Journal of Diabetes and Its Complications, Apr 1, 2017
Selective estrogen receptor modulators (SERMs) are a class of compounds that interact with estrog... more Selective estrogen receptor modulators (SERMs) are a class of compounds that interact with estrogen receptors (ERs) and exert agonist or antagonist effects on ERs in a tissue-specific manner. Tamoxifen, a first generation SERM, is used for treatment of ER positive breast cancer. Raloxifene, a second generation SERM, was used to prevent postmenopausal osteoporosis. The third-generation SERM bazedoxifene (BZA) effectively prevents osteoporosis while preventing estrogenic stimulation of breast and uterus. Notably, BZA combined with conjugated estrogens (CE) is a new menopausal treatment. The menopausal state predisposes to metabolic syndrome and type 2 diabetes, and therefore the effects of SERMs on metabolic homeostasis are gaining attention. Here, we summarize knowledge of SERMs' impacts on metabolic, homeostasis, obesity and diabetes in rodent models and postmenopausal women.
Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands that exhibit ei... more Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands that exhibit either estrogen agonistic or antagonistic activity in a tissue-specific manner. The first and second generation SERMs, tamoxifen and raloxifene, are used for treatment of ER positive breast cancer and postmenopausal osteoporosis respectively. The third-generation SERM, bazedoxifene (BZA), effectively prevents osteoporosis while blocking the estrogenic stimulation in breast and uterus. Notably, BZA combined with conjugated estrogens (CE) in a tissue-selective estrogen complex (TSEC) is a new menopausal treatment. Postmenopausal estrogen deficiency predisposes to metabolic syndrome and type 2 diabetes, and therefore the effects of SERMs and TSECs on metabolic homeostasis are gaining attention. In this article, we summarize current knowledge about the impact of SERMs on metabolic homeostasis and metabolic disorders in animal models and postmenopausal women.
average TTR) if the score ranges from 0 to 2, and those less likely to attain a good TTR (if SAMe... more average TTR) if the score ranges from 0 to 2, and those less likely to attain a good TTR (if SAMe-TT2R2 score >2), for whom a NOAC would be a better treatment option that would spare the patient from taking warfarin for a trial period. The latter could result in a suboptimal TTR during the inception phase, leading to an increased risk of stroke and thromboembolism.4 The most recently published validation trial had a large prospective nationwide cohort of 1056 patients with atrial fibrillation, in whom the SAMe-TT2R2 score was able to discriminate patients who had good anticoagulation control, which was reflected by various parameters (high TTR, proportion of INRs within range, INR variability, time within range, any INR >3, time with INR >4, and INR >4) (C-index approximately 0.6).5 A high SAMe-TT2R2 score has already been shown to be predictive of a labile INR, and the consequent adverse effects of thromboembolism, bleeding, and mortality in patients treated with a VKA; however, the score was not predictive of these adverse events in patients who had not received anticoagulation medication (C-index approximately 0.57).6 We hope that a treatment strategy guided by the SAMe-TT2R2 score can eventually be part of a randomized trial. However, this poses some challenges in countries in which NOACs are already widely used because patient choice may lead to many having a preference for NOACs rather than VKAs.
Journal of Diabetes and Its Complications, Mar 1, 2015
Worldwide, both underdiagnosis and undertreatment leave many patients exposed to long periods of ... more Worldwide, both underdiagnosis and undertreatment leave many patients exposed to long periods of hyperglycemia and contribute to irreversible diabetes complications. Early glucose control reduces the risk of both macrovascular and microvascular complications, while tight control late in diabetes has little or no macrovascular benefit. Insulin therapy offers the most potent antihyperglycemic effect of all diabetes agents, and has a unique ability to induce diabetes remission when used to normalize glycemia in newly diagnosed patients. When used as a second-line therapy, basal insulin is more likely to safely and durably maintain A1C levels ≤7% than when insulin treatment is delayed. The use of basal insulin analogs is associated with a reduced risk of hypoglycemia and weight gain compared to NPH insulin and pre-mixed insulin. Patient selftitration algorithms can improve glucose control while decreasing the burden on office staff. Finally, recent data suggest that addition of incretin agents to basal insulin may improve glycemic control with very little, if any increased risk of hypoglycemia or weight gain.
With a plethora of new drugs for diabetes, and distinct differences in their mechanisms of action... more With a plethora of new drugs for diabetes, and distinct differences in their mechanisms of action and non-glycaemic effects, the selection of a second-line medication to add to metformin is now a complex decision. Guidelines 1,2 offer some suggestions for individualisation of treatment, based on efficacy, side-effects, and cost. But the appropriate choice might be challenging for clinicians, patients, and payers, and older (and cheaper) drugs such as sulfonylureas and thiazolidinediones remain in use despite concerns about side-effects. The scarcity of data on the long-term comparative effectiveness of these drugs is a limitation, although some ongoing trials such as CAROLINA 3 and GRADE 4 might offer some insight in the future. However, the GRADE study will provide limited information on complications because it focuses on glycaemic control, and pioglitazone, sodium-glucose co-transporter-2 inhibitors, and some others are not among the comparator arms, while CAROLINA is comparing the dipeptidyl peptidase-4 inhibitor linagliptin with the sulfonylurea glimepiride. The results of the TOSCA.IT trial, 5 which investigated the cardiovascular effects, safety, and glycaemic efficacy of pioglitazone versus sulfonylureas as add-ons to metformin, reported in The Lancet Diabetes & Endocrinology, might help to fill some of this void and provide useful insight into these drugs. The trial was done at 57 sites in Italy and included 3028 randomly assigned patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin alone. It had a pragmatic design, with the choice of pioglitazone or sulfonylurea (mostly glimepiride or gliclazide) used as determined by local practice. The trial was stopped early, after a median follow-up of 57•3 months, on the basis of a futility analysis, with no between-group difference identified in the primary cardiovascular outcome (a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation; hazard ratio [HR] 0•96, 95% CI 0•74-1•26, p=0•79). The study futility highlights the changing nature of the clinical expression of type 2 diabetes, with the low cardiovascular event rate attributable to effective preventive measures, such as use of statins, antihypertensive agents, and antiplatelet agents. The event rate was less than half of that estimated, based on what was seen in PROACTIVE trial just a decade earlier. 6 Diabetes is no longer universally a cardiovascular risk equivalent, and an appropriate risk evaluation is needed for every patient, although improved methods of risk stratification are needed. One conclusion that could be drawn from TOSCA.IT is that for patients with early diabetes
Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits c... more Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits calcineurin and prevents T cell activation. Post-transplantation diabetes mellitus (PTDM) is a well-established adverse effect of tacrolimus. We report the rare occurrences of DKA and hyperosmolar hyperglycemia syndrome respectively in 2 patients on tacrolimus after renal transplants. Description Case 1: A 25 year old obese (BMI 37.7 kg/m2) black female with no history of DM received a live donor kidney transplant. She was on mycophenolate 720 mg po bid, tacrolimus 7 mg po bid, and prednisone 5 mg daily. Eleven weeks after transplant she presented with polyuria and polydipsia and was admitted for DKA. Labs revealed glucose 1000 mg/dL (74-106) , HCO3 7.0 meq/L (21-32) , beta-hydroxybutyric acid 8.4 mg/dL (0.2 - 2.8) , tacrolimus trough levels 19.6 ng/mL (4.1 - 10.7) . Her A1c was 10.6% compared to 5.3% pre-transplant. Case 2: A 50 year old obese (BMI 35.6 kg/m2) black female with no prior history of DM received a cadaveric kidney transplant due to ESRD. Patient was on mycophenolate 360 mg bid, and tacrolimus 8 mg bid. She was admitted to hospital for HHS 9 weeks later. Labs revealed a glucose 940 mg/dL, serum osmolality 341 msom/kg (275-295) , HCO3 22 mmol/L, tacrolimus trough levels 12.1 ng/mL. Her A1c was 8.7% compared to 5.3% pre-transplant. Discussion: Our 2 patients with no history of DM developed hyperglycemic emergencies within 3 months of receiving kidney transplants and initiating tacrolimus. Both responded well to IV fluids and insulin and were transitioned to SQ insulin by discharge. Risk factors for post-transplant de novo DKA and HHS common to both patients were African American ethnicity, high BMI, and tacrolimus treatment with elevated trough levels. Tacrolimus inhibits insulin secretion and is linked to increased rates of PTDM, which is often reversible with tacrolimus dosage reduction. Both of our patients were prescribed tacrolimus at reduced dosage and were scheduled for outpatient Endocrine clinic evaluation to determine whether they should continue insulin treatment. Disclosure S. Gupta: None. D. Lovre: Other Relationship; AstraZeneca, Bayer AG, Novo Nordisk. R. Galagan: None.
Cardiovascular disease (CVD) is common in patients with diabetes. For these patients, clinicians ... more Cardiovascular disease (CVD) is common in patients with diabetes. For these patients, clinicians should seek diabetes treatment that is beneficial rather than harmful in relation to CVD. Until recently, there have been many treatments for hyperglycemia, whose impact on CVD has been controversial. The aims of this review are to evaluate the effectiveness of antihyperglycemic medications on risk factors for CVD and to examine the impact of these drugs on CVD in cardiovascular (CV) outcome trials. In this article, we summarize current knowledge about the impacts of these drugs on various risk factors as well as CV outcomes. We identify the recent emergence of trials with antihyperglycemic agents showing newly discovered CV benefits as well as past trials with antihyperglycemic agents not showing much benefit on CV events. Rather than focusing on treatment strategies, we review the effects of individual drug classes on CV outcomes. We also briefly review goal-driven glycemia reduction and its impact on CVD. We conclude that antihyperglycemic agents are associated with improvement in CV risk factors in patients with diabetes and insulin resistance; in fact, a few drugs reduced CV events in randomized CV outcome trials. Therefore, the use of these drugs is appropriate for reducing glucose and decreasing CV event risk in a select subpopulation.
Therapeutic Advances in Cardiovascular Disease, Jul 31, 2016
Across the board, MetS, specifically central or abdominal obesity, exhibits higher prevalence in ... more Across the board, MetS, specifically central or abdominal obesity, exhibits higher prevalence in women as compared with men [Mauvais-Jarvis, 2015]. As the population ages, women will spend an increasing share of their lives in menopause. Because menopause is a condition that also predisposes to metabolic dysfunction, the prevalence of MetS will likely increase dramatically in women. During menopause, alterations in body composition and energy homeostasis increase visceral fat and IR, both of which also predispose to MetS in women. Therefore, understanding the effects of menopause and menopausal hormone therapy (MHT) on components of the MetS is critical to the prevention of this condition in women. This review discusses the effect of menopause on metabolic dysfunction with a specific focus on components of the MetS. We also review the effect of MHT on metabolic homeostasis and discuss therapeutic advances of novel menopausal treatment on metabolic function. Effect of menopause on components of the metabolic syndrome Aging is accompanied by decreased lean mass and physical activity. Together, they predispose to increased total fat and IR and ultimately metabolic dysfunction. However, the menopausal transition itself is characterized by changes in body composition and metabolic homeostasis that predispose to MetS [Carr, 2003]. Obesity The increased body mass and adiposity that occur after menopause are difficult to differentiate from the effects of normal aging. Multiple cross-sectional studies have suggested that postmenopausal women exhibit increased total fat mass, increased abdominal fat, and decreased lean body mass (LBM) in comparison to premenopausal women independent of aging [
SAT-014 Background: Pregnant women with obesity are at increased risk for peripartum depression. ... more SAT-014 Background: Pregnant women with obesity are at increased risk for peripartum depression. Maternal obesity is also associated with reduced human placental lactogen (hPL) levels, and decreased hPL transcripts were reported in women with clinical depression. In addition, hPL production may be rescued in women with obesity that were subsequently diagnosed with gestational diabetes and treated with insulin (INS). Objective: Study the effect of INS treatment in pregnancy on the risk for postpartum psychological distress (PPD) in women with and without obesity. Study Design: Using data housed at the Manitoba Centre for Health Policy (2002-2017), cohorts of women (ages 15+) with a single live birth with and without obesity were developed using weight (≥85 and <65.6 kg, respectively) and an average (1.63 m) height. Pre-existing mood and anxiety disorders within 5 years preceding delivery as well as gestational hypertension were excluded. After randomly selecting 1 birth per mother, cohorts were stratified by INS treatment during the gestational period. The risk of PPD within 1 year of delivery was assessed by Poisson regression analysis. Models were adjusted for maternal age and area-level income at delivery. Results: The risk of PPD was 27% greater among women with obesity versus without (adjusted rate ratio (aRR)=1.27, 95% CI 1.16-1.4, p<0.0001). However, women with obesity treated with INS did not have a significantly different risk of PPD compared to women without obesity whether treated with INS (aRR=0.99, 95%CI 0.48-2.02, p=0.974) or not (aRR=1.16, 95%CI 0.86-1.56, p=0.328). This suggests that the risk of PPD among women with obesity may be reduced by INS treatment; however, our ability to detect a significant difference may be limited by small cohort numbers (46 women with obesity received INS in pregnancy) or confounders for receiving INS in pregnancy. Direct comparison of INS treatment within weight groups faced the same limitations but trended toward a reduction in women with obesity who received INS (aRR=0.91, 95%CI 0.68-1.22, p=0.531). The positive association between INS treatment in pregnancy and decreased risk of PPD in women with obesity was lost when pre-existing mood and anxiety disorder was not excluded. Inclusion of pre-existing diabetes in the adjusted models did not improve model fit or contribute significantly to the differences in PPD rates. Conclusions: Maternal obesity increases the risk for PPD but this risk may be reduced by gestational INS treatment in the absence of a pre-existing mood and anxiety disorders. This correlates with the decrease and increase in hPL levels reported previously with maternal obesity without and with INS treatment (for diabetes) in pregnancy, respectively. Thus, hPL levels may serve as a possible indicator of PPD risk and a potential target for gestational INS treatment.
The American Journal of the Medical Sciences, Aug 1, 2017
Women and men with type 2 diabetes mellitus (T2DM) have an increased incidence of atherosclerotic... more Women and men with type 2 diabetes mellitus (T2DM) have an increased incidence of atherosclerotic cardiovascular disease (CVD) which is attributed to multiple risk factors including dyslipidemia characterized by elevated plasma Triglyceride (TG), low levels of High-Density-Lipoprotein Cholesterol (HDL-C) and increased small, dense Low-Density Lipoprotein (sd-LDL) particles. The ratio of TG/HDL-C is sometimes calculated and named the "atherogenic index". Although plasma LDL concentrations are similar to the concentrations in people without diabetes, LDL lowering has been particularly beneficial in people with diabetes. Multiple trials have shown that HMG-CoA reductases (statins) are efficacious in reducing the risk of cardiovascular events (CVEs) in participants with T2DM; however, rates of CVEs remain higher
Midlife women experience changes in cardiometabolic, physical, and psychosocial health during men... more Midlife women experience changes in cardiometabolic, physical, and psychosocial health during menopause that negatively impacts their overall quality of life. Factors that contribute to these increases in cardiometabolic risk include weight gain as well as increases in fat mass (particularly abdominal adiposity), insulin resistance, and vascular dysfunction. Other deleterious changes in physical health (e. g. reduced sleep health, bone density, and balance) as well as changes in psychosocial health (e. g. mood, anxiety, and depression) often coincide and are linked to these increases in cardiometabolic risk. Physical activity and exercise are important lifestyle components that have been demonstrated to improve cardiometabolic, physical, and psychosocial health, yet physical activity and exercise is known to decline during perimenopause and into the postmenopausal years. In this narrative review, we summarize these changes in overall health during menopause as well as how declining ...
Background Pituitary adenomas co-secreting GH, Prolactin and ACTH are rare. Clinical Case A 38-ye... more Background Pituitary adenomas co-secreting GH, Prolactin and ACTH are rare. Clinical Case A 38-year-old male with a past medical history of depression and type 2 diabetes mellitus was seen in the endocrinology clinic for an evaluation of acromegaly. In the preceding four years, the patient had experienced an enlargement of his hands and feet, hyperhidrosis, development of an underbite, snoring, daytime somnolence, erectile dysfunction, headaches, and blurry vision. His visual fields were normal. Physical exam: BP 137/85, BMI 39 kg/m2. He had coarse facial features, acral changes of his hands and feet, and wide spacing of his teeth. There was a notable absence of facial plethora, abdominal obesity with thin extremities, proximal muscle weakness, purple abdominal striae, and galactorrhea. Initial laboratory results: GH 16.9 ng/mL (0.05-3 ng/ml), IGF-1 1,109 ng/mL (82-242 ng/mL), Prolactin (PRL) 96.9 ng/ml (5-20 ng/ml), testosterone 34 ng/dL (200-1000 ng/dL), LH 2.3 miu/ml (1.4–12 miu/...
OBJECTIVE Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney ... more OBJECTIVE Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial. We explored whether baseline HbA1c level and insulin treatment influenced outcomes. RESEARCH DESIGN AND METHODS Patients with T2D, urine albumin-to-creatinine ratio (UACR) of 30–5,000 mg/g, estimated glomerular filtration rate (eGFR) of 25 to <75 mL/min/1.73 m2, and treated with optimized renin–angiotensin system blockade were randomly assigned to receive finerenone or placebo. Efficacy outcomes included kidney (kidney failure, sustained decrease ≥40% in eGFR from baseline, or renal death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite endpoints. Patients were analyzed by baseline insulin use and by baseline HbA1c <7.5% (58 mmol/mol) or ≥7.5%. RESULTS...
multivariable regression models adjusted for age, sex, race, and BMI. BNPMS was not significantly... more multivariable regression models adjusted for age, sex, race, and BMI. BNPMS was not significantly associated with BNPia, possibly partially due to the large percentage whose BNPMS and/or BNPia was undetectably low (44% and 56%, respectively) in this non-heart failure cohort. Discussion: Using a novel UPLC-MS/MS technique, we found that ANPMS is lower in obesity, and BNPMS is lower in black individuals and in those with higher fasting glucose. Our results are consistent with relationships of NPs assessed by traditional immunoassay methods from large epidemiologic studies. Our findings are particularly striking as our sample size was relatively small compared with epidemiologic studies. Our analyses of bioactive NP levels by this specific methodology support the emerging hypothesis that obese and black individuals experience a relative NP deficiency. Future large-scale studies quantifying bioactive NPs by MS are warranted to refine the phenotyping of individuals with relative NP deficiency and determine whether relative NP deficiency contributes to greater cardiometabolic risk.
Objective The impact of comorbidities and biomarkers on COVID-19 severity vary by sex but have no... more Objective The impact of comorbidities and biomarkers on COVID-19 severity vary by sex but have not yet been verified in population-based studies. We examined the association of comorbidities, inflammatory biomarkers, and severe outcomes in men and women hospitalized for COVID-19. Design This is a retrospective cohort analysis based on the National COVID Cohort Collaborative (N3C). We included 574,391 adult patients admitted for COVID-19 at hospitals or emergency rooms between 01/01/2020 and 12/31/2021. Methods We defined comorbidities at or before the first admission for COVID-19 by Charlson Comorbidity Index (CCI) and CCI components. We used the averaged lab values taken within 15 days before or after the admission date to measure biomarkers including c-reactive protein (CRP), ferritin, procalcitonin, N-terminal pro b-type natriuretic peptide (NT proBNP), d-dimer, absolute lymphocyte counts, absolute neutrophil counts, and platelets. Our primary outcome was all-cause mortality; sec...
Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits c... more Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits calcineurin and prevents T cell activation. Post-transplantation diabetes mellitus (PTDM) is a well-established adverse effect of tacrolimus. We report the rare occurrences of DKA and hyperosmolar hyperglycemia syndrome respectively in 2 patients on tacrolimus after renal transplants. Description Case 1: A 25 year old obese (BMI 37.7 kg/m2) black female with no history of DM received a live donor kidney transplant. She was on mycophenolate 720 mg po bid, tacrolimus 7 mg po bid, and prednisone 5 mg daily. Eleven weeks after transplant she presented with polyuria and polydipsia and was admitted for DKA. Labs revealed glucose 1000 mg/dL (74-106) , HCO3 7.0 meq/L (21-32) , beta-hydroxybutyric acid 8.4 mg/dL (0.2 - 2.8) , tacrolimus trough levels 19.6 ng/mL (4.1 - 10.7) . Her A1c was 10.6% compared to 5.3% pre-transplant. Case 2: A 50 year old obese (BMI 35.6 kg/m2) black female with no prior ...
Additional file 1: eFigure 1.A. Multivariable Analysis of Comorbidities and ICU by Race. eFigure ... more Additional file 1: eFigure 1.A. Multivariable Analysis of Comorbidities and ICU by Race. eFigure 1.B. Multivariable Analysis of Comorbidities and IMV by Race. eFigure 1.C. Multivariable Analysis of Comorbidities and Death by Race. eFigure 2.A. Multivariable Analysis of Biomarkers and ICU by Race. eFigure 2.B. Multivariable Analysis of Biomarkers and IMV by Race. eFigure 2.C. Multivariable Analysis of Biomarkers and Death by Race. eTable 1. Demographic Characteristics and comorbidities prior to admission– Blacks vs. non-Blacks. eTable 2. Clinical symptoms and biomarkers at admission – Blacks vs. non-Blacks.
Journal of Diabetes and Its Complications, Apr 1, 2017
Selective estrogen receptor modulators (SERMs) are a class of compounds that interact with estrog... more Selective estrogen receptor modulators (SERMs) are a class of compounds that interact with estrogen receptors (ERs) and exert agonist or antagonist effects on ERs in a tissue-specific manner. Tamoxifen, a first generation SERM, is used for treatment of ER positive breast cancer. Raloxifene, a second generation SERM, was used to prevent postmenopausal osteoporosis. The third-generation SERM bazedoxifene (BZA) effectively prevents osteoporosis while preventing estrogenic stimulation of breast and uterus. Notably, BZA combined with conjugated estrogens (CE) is a new menopausal treatment. The menopausal state predisposes to metabolic syndrome and type 2 diabetes, and therefore the effects of SERMs on metabolic homeostasis are gaining attention. Here, we summarize knowledge of SERMs' impacts on metabolic, homeostasis, obesity and diabetes in rodent models and postmenopausal women.
Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands that exhibit ei... more Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands that exhibit either estrogen agonistic or antagonistic activity in a tissue-specific manner. The first and second generation SERMs, tamoxifen and raloxifene, are used for treatment of ER positive breast cancer and postmenopausal osteoporosis respectively. The third-generation SERM, bazedoxifene (BZA), effectively prevents osteoporosis while blocking the estrogenic stimulation in breast and uterus. Notably, BZA combined with conjugated estrogens (CE) in a tissue-selective estrogen complex (TSEC) is a new menopausal treatment. Postmenopausal estrogen deficiency predisposes to metabolic syndrome and type 2 diabetes, and therefore the effects of SERMs and TSECs on metabolic homeostasis are gaining attention. In this article, we summarize current knowledge about the impact of SERMs on metabolic homeostasis and metabolic disorders in animal models and postmenopausal women.
average TTR) if the score ranges from 0 to 2, and those less likely to attain a good TTR (if SAMe... more average TTR) if the score ranges from 0 to 2, and those less likely to attain a good TTR (if SAMe-TT2R2 score >2), for whom a NOAC would be a better treatment option that would spare the patient from taking warfarin for a trial period. The latter could result in a suboptimal TTR during the inception phase, leading to an increased risk of stroke and thromboembolism.4 The most recently published validation trial had a large prospective nationwide cohort of 1056 patients with atrial fibrillation, in whom the SAMe-TT2R2 score was able to discriminate patients who had good anticoagulation control, which was reflected by various parameters (high TTR, proportion of INRs within range, INR variability, time within range, any INR >3, time with INR >4, and INR >4) (C-index approximately 0.6).5 A high SAMe-TT2R2 score has already been shown to be predictive of a labile INR, and the consequent adverse effects of thromboembolism, bleeding, and mortality in patients treated with a VKA; however, the score was not predictive of these adverse events in patients who had not received anticoagulation medication (C-index approximately 0.57).6 We hope that a treatment strategy guided by the SAMe-TT2R2 score can eventually be part of a randomized trial. However, this poses some challenges in countries in which NOACs are already widely used because patient choice may lead to many having a preference for NOACs rather than VKAs.
Journal of Diabetes and Its Complications, Mar 1, 2015
Worldwide, both underdiagnosis and undertreatment leave many patients exposed to long periods of ... more Worldwide, both underdiagnosis and undertreatment leave many patients exposed to long periods of hyperglycemia and contribute to irreversible diabetes complications. Early glucose control reduces the risk of both macrovascular and microvascular complications, while tight control late in diabetes has little or no macrovascular benefit. Insulin therapy offers the most potent antihyperglycemic effect of all diabetes agents, and has a unique ability to induce diabetes remission when used to normalize glycemia in newly diagnosed patients. When used as a second-line therapy, basal insulin is more likely to safely and durably maintain A1C levels ≤7% than when insulin treatment is delayed. The use of basal insulin analogs is associated with a reduced risk of hypoglycemia and weight gain compared to NPH insulin and pre-mixed insulin. Patient selftitration algorithms can improve glucose control while decreasing the burden on office staff. Finally, recent data suggest that addition of incretin agents to basal insulin may improve glycemic control with very little, if any increased risk of hypoglycemia or weight gain.
With a plethora of new drugs for diabetes, and distinct differences in their mechanisms of action... more With a plethora of new drugs for diabetes, and distinct differences in their mechanisms of action and non-glycaemic effects, the selection of a second-line medication to add to metformin is now a complex decision. Guidelines 1,2 offer some suggestions for individualisation of treatment, based on efficacy, side-effects, and cost. But the appropriate choice might be challenging for clinicians, patients, and payers, and older (and cheaper) drugs such as sulfonylureas and thiazolidinediones remain in use despite concerns about side-effects. The scarcity of data on the long-term comparative effectiveness of these drugs is a limitation, although some ongoing trials such as CAROLINA 3 and GRADE 4 might offer some insight in the future. However, the GRADE study will provide limited information on complications because it focuses on glycaemic control, and pioglitazone, sodium-glucose co-transporter-2 inhibitors, and some others are not among the comparator arms, while CAROLINA is comparing the dipeptidyl peptidase-4 inhibitor linagliptin with the sulfonylurea glimepiride. The results of the TOSCA.IT trial, 5 which investigated the cardiovascular effects, safety, and glycaemic efficacy of pioglitazone versus sulfonylureas as add-ons to metformin, reported in The Lancet Diabetes & Endocrinology, might help to fill some of this void and provide useful insight into these drugs. The trial was done at 57 sites in Italy and included 3028 randomly assigned patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin alone. It had a pragmatic design, with the choice of pioglitazone or sulfonylurea (mostly glimepiride or gliclazide) used as determined by local practice. The trial was stopped early, after a median follow-up of 57•3 months, on the basis of a futility analysis, with no between-group difference identified in the primary cardiovascular outcome (a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation; hazard ratio [HR] 0•96, 95% CI 0•74-1•26, p=0•79). The study futility highlights the changing nature of the clinical expression of type 2 diabetes, with the low cardiovascular event rate attributable to effective preventive measures, such as use of statins, antihypertensive agents, and antiplatelet agents. The event rate was less than half of that estimated, based on what was seen in PROACTIVE trial just a decade earlier. 6 Diabetes is no longer universally a cardiovascular risk equivalent, and an appropriate risk evaluation is needed for every patient, although improved methods of risk stratification are needed. One conclusion that could be drawn from TOSCA.IT is that for patients with early diabetes
Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits c... more Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits calcineurin and prevents T cell activation. Post-transplantation diabetes mellitus (PTDM) is a well-established adverse effect of tacrolimus. We report the rare occurrences of DKA and hyperosmolar hyperglycemia syndrome respectively in 2 patients on tacrolimus after renal transplants. Description Case 1: A 25 year old obese (BMI 37.7 kg/m2) black female with no history of DM received a live donor kidney transplant. She was on mycophenolate 720 mg po bid, tacrolimus 7 mg po bid, and prednisone 5 mg daily. Eleven weeks after transplant she presented with polyuria and polydipsia and was admitted for DKA. Labs revealed glucose 1000 mg/dL (74-106) , HCO3 7.0 meq/L (21-32) , beta-hydroxybutyric acid 8.4 mg/dL (0.2 - 2.8) , tacrolimus trough levels 19.6 ng/mL (4.1 - 10.7) . Her A1c was 10.6% compared to 5.3% pre-transplant. Case 2: A 50 year old obese (BMI 35.6 kg/m2) black female with no prior history of DM received a cadaveric kidney transplant due to ESRD. Patient was on mycophenolate 360 mg bid, and tacrolimus 8 mg bid. She was admitted to hospital for HHS 9 weeks later. Labs revealed a glucose 940 mg/dL, serum osmolality 341 msom/kg (275-295) , HCO3 22 mmol/L, tacrolimus trough levels 12.1 ng/mL. Her A1c was 8.7% compared to 5.3% pre-transplant. Discussion: Our 2 patients with no history of DM developed hyperglycemic emergencies within 3 months of receiving kidney transplants and initiating tacrolimus. Both responded well to IV fluids and insulin and were transitioned to SQ insulin by discharge. Risk factors for post-transplant de novo DKA and HHS common to both patients were African American ethnicity, high BMI, and tacrolimus treatment with elevated trough levels. Tacrolimus inhibits insulin secretion and is linked to increased rates of PTDM, which is often reversible with tacrolimus dosage reduction. Both of our patients were prescribed tacrolimus at reduced dosage and were scheduled for outpatient Endocrine clinic evaluation to determine whether they should continue insulin treatment. Disclosure S. Gupta: None. D. Lovre: Other Relationship; AstraZeneca, Bayer AG, Novo Nordisk. R. Galagan: None.
Cardiovascular disease (CVD) is common in patients with diabetes. For these patients, clinicians ... more Cardiovascular disease (CVD) is common in patients with diabetes. For these patients, clinicians should seek diabetes treatment that is beneficial rather than harmful in relation to CVD. Until recently, there have been many treatments for hyperglycemia, whose impact on CVD has been controversial. The aims of this review are to evaluate the effectiveness of antihyperglycemic medications on risk factors for CVD and to examine the impact of these drugs on CVD in cardiovascular (CV) outcome trials. In this article, we summarize current knowledge about the impacts of these drugs on various risk factors as well as CV outcomes. We identify the recent emergence of trials with antihyperglycemic agents showing newly discovered CV benefits as well as past trials with antihyperglycemic agents not showing much benefit on CV events. Rather than focusing on treatment strategies, we review the effects of individual drug classes on CV outcomes. We also briefly review goal-driven glycemia reduction and its impact on CVD. We conclude that antihyperglycemic agents are associated with improvement in CV risk factors in patients with diabetes and insulin resistance; in fact, a few drugs reduced CV events in randomized CV outcome trials. Therefore, the use of these drugs is appropriate for reducing glucose and decreasing CV event risk in a select subpopulation.
Therapeutic Advances in Cardiovascular Disease, Jul 31, 2016
Across the board, MetS, specifically central or abdominal obesity, exhibits higher prevalence in ... more Across the board, MetS, specifically central or abdominal obesity, exhibits higher prevalence in women as compared with men [Mauvais-Jarvis, 2015]. As the population ages, women will spend an increasing share of their lives in menopause. Because menopause is a condition that also predisposes to metabolic dysfunction, the prevalence of MetS will likely increase dramatically in women. During menopause, alterations in body composition and energy homeostasis increase visceral fat and IR, both of which also predispose to MetS in women. Therefore, understanding the effects of menopause and menopausal hormone therapy (MHT) on components of the MetS is critical to the prevention of this condition in women. This review discusses the effect of menopause on metabolic dysfunction with a specific focus on components of the MetS. We also review the effect of MHT on metabolic homeostasis and discuss therapeutic advances of novel menopausal treatment on metabolic function. Effect of menopause on components of the metabolic syndrome Aging is accompanied by decreased lean mass and physical activity. Together, they predispose to increased total fat and IR and ultimately metabolic dysfunction. However, the menopausal transition itself is characterized by changes in body composition and metabolic homeostasis that predispose to MetS [Carr, 2003]. Obesity The increased body mass and adiposity that occur after menopause are difficult to differentiate from the effects of normal aging. Multiple cross-sectional studies have suggested that postmenopausal women exhibit increased total fat mass, increased abdominal fat, and decreased lean body mass (LBM) in comparison to premenopausal women independent of aging [
SAT-014 Background: Pregnant women with obesity are at increased risk for peripartum depression. ... more SAT-014 Background: Pregnant women with obesity are at increased risk for peripartum depression. Maternal obesity is also associated with reduced human placental lactogen (hPL) levels, and decreased hPL transcripts were reported in women with clinical depression. In addition, hPL production may be rescued in women with obesity that were subsequently diagnosed with gestational diabetes and treated with insulin (INS). Objective: Study the effect of INS treatment in pregnancy on the risk for postpartum psychological distress (PPD) in women with and without obesity. Study Design: Using data housed at the Manitoba Centre for Health Policy (2002-2017), cohorts of women (ages 15+) with a single live birth with and without obesity were developed using weight (≥85 and <65.6 kg, respectively) and an average (1.63 m) height. Pre-existing mood and anxiety disorders within 5 years preceding delivery as well as gestational hypertension were excluded. After randomly selecting 1 birth per mother, cohorts were stratified by INS treatment during the gestational period. The risk of PPD within 1 year of delivery was assessed by Poisson regression analysis. Models were adjusted for maternal age and area-level income at delivery. Results: The risk of PPD was 27% greater among women with obesity versus without (adjusted rate ratio (aRR)=1.27, 95% CI 1.16-1.4, p<0.0001). However, women with obesity treated with INS did not have a significantly different risk of PPD compared to women without obesity whether treated with INS (aRR=0.99, 95%CI 0.48-2.02, p=0.974) or not (aRR=1.16, 95%CI 0.86-1.56, p=0.328). This suggests that the risk of PPD among women with obesity may be reduced by INS treatment; however, our ability to detect a significant difference may be limited by small cohort numbers (46 women with obesity received INS in pregnancy) or confounders for receiving INS in pregnancy. Direct comparison of INS treatment within weight groups faced the same limitations but trended toward a reduction in women with obesity who received INS (aRR=0.91, 95%CI 0.68-1.22, p=0.531). The positive association between INS treatment in pregnancy and decreased risk of PPD in women with obesity was lost when pre-existing mood and anxiety disorder was not excluded. Inclusion of pre-existing diabetes in the adjusted models did not improve model fit or contribute significantly to the differences in PPD rates. Conclusions: Maternal obesity increases the risk for PPD but this risk may be reduced by gestational INS treatment in the absence of a pre-existing mood and anxiety disorders. This correlates with the decrease and increase in hPL levels reported previously with maternal obesity without and with INS treatment (for diabetes) in pregnancy, respectively. Thus, hPL levels may serve as a possible indicator of PPD risk and a potential target for gestational INS treatment.
The American Journal of the Medical Sciences, Aug 1, 2017
Women and men with type 2 diabetes mellitus (T2DM) have an increased incidence of atherosclerotic... more Women and men with type 2 diabetes mellitus (T2DM) have an increased incidence of atherosclerotic cardiovascular disease (CVD) which is attributed to multiple risk factors including dyslipidemia characterized by elevated plasma Triglyceride (TG), low levels of High-Density-Lipoprotein Cholesterol (HDL-C) and increased small, dense Low-Density Lipoprotein (sd-LDL) particles. The ratio of TG/HDL-C is sometimes calculated and named the "atherogenic index". Although plasma LDL concentrations are similar to the concentrations in people without diabetes, LDL lowering has been particularly beneficial in people with diabetes. Multiple trials have shown that HMG-CoA reductases (statins) are efficacious in reducing the risk of cardiovascular events (CVEs) in participants with T2DM; however, rates of CVEs remain higher
Midlife women experience changes in cardiometabolic, physical, and psychosocial health during men... more Midlife women experience changes in cardiometabolic, physical, and psychosocial health during menopause that negatively impacts their overall quality of life. Factors that contribute to these increases in cardiometabolic risk include weight gain as well as increases in fat mass (particularly abdominal adiposity), insulin resistance, and vascular dysfunction. Other deleterious changes in physical health (e. g. reduced sleep health, bone density, and balance) as well as changes in psychosocial health (e. g. mood, anxiety, and depression) often coincide and are linked to these increases in cardiometabolic risk. Physical activity and exercise are important lifestyle components that have been demonstrated to improve cardiometabolic, physical, and psychosocial health, yet physical activity and exercise is known to decline during perimenopause and into the postmenopausal years. In this narrative review, we summarize these changes in overall health during menopause as well as how declining ...
Background Pituitary adenomas co-secreting GH, Prolactin and ACTH are rare. Clinical Case A 38-ye... more Background Pituitary adenomas co-secreting GH, Prolactin and ACTH are rare. Clinical Case A 38-year-old male with a past medical history of depression and type 2 diabetes mellitus was seen in the endocrinology clinic for an evaluation of acromegaly. In the preceding four years, the patient had experienced an enlargement of his hands and feet, hyperhidrosis, development of an underbite, snoring, daytime somnolence, erectile dysfunction, headaches, and blurry vision. His visual fields were normal. Physical exam: BP 137/85, BMI 39 kg/m2. He had coarse facial features, acral changes of his hands and feet, and wide spacing of his teeth. There was a notable absence of facial plethora, abdominal obesity with thin extremities, proximal muscle weakness, purple abdominal striae, and galactorrhea. Initial laboratory results: GH 16.9 ng/mL (0.05-3 ng/ml), IGF-1 1,109 ng/mL (82-242 ng/mL), Prolactin (PRL) 96.9 ng/ml (5-20 ng/ml), testosterone 34 ng/dL (200-1000 ng/dL), LH 2.3 miu/ml (1.4–12 miu/...
OBJECTIVE Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney ... more OBJECTIVE Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial. We explored whether baseline HbA1c level and insulin treatment influenced outcomes. RESEARCH DESIGN AND METHODS Patients with T2D, urine albumin-to-creatinine ratio (UACR) of 30–5,000 mg/g, estimated glomerular filtration rate (eGFR) of 25 to <75 mL/min/1.73 m2, and treated with optimized renin–angiotensin system blockade were randomly assigned to receive finerenone or placebo. Efficacy outcomes included kidney (kidney failure, sustained decrease ≥40% in eGFR from baseline, or renal death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite endpoints. Patients were analyzed by baseline insulin use and by baseline HbA1c <7.5% (58 mmol/mol) or ≥7.5%. RESULTS...
multivariable regression models adjusted for age, sex, race, and BMI. BNPMS was not significantly... more multivariable regression models adjusted for age, sex, race, and BMI. BNPMS was not significantly associated with BNPia, possibly partially due to the large percentage whose BNPMS and/or BNPia was undetectably low (44% and 56%, respectively) in this non-heart failure cohort. Discussion: Using a novel UPLC-MS/MS technique, we found that ANPMS is lower in obesity, and BNPMS is lower in black individuals and in those with higher fasting glucose. Our results are consistent with relationships of NPs assessed by traditional immunoassay methods from large epidemiologic studies. Our findings are particularly striking as our sample size was relatively small compared with epidemiologic studies. Our analyses of bioactive NP levels by this specific methodology support the emerging hypothesis that obese and black individuals experience a relative NP deficiency. Future large-scale studies quantifying bioactive NPs by MS are warranted to refine the phenotyping of individuals with relative NP deficiency and determine whether relative NP deficiency contributes to greater cardiometabolic risk.
Objective The impact of comorbidities and biomarkers on COVID-19 severity vary by sex but have no... more Objective The impact of comorbidities and biomarkers on COVID-19 severity vary by sex but have not yet been verified in population-based studies. We examined the association of comorbidities, inflammatory biomarkers, and severe outcomes in men and women hospitalized for COVID-19. Design This is a retrospective cohort analysis based on the National COVID Cohort Collaborative (N3C). We included 574,391 adult patients admitted for COVID-19 at hospitals or emergency rooms between 01/01/2020 and 12/31/2021. Methods We defined comorbidities at or before the first admission for COVID-19 by Charlson Comorbidity Index (CCI) and CCI components. We used the averaged lab values taken within 15 days before or after the admission date to measure biomarkers including c-reactive protein (CRP), ferritin, procalcitonin, N-terminal pro b-type natriuretic peptide (NT proBNP), d-dimer, absolute lymphocyte counts, absolute neutrophil counts, and platelets. Our primary outcome was all-cause mortality; sec...
Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits c... more Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits calcineurin and prevents T cell activation. Post-transplantation diabetes mellitus (PTDM) is a well-established adverse effect of tacrolimus. We report the rare occurrences of DKA and hyperosmolar hyperglycemia syndrome respectively in 2 patients on tacrolimus after renal transplants. Description Case 1: A 25 year old obese (BMI 37.7 kg/m2) black female with no history of DM received a live donor kidney transplant. She was on mycophenolate 720 mg po bid, tacrolimus 7 mg po bid, and prednisone 5 mg daily. Eleven weeks after transplant she presented with polyuria and polydipsia and was admitted for DKA. Labs revealed glucose 1000 mg/dL (74-106) , HCO3 7.0 meq/L (21-32) , beta-hydroxybutyric acid 8.4 mg/dL (0.2 - 2.8) , tacrolimus trough levels 19.6 ng/mL (4.1 - 10.7) . Her A1c was 10.6% compared to 5.3% pre-transplant. Case 2: A 50 year old obese (BMI 35.6 kg/m2) black female with no prior ...
Additional file 1: eFigure 1.A. Multivariable Analysis of Comorbidities and ICU by Race. eFigure ... more Additional file 1: eFigure 1.A. Multivariable Analysis of Comorbidities and ICU by Race. eFigure 1.B. Multivariable Analysis of Comorbidities and IMV by Race. eFigure 1.C. Multivariable Analysis of Comorbidities and Death by Race. eFigure 2.A. Multivariable Analysis of Biomarkers and ICU by Race. eFigure 2.B. Multivariable Analysis of Biomarkers and IMV by Race. eFigure 2.C. Multivariable Analysis of Biomarkers and Death by Race. eTable 1. Demographic Characteristics and comorbidities prior to admission– Blacks vs. non-Blacks. eTable 2. Clinical symptoms and biomarkers at admission – Blacks vs. non-Blacks.
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