Publications by authors named "Mark Molitch"

189 Publications

Prolactin and Other Pituitary Disorders in Kidney Disease.

Semin Nephrol 2021 Mar;41(2):156-167

Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

Prolactin levels are increased in chronic kidney disease (CKD) as a result of reduced clearance and increased secretion. Hyperprolactinemia manifests as galactorrhea and hypogonadism. Treatment of hyperprolactinemia should focus on improving bothersome galactorrhea or hypogonadism by using dopamine agonists and/or replacement of sex hormone(s). Changes in the hypothalamic-pituitary-adrenal axis in CKD are characterized by increases in adrenocorticotropic hormone (ACTH) and cortisol levels, largely preserved circadian rhythms of ACTH and cortisol, and a normal response of cortisol to ACTH, metyrapone, and insulin-induced hypoglycemia. However, the hypothalamic-pituitary-adrenal axis is less inhibited by 1 mg dexamethasone but retains normal suppression by higher-dose dexamethasone. Diagnosis of adrenal insufficiency in CKD patients, as in normal subjects, usually is made by finding a subnormal cortisol response to ACTH. The mainstay of treatment of adrenal insufficiency is to replace glucocorticoid hormone. Cushing's disease in CKD is difficult to diagnose and relies on the dexamethasone suppression test and the midnight salivary cortisol test because the 24-hour urine free cortisol test is not useful because it is increased already in CKD. Treatment of Cushing's disease involves surgery, complemented by radiation and/or medical therapy if necessary. Growth hormone levels are increased and insulin-like growth factor 1 levels are normal in patients with CKD. In a normal patient with CKD, as in one with acromegaly, there can be a paradoxic increase in growth hormone after an oral glucose load. Therefore, diagnosis of acromegaly in renal insufficiency is challenging. The treatment of choice for acromegaly is surgery, although data for medical treatment for acromegaly in CKD are rare. In patients with renal impairment, arginine vasopressin levels are increased as a result of decreased clearance, and there also is impairment of arginine vasopressin signaling in renal tubules. Diabetes insipidus can be masked in advanced kidney disease until kidney transplantation. Diagnosis of the syndrome of inappropriate antidiuretic hormone is similar in mild or moderate kidney disease as in normal subjects, but is challenging in patients with advanced kidney disease owing to the impairment in urine dilution.
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http://dx.doi.org/10.1016/j.semnephrol.2021.03.010DOI Listing
March 2021

Comparing Patch vs Pen Bolus Insulin Delivery in Type 2 Diabetes Using Continuous Glucose Monitoring Metrics and Profiles.

J Diabetes Sci Technol 2021 May 19:19322968211016513. Epub 2021 May 19.

Calibra Medical, Johnson & Johnson Diabetes Care Companies, Wayne, PA, USA.

Objective: CeQur Simplicity™ (CeQur, Marlborough, MA) is a 3-day insulin delivery patch designed to meet mealtime insulin requirements. A recently reported 48-week, randomized, multicenter, interventional trial compared efficacy, safety and self-reported outcomes in 278 adults with type 2 diabetes (T2D) on basal insulin therapy who initiated and managed mealtime insulin therapy with a patch pump versus insulin pen. We assessed changes in key glycemic metrics among a subset of patients who wore a continuous glucose monitoring (CGM) device.

Methods: Study participants (patch, = 49; pen, = 48) wore a CGM device in masked setting during the baseline period and prior to week 24. Glycemic control was assessed using international consensus guidelines for percentage of Time In Range (%TIR: >70% at 70-180 mg/dL), Time Below Range (%TBR: <4% at <70 mg/dL; <1% at <54 mg/dL), and Time Above Range (%TAR: <25% at >180 mg/dL; <5% at >250 mg/dL).

Results: Both the patch and pen groups achieved recommended targets in %TIR (74.1% ± 18.7%, 75.2 ± 16.1%, respectively) and marked reductions in %TAR >180 mg/dL (21.1% ± 19.9%, 19.7% ± 17.5%, respectively) but with increased %TBR <70 mg/dL (4.7% ± 5.2%, 5.1 ± 5.8, respectively), all < .0001. No significant between-group differences in glycemic improvements or adverse events were observed.

Conclusions: CGM confirmed that the patch or pen can be used to safely initiate and optimize basal-bolus therapy using a simple insulin adjustment algorithm with SMBG. Preference data suggest that use of the patch vs pen may enhance treatment adherence.
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http://dx.doi.org/10.1177/19322968211016513DOI Listing
May 2021

Disease and Treatment-Related Burden in Patients With Acromegaly Who Are Biochemically Controlled on Injectable Somatostatin Receptor Ligands.

Front Endocrinol (Lausanne) 2021 15;12:627711. Epub 2021 Mar 15.

Outcomes Research, Health Outcomes Solutions, Winter Park, FL, United States.

Medical treatment for acromegaly commonly involves receiving intramuscular or deep subcutaneous injections of somatostatin receptor ligands (SRLs) in most patients. In addition to side effects of treatment, acromegaly patients often still experience disease symptoms even when therapy is successful in controlling GH and IGF-1 levels. Symptoms and side effects can negatively impact patients' health-related quality of life. In this study, we examine the disease- and treatment-related burden associated with SRL injections as reported through the use of the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ ) and clinician-reported symptom severity through the Acromegaly Index of Severity (AIS). Patients included in this analysis were enrolled in a randomized phase 3 study, were biochemically-controlled (an IGF-1 < 1.3 × the upper limit of normal [ULN] and average GH < 2.5 ng/ml) and receiving SRL injections for ≥6 months with a stable dose of either long-acting octreotide or lanreotide monotherapy for ≥4 months. The sample (N = 91) was 65% female, 91% Caucasian, with a mean [standard deviation (SD)] age of 53 (1) years. Two-thirds of patients reported that they still experience acromegaly symptoms; 82% of these said they experience symptoms all of the time. Three-fourths experienced gastrointestinal (GI) side effects after injections, and 77% experienced treatment-related injection site reactions (ISRs). Patients commonly reported that these interfered with their daily life, leisure, and work activities. Those with higher symptom severity, as measured by the AIS, scored significantly worse on several Acro-TSQ domains: Symptom Interference, GI Interference, Treatment Satisfaction, and Emotional Reaction. Despite being biochemically controlled with injectable SRLs, most patients reported experiencing acromegaly symptoms that interfere with daily life, leisure, and work. GI side effects and ISRs were also common. This study highlights the significant disease burden that still persists for patients with acromegaly that have achieved biochemical control with the use of injectable SRLs.
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http://dx.doi.org/10.3389/fendo.2021.627711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006928PMC
March 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Am J Kidney Dis 2021 01 26;77(1):94-109. Epub 2020 Oct 26.

George Institute for Global Health, UNSW Sydney, Australia.

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to<90mL/min/1.73m. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.
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http://dx.doi.org/10.1053/j.ajkd.2020.08.003DOI Listing
January 2021

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Diabetes 2021 01 26;70(1):1-16. Epub 2020 Oct 26.

George Institute for Global Health, UNSW Sydney, Australia.

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.
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http://dx.doi.org/10.2337/dbi20-0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162454PMC
January 2021

A Pituitary Society update to acromegaly management guidelines.

Pituitary 2021 Feb 20;24(1):1-13. Epub 2020 Oct 20.

Pituitary Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 2015, Los Angeles, CA, 90048, USA.

Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.
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http://dx.doi.org/10.1007/s11102-020-01091-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864830PMC
February 2021

Multidisciplinary management of acromegaly: A consensus.

Rev Endocr Metab Disord 2020 12 10;21(4):667-678. Epub 2020 Sep 10.

Medical Research Unit in Endcrine Diseases, Hospital de Especialidades, Centro Médico Nacional, Siglo XXI, IMSS, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.
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http://dx.doi.org/10.1007/s11154-020-09588-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942783PMC
December 2020

Maintenance of Acromegaly Control in Patients Switching From Injectable Somatostatin Receptor Ligands to Oral Octreotide.

J Clin Endocrinol Metab 2020 10;105(10)

Cedars-Sinai Medical Center, Los Angeles, California, USA.

Purpose: The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs).

Methods: In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures.

Results: Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience.

Conclusions: OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.
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http://dx.doi.org/10.1210/clinem/dgaa526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470473PMC
October 2020

An evaluation of recurrent hypoglycemia across Chicago, Illinois.

J Diabetes Complications 2020 11 22;34(11):107685. Epub 2020 Jul 22.

Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago IL, USA; Center for Health Services and Outcomes Research, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address:

Aims: Recurrent hypoglycemia is understudied. This study evaluates recurrent hypoglycemia, fragmentation of care and mortality in a large urban center.

Methods: The Chicago HealthLNK Data Repository (CHDR), a de-identified electronic health record data set from institutions across Chicago, identified 9741 patients with diabetes (DM) who had hypoglycemia (emergency department (ED) or inpatient admission (IA)) from 2006 to 2012. Recurrence was defined as more than one hypoglycemia encounter, and fragmentation of health care was defined as an ED visit or IA for hypoglycemia at >1 site.

Results: 187,644 patients were identified with DM; of 9741 patients with hypoglycemia, 2857 (29.3%) had recurrence. Patients with ≥4 hypoglycemic encounters (n = 1035) represented 10.6%, but accounted for 40.3% hypoglycemic encounters. Of 2857 patients with recurrence, 304 patients (10.6%) had fragmented care. In those with high hypoglycemic encounters (≥4), 22% (N = 226) had ≥10 encounters; race and insurance status differences were associated with number of hypoglycemic encounters. Having hypoglycemia was associated with increased mortality compared to no hypoglycemia (n = 2696, 27.7% vs n = 20,188, 11.4%; p < 0.00001 by chi-square).

Conclusion: A small subset of patients with hypoglycemia accounted for a large subset of hypoglycemia encounters. Targeted interventions in this high-risk, high mortality group are needed.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107685DOI Listing
November 2020

Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

N Engl J Med 2020 06;382(26):2493-2503

From the Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston (A.D., A.B.G., S.E.R.); the Division of Geriatrics, Institute of Gerontology (A.T.G., C.W.), the Department of Biostatistics, School of Public Health (A.T.G., C.S.), Statistical Analysis of Biomedical and Educational Research (SABER) (C.S.), and the Department of Internal Medicine, Metabolism, Endocrinology, and Diabetes (R.P.-B.), University of Michigan, Ann Arbor; the Departments of Medicine, Physiology, and Pharmacology and Toxicology (D.Z.C.) and the Division of Endocrinology and Metabolism (B.A.P.), University of Toronto, the Division of Nephrology, University Health Network (D.Z.C.), LMC Diabetes and Endocrinology (R.A.), and Lunenfeld-Tanenbaum Research Institute, Sinai Health System (B.A.P.), Toronto, the Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, AB (R.J.S.), BCDiabetes, Vancouver (T.G.E.), and the Division of Endocrinology, University of Alberta, Edmonton (P.S.) - all in Canada; the Departments of Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (A.P.); Steno Diabetes Center, and the Department of Clinical Medicine, University Copenhagen, Copenhagen (P.R.); the Division of Nephrology, Department of Medicine, University of California, Davis (M.A.), and the Department of Pediatrics and Stanford Diabetes Research Center, Stanford University, Palo Alto (D.M.M.) - both in California; the Departments of Medicine and Pediatrics (M.L.C., W.N.R.. M.M.) and Laboratory Medicine and Pathology (A.B.K.), University of Minnesota, Minneapolis; the Division of Endocrinology and Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine (J.P.C.), and JDRF (Juvenile Diabetes Research Foundation) (M.P.), New York; the Department of Medicine (I.H.B., I.B.H.) and the Nephrology Division (K.R.T.), University of Washington, and the Institute of Translational Health Sciences, Kidney Research Institute (K.R.T.), Seattle, and Providence Health Care, Spokane (K.R.T.) - both in Washington; the Department of Medicine, Emory University, Atlanta (J.S.H., G.E.U.); the Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis (J.B.M.); the Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago (M.E.M., A.W.); the Barbara Davis Center for Diabetes, University of Colorado, Aurora (S.P.); and the Department of Medicine, State University of New York Upstate Medical University, Syracuse (R.S.W.).

Background: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease.

Methods: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed.

Results: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m in the allopurinol group and 67.3 ml per minute per 1.73 m in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m per year with allopurinol and -2.5 ml per minute per 1.73 m per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups.

Conclusions: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).
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http://dx.doi.org/10.1056/NEJMoa1916624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375708PMC
June 2020

Dopamine agonists and antipsychotics.

Authors:
Mark E Molitch

Eur J Endocrinol 2020 Sep;183(3):C11-C13

Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

There can potentially be a number of clinical interactions that could adversely affect patient outcomes in a patient with a prolactinoma and psychiatric disease that might require antipsychotic and dopamine agonist treatment. Dopamine agonists stimulate the dopamine D2 receptor, resulting in a decrease in prolactin (PRL) levels and in prolactinoma size but action on dopamine receptors in the meso-limbic system may rarely cause psychosis and more commonly cause impulse control disorders. The psychiatric benefits of antipsychotic agents involve blocking the D2 and other dopamine receptors but this blockade often also causes hyperprolactinemia. In patients with macroprolactinomas and psychosis, observation, estrogen/progestin replacement, and surgery can be considered in addition to dopamine agonists. In those who require dopamine agonists for PRL and tumor size control, the introduction of antipsychotics may blunt this effect, so that higher doses of the dopamine agonists may be needed. Alternatively, antipsychotics that have less of a blocking effect at the D2 receptor, such as aripiprazole, can be tried, if appropriate. For patients already on antipsychotic drugs who are found to have a macroprolactinoma for which dopamine agonists are required, dopamine agonists can be initiated at low dose and the dose escalated slowly. However, such patients require careful monitoring of psychiatric status to avoid the rare complication of exacerbation of the underlying psychosis. Again, if appropriate, use of antipsychotics that have less of a blocking effect at the D2 receptor may allow lower doses of dopamine agonists to be used in this situation.
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http://dx.doi.org/10.1530/EJE-20-0607DOI Listing
September 2020

Exercise based assessment of cardiac autonomic function in type 1 versus type 2 diabetes mellitus.

Cardiol J 2020 May 7. Epub 2020 May 7.

University of Miami Miller School of Medicine, Division of Endocrinology, 1120 NW 14th Street., 33136 Miami, United States.

Background: Cardiac autonomic neuropathy (CAN) is a complication of diabetes mellitus (DM) that is associated with increased mortality. Exercise-based assessment of autonomic function has identified diminished parasympathetic reactivation after exercise in type 2 DM. It is postulated herein, that this would be more prominent among those with type 1 DM.

Methods: Sixteen subjects with type 1 DM (age 32.9 ± 10.1 years), 18 subjects with type 2 DM (55.4 ± 8.0 years) and 30 controls (44.0 ± 11.6 years) underwent exercise-based assessment of autonomic function. Two 16-min submaximal bicycle tests were performed followed by 45 min of recovery. On the 2nd test, atropine (0.04 mg/kg) was administered near end-exercise so that all of the recovery occurred under parasympathetic blockade. Plasma epinephrine and norepinephrine levels were measured at rest, during exercise, and during recovery.

Results: There were no differences in resting or end-exercise heart rates in the three groups. Parasympathetic effect on RR-intervals during recovery (p < 0.03) and heart rate recovery (p = 0.02) were blunted in type 2 DM. Type 1 DM had higher baseline epinephrine and norepinephrine levels (p < 0.03), and exhibited persistent sympathoexcitation during recovery.

Conclusions: Despite a longer duration of DM in the study patients with type 1 versus type 2 DM, diminished parasympathetic reactivation was not noted in type 1 DM. Instead, elevation in resting plasma catecholamines was noted compared to type 2 DM and controls. The variable pathophysiology for exercise-induced autonomic abnormalities in type 1 versus type 2 DM may impact prognosis.
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http://dx.doi.org/10.5603/CJ.a2020.0064DOI Listing
May 2020

Growth hormone replacement in adults: Real-world data from two large studies in US and Europe.

Growth Horm IGF Res 2020 02 26;50:71-82. Epub 2019 Oct 26.

Neuroendocrine Unit, Massachusetts General Hospital, Bulfinch 457B, Massachusetts General Hospital, Fruit St., Boston, MA 02114, USA.

Objective: This report describes the effectiveness and safety of growth hormone replacement in 3180 adult patients with growth hormone deficiency followed-up for 0.0-12.2 years in two completed, complementary, non-interventional, multicentre studies, NordiNet® International Outcome Study (IOS) (NCT00960128) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program (NCT01009905).

Design: In both studies, Norditropin® (somatropin; Novo Nordisk A/S, Denmark) was administered at the discretion of the treating physician and according to routine practice. We present data on baseline characteristics, growth hormone dose, safety data and change from baseline in waist circumference, body mass index and bioimpedance (NordiNet® IOS only).

Results: Mean (SD) baseline characteristics (effectiveness analysis set) in NordiNet® IOS (n = 971) and ANSWER (n = 304): females, 45%; 69%; mean growth hormone dose (mg/day) (female, 0.338 [0.177]; male, 0.289 [0.157]); (female, 0.501 [0.313]; male, 0.505 [0.351]). Most patients had BMI ≥25 kg/m. Median (P10,P90) exposure (females, 3.5 [0.42,11.0]; 1.6 [3.2; 0.3,8.6]; males, 4.1 [0.33,10.8]; 2.3 [2.9; 0.0,7.5] years). Mean (SD) change from baseline for waist circumference (-0.46 [6.38] cm [n = 403], BMI (0.30 [3.30] kg/m [n = 857]) and bioimpedance (-17.4 (59.19) ohm [n = 239]) were associated with growth hormone dose (waist/bioimpedance) and duration of follow-up (BMI/bioimpedance). No new safety signals were observed among patients in the full analysis set (NordiNet® IOS, n = 2321; ANSWER, n = 859).

Conclusions: Long-term growth hormone replacement is associated with an improvement in body composition. The accumulated data from >10 years of follow-up support the long-term effectiveness and safety of growth hormone replacement as prescribed in clinical practice.
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http://dx.doi.org/10.1016/j.ghir.2019.09.002DOI Listing
February 2020

Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus.

Physiol Rep 2019 10;7(19):e14242

Northwestern University Feinberg School of Medicine, Chicago, Illinois.

We examined if urinary angiotensinogen (uAOG), a marker of intrarenal renin-angiotensin system activity, antedates stage 3 chronic kidney disease (CKD) using samples from participants in the Diabetes Control and Complications Trial (DCCT) and later in the Epidemiology of Diabetes Intervention and Complications (EDIC) trial. In a nested case-control design, cases were matched at the outcome visit (eGFR less than 60, 21-59 mL/min per 1.73 m ) on age, gender, and diabetes duration, with controls: eGFR (95, 75-119, mL/min per 1.73 m .) Additionally, in an exploratory analysis progressive renal decline (PRD), defined as eGFR loss >3.5 mL/min per 1.73m /year, was evaluated using only data from EDIC because no progressions were observed during DCCT. At the EDIC visit, which antedated the GFR outcome visit by 2 years (range 1-7years) the median uAOG/creatinine was markedly higher in cases than in controls (13.9 vs. 3.8 ng/mg P = 0.003) whereas at the DCCT visit, which antedated the GFR outcome by 17 to 20 years it was not (2.75 vs. 3.16 ng/mg, respectively). The Odds Ratio for uAOG and CKD stage 3 development was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 1.82 (1.00-3.29) but no longer significant when Albumin Excretion Ratio (AER) was included 1.21 (0.65-2.24).In the PRD analysis, uAOG/creatinine was sixfold higher in participants who experienced PRD than in those who did not (26 vs. 4.0 ng/mg, P = 0.003). The Odds Ratio for uAOG and PRD was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 2.48 (1.46-4.22) but no longer significant when AER was included 1.32 (0.76-2.30). In people with type1 diabetes, a robust increase in uAOG antedates the development of stage 3 CKD but is not superior to AER in predicting this renal outcome. Increased uAOG moreover is associated with PRD, an index of progression to End Stage Kidney Disease (ESKD).
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http://dx.doi.org/10.14814/phy2.14242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788980PMC
October 2019

Prostate-Specific Antigen Levels During Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial.

J Clin Endocrinol Metab 2019 12;104(12):6238-6246

Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Context: Prostate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated.

Design: Double-blinded, placebo-controlled trial.

Setting: Twelve US academic medical centers.

Participants: Seven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded.

Interventions: Testosterone or placebo gel for 12 months.

Main Outcomes: Percentile changes in PSA during testosterone treatment of 12 months.

Results: Testosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8.

Conclusions: When hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL.
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http://dx.doi.org/10.1210/jc.2019-00806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823728PMC
December 2019

Rebuttals to "The Debate on Insulin vs. Non-insulin Use in the Hospital Setting-Continued Use of Insulin or Time to Revise the Guidelines?"

Curr Diab Rep 2019 07 29;19(9):66. Epub 2019 Jul 29.

Emory University School of Medicine, 69 Jesse Hill Jr. Dr, Atlanta, GA, 30303, USA.

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http://dx.doi.org/10.1007/s11892-019-1185-7DOI Listing
July 2019

Use of Insulin in the Inpatient Setting: Need for Continued Use.

Curr Diab Rep 2019 07 26;19(9):64. Epub 2019 Jul 26.

Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave., Suite 530, Chicago, IL, 60611, USA.

Purpose Of Review: Insulin has been the standard of care for the management of inpatient diabetes for achieving strict glycemic control. This review supports continuing insulin therapy for hyperglycemic management in the hospital compared with the use of non-insulin treatment regimens.

Recent Findings: Oral hypoglycemic agents and glucagon-like peptide 1 (GLP-1) receptor agonists have typically not been used in the inpatient setting. Recent studies regarding DPP-4 inhibitors have led to variable results with fairly high glycemic values during the hospitalization. Similarly, studies looking at GLP-1 receptor agonists are limited, but gastrointestinal side effects limit their inpatient use. Overall, there is a paucity of data to support the use of non-insulin-based therapy in the inpatient setting. Insulin has repeatedly demonstrated that its advantageous quality of being easily titratable leads to more consistently efficacious glycemic control that improves morbidity and mortality.
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http://dx.doi.org/10.1007/s11892-019-1183-9DOI Listing
July 2019

Pregnancy and Endocrine Disorders.

Authors:
Mark E Molitch

Endocrinol Metab Clin North Am 2019 09;48(3):xv-xvi

Division of Endocrinology, Metabolism & Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 530, Chicago, IL 60611, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2019.06.001DOI Listing
September 2019

Pituitary Tumors in Pregnancy.

Endocrinol Metab Clin North Am 2019 09 13;48(3):569-581. Epub 2019 Jun 13.

Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 530, Chicago, IL 60611, USA. Electronic address:

Pituitary adenomas are common. The impact of pituitary tumors on fertility are mainly caused by oversecretion and/or undersecretion of pituitary hormones or compression of pituitary stalk and normal pituitary tissue by the tumor. Diagnosing and managing pituitary tumors during pregnancy involve many challenges, including the effect of hormone excess or deficiency on pregnancy outcome, changes in the pituitary or pituitary-related hormones, changes in tumor size, and the impact of various treatments of pituitary tumors on maternal and fetal outcomes. This article discusses the diagnosis and treatment of patients with prolactinomas, acromegaly, Cushing disease, and other pituitary tumors during pregnancy.
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http://dx.doi.org/10.1016/j.ecl.2019.05.004DOI Listing
September 2019

Preventing Early Renal Loss in Diabetes (PERL) Study: A Randomized Double-Blinded Trial of Allopurinol-Rationale, Design, and Baseline Data.

Diabetes Care 2019 08 11;42(8):1454-1463. Epub 2019 Jun 11.

Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY.

Objective: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics.

Research Design And Methods: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period.

Results: Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m, and historical eGFR slope -3.5 mL/min/1.73 m/year. Compared with participants with albuminuria ( = 419), those with NDKF ( = 94) were significantly older (56 vs. 52 years), had lower HbA (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m/year). These differences persisted when comparing groups with similar rates of historical eGFR loss.

Conclusions: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.
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http://dx.doi.org/10.2337/dc19-0342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647051PMC
August 2019

Early Glomerular Hyperfiltration and Long-Term Kidney Outcomes in Type 1 Diabetes: The DCCT/EDIC Experience.

Clin J Am Soc Nephrol 2019 06 23;14(6):854-861. Epub 2019 May 23.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Background And Objectives: Glomerular hyperfiltration has been considered to be a contributing factor to the development of diabetic kidney disease (DKD). To address this issue, we analyzed GFR follow-up data on participants with type 1 diabetes undergoing I-iothalamate clearance on entry into the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study.

Design, Setting, Participants, & Measurements: This was a cohort study of DCCT participants with type 1 diabetes who underwent an I-iothalamate clearance (iGFR) at DCCT baseline. Presence of hyperfiltration was defined as iGFR levels ≥140 ml/min per 1.73 m, with secondary thresholds of 130 or 150 ml/min per 1.73 m. Cox proportional hazards models assessed the association between the baseline hyperfiltration status and the subsequent risk of reaching an eGFR <60 ml/min per 1.73 m.

Results: Of the 446 participants, 106 (24%) had hyperfiltration (iGFR levels ≥140 ml/min per 1.73 m) at baseline. Over a median follow-up of 28 (interquartile range, 23, 33) years, 53 developed an eGFR <60 ml/min per 1.73 m. The cumulative incidence of eGFR <60 ml/min per 1.73 m at 28 years of follow-up was 11.0% among participants with hyperfiltration at baseline, compared with 12.8% among participants with baseline GFR <140 ml/min per 1.73 m. Hyperfiltration was not significantly associated with subsequent risk of developing an eGFR <60 ml/min per 1.73 m in an unadjusted Cox proportional hazards model (hazard ratio, 0.83; 95% confidence interval, 0.43 to 1.62) nor in an adjusted model (hazard ratio, 0.77; 95% confidence interval, 0.38 to 1.54). Application of alternate thresholds to define hyperfiltration (130 or 150 ml/min per 1.73 m) showed similar findings.

Conclusions: Early hyperfiltration in patients with type 1 diabetes was not associated with a higher long-term risk of decreased GFR. Although glomerular hypertension may be a mechanism of kidney injury in DKD, higher total GFR does not appear to be a risk factor for advanced DKD.
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http://dx.doi.org/10.2215/CJN.14831218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556717PMC
June 2019

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

J Clin Endocrinol Metab 2019 05;104(5):1520-1574

King's College, London, United Kingdom.

Objective: The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults.

Conclusions: Diabetes, particularly type 2, is becoming more prevalent in the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects.
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http://dx.doi.org/10.1210/jc.2019-00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271968PMC
May 2019

Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association.

Circulation 2019 04;139(16):e840-e878

Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need for a cardiorenal education track that will guide future cardiorenal trials and integrate the clinical and research needs of this important field in the future.
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http://dx.doi.org/10.1161/CIR.0000000000000664DOI Listing
April 2019

Risk Factors for Kidney Disease in Type 1 Diabetes.

Diabetes Care 2019 05 4;42(5):883-890. Epub 2019 Mar 4.

Biostatistics Center, The George Washington University, Rockville, MD

Objective: In type 1 diabetes (T1D), the course of microalbuminuria is unpredictable and timing of glomerular filtration rate (GFR) loss is uncertain. Thus, there is a need to identify the risk factors associated with the development of more advanced stages of kidney disease through large, long-term systematic analysis.

Research Design And Methods: Multivariable Cox proportional hazards models assessed the association of baseline and time-dependent glycemic and nonglycemic risk factors for incident macroalbuminuria and reduced estimated GFR (eGFR; defined as <60 mL/min/1.73 m) over a mean of 27 years in the Diabetes Control and Complications Trial (DCCT) cohort.

Results: Higher mean HbA (hazard ratio [HR] 1.969 per 1% higher level [95% CI 1.671-2.319]) and male sex (HR 2.767 [95% CI 1.951-3.923]) were the most significant factors independently associated with incident macroalbuminuria, whereas higher mean triglycerides, higher pulse, higher systolic blood pressure (BP), longer diabetes duration, higher current HbA, and lower mean weight had lower magnitude associations. For incident reduced eGFR, higher mean HbA (HR 1.952 per 1% higher level [95% CI 1.714-2.223]) followed by higher mean triglycerides, older age, and higher systolic BP were the most significant factors.

Conclusions: Although several risk factors associated with macroalbuminuria and reduced eGFR were identified, higher mean glycemic exposure was the strongest determinant of kidney disease among the modifiable risk factors. These findings may inform targeted clinical strategies for the frequency of screening, prevention, and treatment of kidney disease in T1D.
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http://dx.doi.org/10.2337/dc18-2062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489116PMC
May 2019

Development of a Predictive Model for Hyperglycemia in Nondiabetic Recipients After Liver Transplantation.

Transplant Direct 2018 Oct 20;4(10):e393. Epub 2018 Sep 20.

Division of Endocrinology Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

Background: Posttransplant hyperglycemia has been associated with increased risks of transplant rejection, infections, length of stay, and mortality.

Methods: To establish a predictive model to identify nondiabetic recipients at risk for developing postliver transplant (LT) hyperglycemia, we performed this secondary, retrospective data analysis of a single-center, prospective, randomized, controlled trial of glycemic control among 107 adult LT recipients in the inpatient period. Hyperglycemia was defined as a posttransplant glucose level greater than 200 mg/dL after initial discharge up to 1 month following surgery. Candidate variables with less than 0.10 in univariate analyses were used to build a multivariable logistic regression model using forward stepwise selection. The final model chosen was based on statistical significance and additive contribution to the model based on the Bayesian Information Criteria.

Results: Forty-three (40.2%) patients had at least 1 episode of hyperglycemia after transplant after the resolution of the initial postoperative hyperglycemia. Variables selected for inclusion in the model (using model optimization strategies) included length of hospital stay (odds ratio [OR], 0.83; < 0.001), use of glucose-lowering medications at discharge (OR, 3.76; = 0.03), donor female sex (OR, 3.18; = 0.02) and donor white race (OR, 3.62; = 0.01). The model had good calibration (Hosmer-Lemeshow goodness-of-fit test statistic = 9.74, = 0.28) and discrimination (C-statistic = 0.78; 95% confidence interval, 0.65-0.81, bias-corrected C-statistic = 0.78).

Conclusions: Shorter hospital stay, use of glucose-lowering medications at discharge, donor female sex and donor white race are important determinants in predicting hyperglycemia in nondiabetic recipients after hospital discharge up to 1 month after liver transplantation.
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http://dx.doi.org/10.1097/TXD.0000000000000830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233666PMC
October 2018

Hyperglycemia in the Posttransplant Period: NODAT vs Posttransplant Diabetes Mellitus.

J Endocr Soc 2018 Nov 15;2(11):1314-1319. Epub 2018 Oct 15.

Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Objective: To characterize the types of hyperglycemia that occur up to 1 year following liver transplant and to clarify the nomenclature for posttransplant hyperglycemia.

Design: We analyzed 1-year glycemic follow-up data in 164 patients who underwent liver transplant and who had been enrolled in a randomized controlled trial comparing moderate to intensive insulin therapy to determine if patients had preexisting known diabetes, transient hyperglycemia, persistent hyperglycemia, or new-onset diabetes after transplantation (NODAT).

Results: Of 119 patients with posttransplant hyperglycemia following hospital discharge, 49 had preexisting diabetes, 5 had insufficient data for analysis, 48 had transient hyperglycemia (16 resolved within 30 days and 32 resolved between 30 days and 1 year), 13 remained persistently hyperglycemic out to 1 year and most likely had preexisting diabetes that had not been diagnosed or insulin resistance/insulinopenia prior to transplant, and 4 had NODAT (, patients with transient hyperglycemia after transplant that resolved but then later truly developed sustained hyperglycemia, meeting criteria for diabetes).

Conclusions: Distinct categories of patients with hyperglycemia following organ transplant include known preexisting diabetes, persistent hyperglycemia (most likely unknown preexisting diabetes or insulin resistance/insulinopenia), transient hyperglycemia, and NODAT. Those with preexisting diabetes for many years prior to transplant may well have very different long-term outcomes compared with those with true NODAT. Therefore, it would be prudent to classify patients more carefully. Long-term outcome studies are needed to determine if patients with true NODAT have the same poor prognosis as patients with preexisting diabetes (diagnosed and undiagnosed) undergoing transplant.
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http://dx.doi.org/10.1210/js.2018-00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223248PMC
November 2018

Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: secondary analyses of the Testosterone Trials.

Lancet Diabetes Endocrinol 2018 11;6(11):879-890

Section of Geriatric Medicine, Yale School of Medicine, New Haven, CT, USA.

Background: The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors.

Methods: The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff masked to intervention allocation. The primary outcome of the PFT was an increase in 6 min walk test (6MWT) distance of 50 m or more. Here we report data for absolute change in 6MWT distance and physical component of Short Form-36 (PF10), and for PGIC and falls. Data are reported for men enrolled in the PFT and those who were not, and for all men in TTrials; data are also reported according to baseline walking speed and mobility limitation. Analyses were done in a modified intention-to-treat population in all patients who were allocated to treatment, had a baseline assessment, and at least one post-intervention assessment. The TTrials are registered with ClinicalTrials.gov, number NCT00799617.

Findings: The TTrials took place between April 28, 2011 and June 16, 2014. Of 790 TTrials participants, 395 were allocated to testosterone and 395 to placebo; of the 390 participants enrolled in the PFT, 193 were allocated to testosterone and 197 to placebo. As reported previously, 6MWT distance improved significantly more in the testosterone than in the placebo group among all men in the TTrials, but not in those who were enrolled in the PFT; among TTrials participants not enrolled in the PFT, 6MWT distance improved with a treatment effect of 8·9 m (95% CI 2·2-15·6; p=0·010). As reported previously, PF10 improved more in the testosterone group than in the placebo group in all men in TTrials and in men enrolled in the PFT; among those not enrolled in the PFT, PF10 improved with an effect size of 4·0 (1·5-6·5; p=0·0019). Testosterone-treated men with baseline walking speed of 1·2 m/s or higher had significantly greater improvements in 6MWT distance (treatment effect 14·2 m, 6·5-21·9; p=0·0004) and PF10 (4·9, 2·2-7·7; p=0·0005) than placebo-treated men. Testosterone-treated men reporting mobility limitation showed significantly more improvement in 6MWT distance (7·6 m, 1·0-14·1; p=0·0237) and PF10 (3·6, 1·3-5·9; p=0·0018) than placebo-treated men. Men in the testosterone group were more likely to perceive improvement in their walking ability (PGIC) than men in the placebo group, both for men enrolled in the PFT (effect size 2·21, 1·35-3·63; p=0·0018) and those not enrolled in the PFT (3·01, 1·61-5·63; p=0·0006). Changes in 6MWT distance were significantly associated with changes in testosterone, free testosterone, dihydrotestosterone, and haemoglobin concentrations. Fall frequency during the intervention period was identical in the two treatment groups of the TTrials (103 [27%] of 380 analysed in both groups had at least one fall).

Interpretation: Testosterone therapy consistently improved self-reported walking ability, modestly improved 6MWT distance (across all TTtrials participants), but did not affect falls. The effect of testosterone on mobility measures were related to baseline gait speed and self-reported mobility limitation, and changes in testosterone and haemoglobin concentrations.

Funding: US National Institute on Aging and AbbVie.
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http://dx.doi.org/10.1016/S2213-8587(18)30171-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816466PMC
November 2018

Effects of bardoxolone methyl on body weight, waist circumference and glycemic control in obese patients with type 2 diabetes mellitus and stage 4 chronic kidney disease.

J Diabetes Complications 2018 Dec 13;32(12):1113-1117. Epub 2018 Sep 13.

Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, DK-2820, Gentofte, Denmark. Electronic address:

Aims: Obesity is associated with progression of chronic kidney disease (CKD). Treatment with bardoxolone methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with bardoxolone methyl.

Methods: Eligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to <30 mL/min/1.73 m) were randomized 1:1 to receive once-daily oral dose of bardoxolone methyl (20 mg) or placebo.

Results: BEACON enrolled 2185 patients. Patients randomized to bardoxolone methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (-5.7 kg; 95% CI: -6.0 to -5.3 kg; p < 0.001). In patients randomized to bardoxolone methyl, rate and magnitude of body weight loss were proportional to baseline BMI. Bardoxolone methyl resulted in significant reductions in waist circumference and improved glycemic control.

Conclusions: Bardoxolone methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI.
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http://dx.doi.org/10.1016/j.jdiacomp.2018.09.005DOI Listing
December 2018

New Onset Diabetes After Transplant: Data from the Folic Acid for Vascular Outcome Reduction in Transplantation Trial.

Am J Med 2018 08;131(8):e347

Northwestern University Feinberg School of Medicine, Chicago, Ill.

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http://dx.doi.org/10.1016/j.amjmed.2018.03.005DOI Listing
August 2018
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