through MEDLINE and EMBASE databases. RESULTS: Seven randomized controlled trials met the inclusion criteria. Two studies included exclusively patients with diabetes, whereas the remaining 5 studies included patients with diabetes as a subgroup. Two studies were excluded because they did not provide diabetes-specific data. Overall, aspirin was associated with a nonsignificant reduction in the hazard rate of the composite endpoint of major cardiovascular events compared with control (hazard ratio = 0.89, 95% confidence interval: 0.70-1.13, P = 0.33). Similarly, there was a nonsignificant reduction in the hazard rate of the individual endpoints of myocardial infarction, stroke, cardiovascular and all-cause mortality. The risk of major bleeding increased nonsignificantly with aspirin compared with control (relative risk = 3.02, 95% confidence interval: 0.48-18.86, P = 0.24). DISCUSSION: The role of low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes remains unproven, and its routine use cannot be justified at present. More trials are needed to definitively address this issue.

Diabetes, insulin treatment, and cancer risk: what is the evidence?

Diabetes, in particular type 2, is associated with an increased incidence of cancer. Although the mortality attributable to cancer in type 2 diabetes is overshadowed by that due to cardiovascular disease, emerging data from epidemiologic studies suggest that insulin therapy may confer added risk for cancer, perhaps mediated by signaling through the IGF-1 (insulin-like growth factor-1) receptor. Co-administered metformin seems to mitigate the risk associated with insulin. A recent series of publications in Diabetologia addresses the possibility that glargine, the most widely used long-acting insulin analogue, may confer a greater risk than other insulin preparations, particularly for breast cancer. This has led to a heated controversy. Despite this, there is a consensus that the currently available data are not conclusive and should not be the basis for any change in practice. Further studies and more thorough surveillance of cancer in diabetes are needed to address this important issue.

Web-based management of diabetes through glucose uploads: has the time come for telemedicine?

This review focuses on the burgeoning use of web-based systems allowing patient-initiated glucometer uploads to facilitate provider treatment intensification. Studies in type 1 diabetes tended to show equivalent HbA1c improvements in both intervention and control groups without statistically significant difference. In contrast, type 2 patients seemed to do better than controls with significant differences in HbA1c. Patients were the beneficiaries of web-based diabetes management both through savings in time and cost. Major obstacles to wider implementation are patient computer skills, adherence to the technology, architectural and technical design, and the need to reimburse providers for their care.

[Interest of the noninvasive techniques for the measurement of the blood pressure in critical care]. / Intérêt des techniques non invasives pour la mesure de la pression artérielle en réanimation.

OBJECTIVE: The goal of this study is to compare three techniques for the measurement of arterial blood pressure (invasive (I), oscillometric (O), and sphygmomanometric (S)) in critically ill patients to determine if the noninvasive techniques can replace the arterial catheterization, and to see whether the relation between these three methods varies over time. MATERIAL AND METHODS: Thiyty-three patients were recruited in the medical critical care unit at Hôtel-Dieu de France hospital. Each patient included had an arterial catheter inserted in the right femoral artery. The cuff of the oscillometer was positioned on the level of the right arm and measurements by sphygmomanometric technique were carried out on the level of the left arm. All measurements were taken at the same time, three times per day, during the patient stay in the critical care unit. RESULTS: The study period was five days with an overall of fifteen measurements for each technique. At t0, the calculation of the correlation coefficients of Spearman showed a very good correlation between the three measurements techniques for systolic (I/O: r = 0.7258, p < 0.001; I/S: r = 0.8824, p < 0.001; O/S: r = 0.8675, p < 0.001), diastolic (I/O: r = 0.7620, p < 0.001; I/S: r = 0.7910, p < 0.001; O/S: r = 0.7152, p < 0.001) and mean (I/O: r = 0.7725, p < 0.001; I/S: r = 0.8221, p < 0.001; O/S: r = 0.8363, p < 0.001) pressures. Between t1 and t15, analysis of variance (ANOVA) showed that the three methods remained well correlated (systolic p = 0.175; diastolic p = 0.107; mean p = 0.550). The calculation of the limits of agreement between the three techniques showed a lack of agreement between the invasive technique and the sphygmomanometric technique in 25% of the cases, and a good agreement between invasive and oscillometric techniques in 87.5% of the cases. CONCLUSION: Oscillometry can replace the direct intra-arterial standard technique for the monitoring of the blood pressure in the intensive care unit. In contrast, the sphygmomanometry in the ICU gives inaccurate results that could lead to inappropriate therapeutic attitudes.