Providing News and Information About Medications and Their Proper Use

PNN Pharmacotherapy Line

Jan. 3, 2017 * Vol. 24, No. 1

Providing news and information about medications and their proper use

>Internal Medicine Report

Source: Early-release articles from and Jan. 3 issue of the Annals of Internal Medicine (2017; 166).

Oral Treatment of Type 2 Diabetes: In an update to a 2012 clinical practice guideline, the American College of Physicians recommends first-line use of metformin for oral pharmacologic treatment of type 2 diabetes in adults (10.7326/M16-1860). The guideline, endorsed by the American Academy of Family Physicians, cites the safety advantages of metformin over other oral agents, particularly its weight loss effect. Based on a systematic review and meta-analysis of monotherapy and metformin-based combination therapy (2016;164:740–51; N. M. Maruthur, ), ACP makes these recommendations (A. Qaseem, ):

* ACP recommends that clinicians prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control. (Grade: strong recommendation; moderate-quality evidence)

* ACP recommends that clinicians consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered. (Grade: weak recommendation; moderate-quality evidence.) ACP recommends that clinicians and patients select among medications after discussing benefits, adverse effects, and costs.

Evidence Supporting Increased Metformin Use: Describing evidence that supports recent changes in recent FDA-approved labeling of metformin-containing products, authors of a systematic review conclude that “metformin use in patients with moderate [chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD)] with hepatic impairment is associated with improvements in key clinical outcomes” (10.7326/M16-1901). Studies selected for inclusion in the review assessed metformin’s effects in adults with type 2 diabetes and CKD, defined as estimated glomerular filtration rate less than 60 mL/min/1.73 sq m, and reported all-cause mortality, major adverse cardiovascular events, and other outcomes. The data showed: “On the basis of quantitative and qualitative syntheses involving 17 observational studies, metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF.” (M. J. Crowley, )

Treatment of Gout: One of several articles in this issue on treatment of gout (pp. 26–36, S. J. Newberry, ; pp. 37–51, P. G. Shekelle, ; pp. 73–4, R. M. McLean, ; pp. 1–16, A. Qaseem), an editorial concludes that “although some approaches have not yet been formally tested in trials, a clear understanding of the pathophysiology of gout provides a strong foundation for rational recommendations while we await clarity on these important clinical issues” (pp. 71–2): “We acknowledge that the existing literature only indirectly addresses what the optimal serum urate target is. However, it is a disservice to our patients and primary care colleagues to suggest that treating to avoid symptoms is acceptable with [urate-lowering therapy (ULT)] in the absence of evidence. At the very least, based on the biochemistry of urate, a treatment target below the physiologic threshold of urate crystallization (<6.8 mg/dL) would be appropriate, even if a lower target is not yet supported by randomized trials. A target of less than 6.8 mg/dL (or <357 µmol/L [<6 mg/dL] with assay variation taken into account) seems reasonable, based on the authors’ own admission that serum urate levels exceeding this threshold are the cause of gout.” (T. Neogi)

>PNN JournalWatch

* 2017 Standards of Medical Care in Diabetes, in Diabetes Care, 2017; 40 (suppl 1). (American Diabetes Association)

* Hypnotic Medications and Suicide: Risk, Mechanisms, Mitigation, and the FDA, in American Journal of Psychiatry, 2017; 174: 18–25. (W. V. McCall)

* Risk Stratification for Opioid Misuse in Children, Adolescents, and Young Adults: A Quality Improvement Project, in Pediatrics, 2017; 139: 10.1542/peds.2016-0258. (R. Thienprayoon)

* Sweet Solutions to Reduce Procedural Pain in Neonates: A Meta-analysis, in Pediatrics, 2017; 139: 10.1542/peds.2016-0955. (D. Harrison)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail to request missing copies of PNN. Quarterly files archived at

PNN Pharmacotherapy Line

Jan. 4, 2017 * Vol. 24, No. 2

Providing news and information about medications and their proper use

>JAMA Report

Source: Jan. 3 issue of JAMA (2017; 317).

Trastuzumab Biosimilar in Metastatic Breast Cancer: In a randomized comparison, a proposed trastuzumab biosimilar performed similarly to the originator product in women with ERBB2 (HER2)–positive metastatic breast cancer, researchers report (pp. 37–47). The phase 3 trial included 500 women treated with a taxane plus either the biosimilar or trastuzumab, with these results: “Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The [overall response rate (ORR)] was 69.6% (95% CI, 63.62%–75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%–70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974–1.211) and ORR difference (5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%).” (H. S. Rugo, )

In addition to exploring the impact of a biosimilar on treatment in developing countries, editorialists delve into the effect on prices in the U.S. (pp. 30–2): “The trastuzumab biosimilar will probably reduce prices, although this will not take full effect until the patent on trastuzumab expires in 2019. Under the prevailing ‘buy and bill’ system of Medicare Part B, oncology practices are reimbursed for chemotherapy based on a drug’s average sales price plus a 6% margin intended to cover overhead and inventory management. To mitigate the financial disincentive to prescribe inexpensive alternatives, the Centers for Medicare & Medicaid Services has wisely pegged reimbursement for biosimilar products to the average sales price of the biosimilar plus 6% of the branded version, that is, the 6% is based on the cost of the more expensive drug.” (D. Schrag, )

JAMA editors explain their decision to publish this article in light of trial sponsorship by the biosimilar developers, including Mylan, which has been under scrutiny for its pricing of EpiPen (pp. 33–4): “Ultimately, the decision to publish this article was based on the determination that the scientific merit and potential to contribute meaningful clinical information for care of patients with breast cancer outweighed other considerations. The controversy over the pricing of drugs in the United States and around the world is an ongoing debate, and not unique to 1 company or 1 product. The authors have provided assurance to the editors that the study was conducted ethically and appropriately. The lead academic author indicates that she had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The data from this study will also be subject to additional scrutiny by regulatory agencies in making determinations about approval of the proposed trastuzumab biosimilar product.” (H. Bauchner, )

Longer Dosing Interval for Zoledronic Acid: Administration of zoledronic acid in patients with cancer every 12 weeks was noninferior to every-4-week dosing in a randomized open-label trial (pp. 48–58): “Among 1,822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of −0.3% [1-sided 95% CI, −4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma.…” (A. L. Himelstein, )

PNN Pharmacotherapy Line

Jan. 5, 2017 * Vol. 24, No. 3

Providing news and information about medications and their proper use

>NEJM Report

Source: Jan. 5 issue of the New England Journal of Medicine (2017; 376).

Inclisiran for PCSK9–Mediated Cholesterol Lowering: A long-acting RNA interference therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), inclisiran significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months without serious adverse events, researchers report (pp. 41–51). Tested in ascending and multiple doses in a phase 1 trial, inclisiran produced these results in small numbers of healthy volunteers: “The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the gamma-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).” (K. Fitzgerald, )

Entry of inclisiran into clinical testing brings attention to the new field of oligonucleotide therapeutics, according to the author of a Perspective article (pp. 4–7): “The [small interfering RNAs (siRNAs)] consist of two strands, guide and passenger. The guide strand carries the sequence information necessary for target-gene recognition, while the passenger strand serves as a prodrug that supports the geometry required for loading into the RNA-induced silencing complex (RISC). When siRNAs are introduced into the cells, the guide strand enters the RISC and reprograms the powerful natural mechanism RNA interference (RNAi), silencing genes on demand. The loaded RISC has a long half-life, and as few as 100 to 200 loaded RISC complexes per cell are sufficient to eliminate expression of the targeted gene. The importance of this fundamental mechanism is well recognized — indeed, the two scientists who discovered it, Craig Mello and Andrew Fire, were awarded the Nobel Prize in 2006.” (A. Khvorova)

Oligonucleotide technology is also being tested with antisense agents, writes the author of a Clinical Implications of Basic Research article (pp. 86–8). “The advantages of the targeted delivery strategy are … demonstrated by comparing the results of a pair of phase 2 studies in which the activity of two antisense oligonucleotides against apolipoprotein(a), which is expressed in the liver, were compared,” the author explains. “One of the antisense oligonucleotides was nontargeted, and the second was targeted to hepatocytes with the use of triantennary [N-acetylgalactosamine]. On the basis of the reductions in the mean change in circulating levels of apolipoprotein(a) according to dose, targeted delivery was determined to result in a median effective dose that was one thirtieth of that associated with nontargeted delivery, which clearly underscored the potential advantage of the approach.” (A. A. Levin)

Ticagrelor in Symptomatic Peripheral Artery Disease: In 13,885 patients with symptomatic peripheral artery disease, ticagrelor was not superior to clopidogrel for reduction of cardiovascular events, and major bleeding rates were similar (pp. 32–40). A primary efficacy composite end point of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke occurred in 751 of 6,930 patients (10.8%) receiving ticagrelor and in 740 of 6,955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P = 0.65), the investigators report. (M. R. Patel, )

>PNN NewsWatch

*FDA, now classifying an October recall as Class I, yesterday issued an alert about a potential link between us of Nurse Assist I.V. Flush Syringes with Burkholderia cepacia bloodstream infections.

PNN Pharmacotherapy Line

Jan. 6, 2017 * Vol. 24, No. 4

Providing news and information about medications and their proper use

>Diabetes Report

Source:Jan. issue and annual standards supplement of Diabetes Care (2017; 40).

2017 Standards of Medical Care in Diabetes: Psychosocial issues have been added to the ADA’s Standards of Care for 2017, including self-management, mental health, communication, complications, comorbidities, and life-stage considerations (supplement 1). Several tweaks were made to the pharmacotherapy recommendations, including the following (Am. Diabetes Assoc.):

* Patients on long-term metformin therapy should have periodic B12 measurements and supplementation as needed.

* A new section describes newly available biosimilar insulins.

* Empagliflozin or liraglutide are recommended in patients with established cardiovascular disease to reduce the risk of mortality.

* A figure illustrating antihyperglycemic therapy in type 2 diabetes is updated to acknowledge the high cost of insulin.

* An algorithm for the use of combination injectable therapy in patients with type 2 diabetes is changed to reflect studies demonstrating the noninferiority of basal insulin plus glucagon-like peptide 1 receptor agonist versus basal insulin plus rapid-acting insulin versus two daily injections of premixed insulin, as well as studies demonstrating the noninferiority of multiple-dose premixed insulin regimens versus basal-bolus therapy.

* New tables show the median costs of noninsulin agents.

Metformin & Gut Microbiome: Clinical data support an emerging hypothesis that use of metformin “shifts gut microbiota composition through the enrichment of mucin-degrading Akkermansia muciniphila as well as several [short-chain fatty acid (SCFA)]–producing microbiota,” researchers report (pp. 54–62). Among 28 patients with type 2 diabetes, half of whom were taking metformin, and 84 participants without diabetes, these results were found in clinical tests and gene sequencing of fecal samples: “We found an association between diabetes and gut microbiota that was modified by metformin use. Compared with participants without diabetes, participants with diabetes taking metformin had higher relative abundance of Akkermansia muciniphila, a microbiota known for mucin degradation, and several gut microbiota known for production of SCFAs, including Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and an operational taxonomic unit of Prevotella. In contrast, compared with participants without diabetes, participants with diabetes not taking metformin had higher relative abundance of Clostridiaceae 02d06 and a distinct operational taxonomic unit of Prevotella and a lower abundance of Enterococcus casseliflavus.” (J. S. Escobar, )

Saxagliptin & Renal Outcomes: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, saxagliptin significantly improved albumin/creatinine ratios (ACRs) among patients with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, an effect that could not be explained by the drug’s glycemic actions (pp. 69–76). “Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively),” the authors wrote of the 16,492 study participants. “At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was −19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), −105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and −245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA.…” (I. Raz, )

>PNN NewsWatch

* After a very quiet beginning of the 2016–17 influenza season, the bug produced its annual holiday bump in surveillance data during the week before Christmas as Americans shared a viral gift with other travelers and loved ones. Nationally, 10.4% of respiratory specimens tested positive for influenza that week, and 9 of the 10 regions in the U.S. had elevated activity. Remind patients that it’s not too late to get vaccinated and that peak activity last season was in March.

PNN Pharmacotherapy Line

Jan. 9, 2017 * Vol. 24, No. 5

Providing news and information about medications and their proper use

>Lancet Highlights

Source: Jan. 7 issue of Lancet (2017; 389).

Regorafenib in Hepatocellular Carcinoma: In a phase 3 trial of 567 patients with sorafenib-resistant hepatocellular carcinoma (HCC), regorafenib significantly improved overall and median survival, researchers report (pp. 56–66). “Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment,” the group concludes based on these study results: “Regorafenib improved overall survival with a hazard ratio of 0.63 (95% CI 0.50–0.79; one-sided p <0.0001); median survival was 10.6 months (95% CI 9.1–12.1) for regorafenib versus 7.8 months (6.3–8.8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand–foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group.” (J. Bruix, )