Deprescribing antihyperglycemic agents in older persons: evidence-based clinical practice guideline

OBJECTIVE: To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper, stop, or switch antihyperglycemic agents in older adults. METHODS: We focused on the highest level of evidence available and sought input from primary care professionals in guideline development, review, and endorsement processes. Seven clinicians (2 family physicians, 3 pharmacists, 1 nurse practitioner, and 1 endocrinologist) and a methodologist comprised the overall team; members disclosed conflicts of interest. We used a rigorous process, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, for guideline development. We conducted a systematic review to assess evidence for the benefits and harms of deprescribing antihyperglycemic agents. We performed a review of reviews of the harms of continued antihyperglycemic medication use, and narrative syntheses of patient preferences and resource implications. We used these syntheses and GRADE quality-of-evidence ratings to generate recommendations. The team refined guideline content and recommendation wording through consensus and synthesized clinical considerations to address common front-line clinician questions. The draft guideline was distributed to clinicians and stakeholders for review and revisions were made at each stage. A decision-support algorithm was developed to accompany the guideline. RECOMMENDATIONS: We recommend deprescribing antihyperglycemic medications known to contribute to hypoglycemia in older adults at risk or in situations where antihyperglycemic medications might be causing other adverse effects, and individualizing targets and deprescribing accordingly for those who are frail, have dementia, or have a limited life expectancy. CONCLUSION: This guideline provides practical recommendations for making decisions about deprescribing antihyperglycemic agents. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients.

Successful long-term management of a gonadotroph adenoma with bromocriptine.

OBJECTIVE: To report the successful 10-year management of a gonadotroph macroadenoma with bromocriptine and review the management of gonadotroph adenomas with bromocriptine. METHODS: We present a case and review the pertinent literature. The effectiveness of bromocriptine in the management of gonadotroph adenomas is evaluated. RESULTS: A 62-year-old man was found to have a pituitary tumor after seeking medical assistance because of a 6-month history of headaches and blurred vision. He had decreased visual acuity and bitemporal field defects. Serum follicle-stimulating hormone (FSH) levels were increased, whereas serum luteinizing hormone and total testosterone levels were normal. Treatment with bromocriptine resulted in a decrease in serum FSH levels, complete resolution of his symptoms, and considerable improvement in his visual acuity and visual field defects. Treatment with only bromocriptine for 10 years resulted in maintenance of normal serum FSH levels and no recurrence of symptoms. CONCLUSION: In the management of a gonadotroph adenoma, we recommend consideration of a therapeutic trial of bromocriptine. In cases that are refractory to this therapy, surgical treatment or external pituitary irradiation could then be used.

Functional activity of the human prolactin receptor and its ligands.

Prolactin receptors (PRLR) have been identified in a number of human tissues and cell lines, although little is known about the human receptor protein. The cloning of the human PRLR cDNA has enabled further characterization of the receptor protein in transfected cells. Since the human cDNA is expressed at lower levels than the rat cDNA, we have constructed a hybrid cDNA (pECE r5'hPRLR) containing nucleotides of the 5' untranslated region and signal peptide of the rat PRLR and the protein coding and 3' untranslated portion of the human receptor. Expression of the hybrid receptor was increased more than two-fold compared to the human receptor as detected by specific binding of 125I-human growth hormone (GH) to transfected COS-7 cells. The relative molecular mass of the receptor was 93,000 Da, as determined by chemical cross-linking studies. Transcriptional assays were used to show the human PRLR was able to activate two milk protein genes; ovine beta-lactoglobulin and rat beta-casein. Transfected cells expressing the human PRLR receptor, treated with human GH or prolactin (PRL), induced a dose-dependent increase in transcriptional activation of the beta-casein/luciferase fusion gene. Glycosylated, and non-glycosylated human PRL, and ovine PRL were equally effective in activating the beta-casein promoter. Human placental lactogen and bovine PRL could also induce a greater than 10-fold induction, whereas insulin did not significantly stimulate the beta-casein promoter. The results show that the human PRLR can activate both beta-lactoglobulin and beta-casein milk gene promoters and that these reporter genes can be used to evaluate the functional activity of agonists and antagonists of the human PRLR.

Receptor domains involved in signal transduction of prolactin and growth hormone.

Prolactin (PRL) and growth hormone (GH) receptors are members of a superfamily that include receptors for a number of cytokines. GH and its receptor form an unusual homodimer consisting of one molecule of GH and two molecules of receptor. A similar homodimer of the PRL receptor is probably required for biological effects to be seen. Using specific assays to measure the functional activity of PRL and GH receptors, a 25 amino acid juxtamembrane region has been identified as essential but not sufficient for normal action. More detailed studies have limited the region to eight amino acids, rich in prolines, that is highly conserved in many members of the receptor superfamily. Finally, GH and PRL have been shown to induce the rapid tyrosine phosphorylation of an associated kinase, Janus kinase 2, and of the receptor itself.

Identification of binding proteins for nuclear localization signals of the glucocorticoid and thyroid hormone receptors.

Nuclear entry of proteins the size of the glucocorticoid and thyroid hormone receptors appears to be mediated by an interaction of nuclear localization signals (NLSs) within the proteins and specific NLS-binding proteins. NLSs have been identified in the hinge region of both receptors. We have identified the cellular binding proteins of the glucocorticoid receptor NLS and the thyroid hormone receptor NLS after cross-linking of radiolabeled signal peptides to subcellular fractions. Two S49 lymphoma cytosolic polypeptides of 60 and 76 kilodaltons (kDa) were specifically bound to either the glucocorticoid or thyroid hormone receptor NLS. The two binding sites demonstrated saturable binding. A competitive binding assay showed that the binding sites were specific for NLSs and that a mutated NLS was a poor competitor for the binding of labeled glucocorticoid receptor NLS. However, competition studies with peptides unrelated to NLSs, yet resembling NLSs in that they had a net positive charge, revealed that the 60-kDa entity demonstrated greater specificity for binding to NLSs than did the 76-kDa polypeptide. Glucocorticoid receptor NLS and thyroid hormone receptor NLS-binding proteins of 60 and 76 kDa were also identified in nuclear fractions. Although the unoccupied glucocorticoid receptor resides in the cytoplasm, while the unoccupied thyroid hormone receptor is always found in the nucleus, the hinge NLS interactions do not specify these different localizations of the unoccupied receptors. Rather, the data support roles for the hinge NLS in general steps of nuclear import and the 60-kDa cross-linked product as a chaperone of both receptors into the nucleus. Its cellular localization also suggests a role for the 76-kDa cross-linked product as a chaperone, but its relatively less stringent binding specificity may indicate that this polypeptide has a different physiological function.

11 beta-hydroxyandrostenedione: a marker of adrenal function in hirsutism.

To assess the role of the adrenal glands in the development of hirsutism, levels of 11 beta-hydroxyandrostenedione (11 beta-OHA), 17 alpha-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulphate (DHEAS), androstenedione (delta 4A), and free and total testosterone (T) were measured in 63 hirsute females and 30 control patients. Six of the hirsute patients had basal levels of 11 beta-OHA and 17-OHP and responses to adrenocorticotropic hormone that were significantly greater than these values in controls and the other hirsute women. These women were designated as having an adrenal source for their hirsutism. Women with polycystic ovarian syndrome and idiopathic hirsutism had normal values of 11 beta-OHA and 17-OHP. Levels of total and free T, DHEAS and delta 4A were significantly higher than control values in all of the hirsute women. This study demonstrates that 11 beta-OHA can be used as a marker to assess the adrenal contribution to hirsutism.

Rotavirus inactivation by chemical disinfectants and antiseptics used in hospitals.

Nosocomial outbreaks of rotaviral gastroenteritis are a common occurrence. Although proper disinfection practices in the hospital environment are considered to be important in the prevention and control of such outbreaks, very little information has been available on the rotavirus-inactivating capacity of chemical disinfectants and antiseptics commonly used in hospitals. In view of this, 11 such products were selected and screened for their capacity to bring about at least a 3 log10 reduction in the plaque titre of rotavirus SA-11 after a contact time of 1-30 min. Consept "D" (1:100), D.R.X. (1:80), Dustbane Germicidal (1:80), Hibitane, and Wescodyne (1:200) were found to be ineffective under these test conditions even in the absence of an added organic load. The virucidal capacity of Savlon (1:200) and Zephiran was completely neutralized when single-strength tryptose phosphate broth was added to the virus-disinfectant mixture to simulate an organic load. Cidex (2% acid glutaraldehyde), Proviodine (10% solution of povidone-iodine), Septisol (0.75% hexachlorophene), and Sana Rinse (70% isopropylalcohol, 0.1% hexachlorophene) were able to produce at least a 3 log10 (99.9%) reduction in the virus plaque titre even in the presence of added organic matter. These findings should be of help in the prevention and control of outbreaks of rotaviral diarrhea in the hospital environment.