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Drug Information Newsletter Spring 2020

In this issue… • Rybelsus® (Oral Semaglutide): New Drug Review

Merin Panthapattu, PharmD • CDC and FDA Warn Against THC Vaping Products – Safety Update

Troy Hoelzl, PharmD • Risk of Hip Fracture in Older Adults as Related to Concurrent Use of

Multiple Fracture-Associated Drugs Amanda Foster, PharmD

The University at Buffalo School of Pharmacy and Pharmaceutical Sciences (UB SPPS) Drug Information Newsletter is dedicated to providing timely information relevant to healthcare practitioners in New York. The newsletter supplies information on clinical practice guidelines, medication safety issues, new drug approvals/medications under development, medication shortages, and drug class reviews.

Rybelsus® (Oral Semaglutide): New Drug Review Merin Panthapattu, PharmD

Background In September 2019, the United States Food and Drug Administration (FDA) approved oral semaglutide (Rybelsus®), for improved glycemic control in adults with type 2 diabetes mellitus (T2DM), when used as an adjunct to diet and exercise.1-3 Rybelsus® is the first and only oral glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1 agonists target the incretin system when glucose levels are elevated.4 Peripherally, GLP-1 reduces gut motility and inhibits glucagon secretion. Centrally, GLP-1 agonists induce satiety which leads to less intake of food. GLP-1 agonists also increase insulin secretion from the pancreas. Since the mechanism of GLP-1 agonists is dependent on glucose levels, the incidence of hypoglycemic events with use of these agents is relatively low.3

The 2020 American Diabetes Association (ADA) standards of care recommend use of a GLP-1 agonist with proven cardiovascular benefit, as an add-on to metformin, in patients with a diagnosis of diabetes mellitus and established cardiovascular disease (CVD) or indicators of high risk such as established kidney disease or heart failure.5 Similarly, the American Association of Clinical Endocrinologists (AACE) endorses the use of a GLP-1 agonist with proven cardiovascular benefits, as an add-on to metformin, in patients with atherosclerotic CVD, or at high cardiovascular risk.6

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Available literature Avgerinos et al conducted a systematic review and meta-analysis to assess the safety and efficacy of oral semaglutide.7 The systematic review identified studies indexed on Medline, Embase, the Cochrane Library and in grey literature for randomized controlled trials (RCTs) which compared oral semaglutide with placebo and other antidiabetic agents. The meta-analysis included 11 RCTs, with 9890 patients. The primary outcome was change from baseline in glycosylated hemoglobin A1c (A1c). Secondary outcomes included change from baseline in body weight and blood pressure. Safety outcomes included cardiovascular endpoints, severe hypoglycemia, gastrointestinal adverse events, all-cause mortality, and diabetic retinopathy. The meta-analysis utilized weighted mean difference (WMD) for continuous outcomes and odds ratios (OR) for dichotomous outcomes. Compared to placebo, oral semaglutide reduced A1c and body weight with a WMD of -0.89% [-1.07, -0.71] (95% confidence interval represented in brackets) and -2.99 kg [-3.69, -2.30], respectively. Compared to active controls, oral semaglutide reduced A1c by a WMD of -0.35% [-0.43, -0.26] and weight by a WMD of -1.48 kg [-2.28, -0.67]. Compared to placebo, oral semaglutide reduced all-cause mortality, OR 0.58 [0.37, 0.92], and cardiovascular mortality, OR 0.55 [0.31, 0.98]; no differences were noted in comparisons with other antidiabetic agents. Treatment with oral semaglutide increased the incidence of gastrointestinal adverse events but was not associated with an increase in the incidence of diabetic retinopathy adverse events. The manufacturer of oral semaglutide, Novo Nordisk, funded a series of clinical trials collectively known as the Peptide Innovation for Early Diabetes Treatment (PIONEER) trials, each of which compares safety and efficacy of oral semaglutide to placebo or to currently available antidiabetic agents.2,8-15 Selected characteristics of these trials may be seen in Table l. All of the studies were RCTs with a parallel-group design, and the durations ranged from 26 weeks to 78 weeks.8-15 All studies included adult patients with T2DM. Uniquely, patients in trial 5 had moderate renal impairment, and patients in trial 6 had either established CVD or chronic kidney disease, or 1 or more risk factors for CVD.12,13 Trials 1, 4-6, and 8 were placebo-controlled;8,11-13,15 active comparators were utilized in trials 2-4 and 7 and included empagliflozin (trial 2), sitagliptin (trials 3 and 7), and liraglutide (trial 4).9-11,14 Semaglutide was administered at different doses across the trials; trials 1, 3, and 8 randomized patients to receive 3 different doses daily, while trials 2 and 4-6 titrated patients to a final dose of 14 mg daily, and trial 7 employed variable dosing.8-15 Though the durations of the studies varied, the primary outcome for most of the PIONEER trials (1-5 and 8) was mean change in A1c from baseline to 26 weeks.8-12,15 Primary endpoints for PIONEER 6 and 7 were, respectively, time to first occurrence of major adverse cardiovascular events (MACE) and proportion of patients achieving A1c <7% at 52 weeks.13,14 In addition to these endpoints, nearly all of the trials investigated changes in weight from baseline (all except PIONEER 6).8-15 With regard to glycemic effects, statistically significant results were observed in all of the relevant trials for oral semaglutide (administered at doses of 7 mg and 14 mg daily) at 26 weeks.8-12,15 Results remained statistically significant at 52 weeks (trials 2, 4, and 8) and 78 weeks (trial 3), primarily for semaglutide administered at the highest dose (14 mg daily).9-11,15 Notably, absolute differences from placebo and active comparators were relatively small.8-12,15 Comparing semaglutide 14 mg daily to placebo, mean differences in A1c at 26 weeks ranged from -0.8% to -1.3%; comparing the same dose to active controls, mean differences ranged from -0.1% to -0.5%. Results were similar at 52 weeks and 78 weeks. With regard to weight changes, statistically significant reductions were observed with semaglutide from baseline.8-12,14,15 Absolute differences from placebo at 26 weeks ranged from -0.1 kg to -3.8 kg.8,11-12,15 Mean differences from active comparators were relatively small, ranging from -0.2 kg to -2.5 kg.9-11,14

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As mentioned previously, trials 6 and 7 were unique in their primary endpoints.13,14 PIONEER 6 was an event-driven trial designed to evaluate non-inferiority of semaglutide to placebo in the occurrence of MACE.13 Based on their findings, the investigators determined semaglutide to be non-inferior to placebo in the occurrence of MACE. Interestingly, when reviewing singular outcomes, statistically significant results were observed in the occurrence of cardiovascular death and all-cause mortality favoring semaglutide. Though not statistically significant, occurrence of nonfatal myocardial infarction was higher in those receiving semaglutide. PIONEER 7 focused on glycemic outcomes and demonstrated significantly greater achievement of A1c <7% in patients using semaglutide vs. sitagliptin.14 Dosage, storage and administration The recommended starting dose of oral semaglutide is 3 mg daily, which must be maintained for 30 days.3 This dose is not effective for glycemic control but is intended to help patients adjust to therapy. After 30 days on the starting dose, patients should be transitioned to the maintenance dose of 7 mg daily. If additional blood glucose control is needed after being maintained on oral semaglutide 7 mg for 30 days, patients can be transitioned onto a maintenance dose of 14 mg daily. Patients should be counseled to take oral semaglutide first thing in the morning, at least 30 minutes before consuming any food, beverage or other oral medications, with no more than 4 ounces of plain water.3 Oral semaglutide comes prepackaged in a blister pack. As such, patients should keep the blister pack away from moisture. When taking the dose of oral semaglutide, patients should push the tablet out of the blister pack, and swallow the tablet whole with a sip of water. The tablet cannot be cut, crushed, or chewed. It is not recommended for a patient to take two 7 mg tablets for a 14 mg dose. Contraindications Use of oral semaglutide is contraindicated in patients with a personal, or family history of medullary thyroid carcinoma (MTC), and in patients with multiple endocrine neoplasia syndrome type 2.3 Use of oral semaglutide is also contraindicated in patients with known hypersensitivity to semaglutide or any of the components in oral semaglutide.

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Table 1. Selected characteristics of PIONEER trials 1-8.8-15

Pioneer trial #

Study design,

duration Population Interventions Mean baseline

A1c Mean change in A1c from

baselinea,b Other outcomes/resultsb

1 R, DB, PC, PG 26 weeks

n=703 adults with T2DM inadequately controlled with diet and exercise, when compared to placebo

OS (1 dose daily): 3 mg (n=175) 7 mg (n=175) 14 mg (n=175) Placebo (n=178)

OS 3 mg: 7.9% OS 7 mg: 8.0% OS 14 mg: 8.0% Placebo: 7.9%

At 26 weeks: Placebo-adjusted differences: OS 3 mg: -0.6%, p<0.001 OS 7 mg: -1.2%, p<0.001 OS 14 mg: -1.1%, p<0.001

Mean weight changec from baseline at 26 weeks: OS 3 mg: -1.5 kg OS 7 mg: -2.3 kg OS 14 mg: -3.7 kg Placebo: -1.4 kg Differences from placebo: OS 3 mg: -0.1 kg [-0.9, 0.8] OS 7 mg: -0.9 kg [-1.9, 0.1] OS 14 mg: -2.3 kg [-3.1, -1.5]

2 R, OL, AC, PG 52 weeks

n=822 adults with T2DM inadequately controlled on MET

OS 14 mg daily (n=411) Empagliflozin 25 mg PO daily (n=410)

OS 14 mg: 8.1% Empagliflozin 25 mg: 8.1%

At 26 weeks: OS 14 mg: -1.3% Empagliflozin 25 mg: -0.9% Difference: -0.4% [-0.6, -0.3] At 52 weeks: Difference from empagliflozin: -0.4% [-0.5, -0.3]

Mean weight changec from baseline at 26 weeks: OS 14 mg: -3.8 kg Empagliflozin 25 mg: -3.7 kg Difference: -0.1 kg [-0.7, 0.5] At 52 weeks: Difference from empagliflozin: -0.2 kg [-0.9, 0.5]

3 R, DB, AC, PG 78 weeks

n=1864 adults with T2DM inadequately controlled on MET +/- SU

OS (1 dose daily): 3 mg (n=466) 7 mg (n=465) 14 mg (n=467) Sitagliptin 100 mg PO daily (n=467)

OS 3 mg: 8.3% OS 7 mg: 8.4% OS 14 mg: 8.3% Sitagliptin 100 mg: 8.3%

At 26 weeks: Differences from sitagliptin: OS 3 mg: 0.2% [0.0, 0.3] OS 7 mg: -0.3% [-0.4, -0.1] OS 14 mg: -0.5% [-0.6, -0.4] At 78 weeks: OS 3 mg: 0.0% [-0.1, 0.2] OS 7 mg: -0.1% [-0.3, 0.0] OS 14 mg: -0.4% [-0.6, -0.3]

Mean weight changec from baseline at 26 weeks: OS 3 mg: -1.2 kg OS 7 mg: -2.2 kg OS 14 mg: -3.1 kg Sitagliptin 100 mg: -0.6 kg Differences from sitagliptin: OS 3 mg: -0.6 kg [-1.1, -0.1] OS 7 mg: -1.6 kg [-2.0, -1.1] OS 14 mg: -2.5 kg [-3.0, -2.0] At 78 weeks: Differences from sitagliptin: OS 3 mg: -0.8 kg [-1.5, -0.1] OS 7 mg: -1.7 kg [-2.3, -1.0] OS 14 mg: -2.1 kg [-2.8, -1.5]

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Pioneer trial #

Study design,

duration Population Interventions Mean baseline

A1c Mean change in A1c from

baselinea,b Other outcomes/resultsb

4 R, DB, DD, AC, PC, PG 52 weeks

n=711 adults with T2DM inadequately controlled on MET +/- SGLT2-i, when compared to liraglutide

OS 14 mg daily (n=285) Liraglutide 1.8 mg PO daily (n=284) Placebo (n=142)

OS 14 mg: 8.0% Liraglutide 1.8 mg: 8.0% Placebo: 7.9%

At 26 weeks: OS 14 mg: -1.2% Liraglutide 1.8 mg: -1.1% Placebo: -0.2% Difference from placebo: -1.1% [-1.2, -0.9] Difference from liraglutide: -0.1% [-0.3, 0.0] At 52 weeks: OS 14 mg: -1.2% Liraglutide 1.8 mg: -0.9% Placebo: -0.2% Difference from placebo: -1.0% [-1.2, -0.8] Difference from liraglutide: -0.3% [-0.5, -0.1]

Mean weight changec from baseline at 26 weeks: OS 14 mg: -4.4 kg Liraglutide 1.8 mg: -3.1 kg Placebo: -0.5 kg Difference from placebo: OS 14 mg: -3.8 kg [-4.7, -3.0] Difference from liraglutide 1.8 mg: OS 14 mg: -1.2 kg [-1.9, -0.6] At 52 weeks: OS 14 mg: -4.3 kg Liraglutide 1.8 mg: -3.0 kg Placebo: -1.0 kg Difference from placebo: OS 14 mg: -3.3 kg [-4.3, -2.4] Difference from liraglutide 1.8 mg: OS 14 mg: -1.3 kg [-2.1, -0.5]

5 R, DB, PC, PG 26 weeks

n=324 adults with T2DM inadequately controlled on MET, MET +/- SU, MET +/- basal insulin, in patients with moderate renal impairment (GFR 30-59 mL/min)

OS 14 mg daily (n=163) Placebo (n=161)

OS 14 mg: 8.0% Placebo: 7.9%

At 26 weeks: OS 14 mg: -1.0% Placebo: -0.2% Difference from placebo: -0.8% [-1.0, -0.6]

Mean weight changec from baseline at 26 weeks: OS 14 mg: -3.4 kg Placebo: -0.9 kg Difference: -2.5 kg [-3.2, -1.8]

6 R, DB, PC, PG, GB Median 15.9 months

n=3183 adults with T2DM at high risk for CV events defined as either ≥50 YO with CVD or CKD or ≥60 YO without established CVD

OS 14 mg daily (n=1591) Placebo (n=1592)

OS 14 mg: 8.2% Placebo: 8.2%

Not a primary endpoint Composite endpoint of the time to 1st occurrence of CV death, nonfatal MI, or nonfatal stroke: OS vs. placebo: 3.8% vs. 4.8% HR 0.79 [0.57, 1.11] CV death: OS vs. placebo: 0.9% vs. 1.9% HR 0.49 [0.27, 0.92]

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Pioneer trial #

Study design,

duration Population Interventions Mean baseline

A1c Mean change in A1c from

baselinea,b Other outcomes/resultsb

but ≥1 risk factor for CVD

Nonfatal MI: OS vs. placebo: 2.3% vs. 1.9% HR 1.18 [0.73, 1.90] Nonfatal stroke: OS vs. placebo: 0.8% vs. 1.0% HR 0.74 [0.35, 1.57] All-cause mortality: OS vs. placebo: 1.4% vs. 2.8% HR 0.51 [0.31, 0.84]

7 R, OL, AC, PG 52 weeks

n=504 adults with T2DM inadequately controlled on 1-2 OAD (MET, SU, SGLT-2i, TZD)

OS, flexible dose adjustments to 3, 7, or 14 mg daily (n=253) Sitagliptin 100 mg PO daily (n=251)

OS variable: 8.3% Sitagliptin 100 mg: 8.3%

Not a primary endpoint Proportion of patients achieving A1c <7% at 52 weeks: OS variable: 58% Sitagliptin 100 mg: 25% OR 4.40 [2.89, 6.70]d Mean weight change from baseline at 52 weeks: OS variable: -2.6 kg Sitagliptin 100 mg: -0.7 kg Difference: -1.9 kg [-2.6, -1.2]

8 R, DB, PC, PG 52 weeks

n=731 adults with T2DM inadequately controlled on MET +/- insulin

OS (1 dose daily): 3 mg (n=184) 7 mg (n=182) 14 mg (n=181) Placebo (n=184)

OS 3 mg: 8.2% OS 7 mg: 8.2% OS 14 mg: 8.2% Placebo: 8.2%

At 26 weeks: Placebo-adjusted differences: OS 3 mg: -0.5% [-0.7, -0.3] OS 7 mg: -0.9% [-1.1, -0.7] OS 14 mg: -1.3% [-1.4, -1.0] At 52 weeks: OS 3 mg: -0.4% [-0.6, -0.2] OS 7 mg: -0.6% [-0.8, -0.4] OS 14 mg: -0.9% [-1.1, -0.7]

Mean weight changec from baseline at 26 weeks: OS 3 mg: -1.4 kg OS 7 mg: -2.4 kg OS 14 mg: -3.7 kg Placebo: - 0.4 kg Differences from placebo: OS 3 mg: -0.9 kg [-1.8, 0.0] OS 7 mg: -2.0 kg [-3.0, -1.0] OS 14 mg: -3.3 kg [-4.2, -2.3] At 52 weeks: OS 3 mg: -1.3 kg [-2.4, -0.3] OS 7 mg: -2.5 kg [-3.6, -1.4] OS 14 mg: -4.3 kg [-5.3, -3.2]

aPrimary endpoint for PIONEER 1-5 and 8; PIONEER 6 investigated major adverse cardiovascular events, and PIONEER 7 investigated achievement of A1c less than 7% at week 52 b95% confidence intervals reported in brackets cOS is not FDA-approved for weight loss

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dOdds ratio of achieving A1c less than 7% +/-=with or without; A1c=glycosylated hemoglobin; AC=active controlled; CV=cardiovascular; CVD=cardiovascular disease; CKD=chronic kidney disease; DB=double-blind; DD=double-dummy; GB=global trial; GFR=glomerular filtration rate; HR=hazard ratio; MC=multicenter; MET=metformin; MI=myocardial infarction; OAD=oral antidiabetic; OL=open label; OR=odds ratio; OS=oral semaglutide; PC=placebo-controlled; PG=parallel-group; R=randomized; SGLT-2i= sodium-glucose cotransporter 2 inhibitor; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedione; YO=years-old

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Warnings and precautions Although oral semaglutide caused a dose dependent and treatment-duration dependent increase in the incidence of thyroid C-cell tumors in mice and rats, it is unknown whether oral semaglutide causes thyroid C-cell tumors in adult humans.3 Patients using oral semaglutide should be counseled on risk of MTC, and be informed of symptoms of MTC such as a mass in the neck, dysphagia, dyspnea, and persistent hoarseness. Pancreatitis is a serious adverse event that has been reported in patients who use oral semaglutide. On initiation, patients should be counseled on signs and symptoms of pancreatitis such as severe abdominal pain, and vomiting. Rapid improvement in glucose control has been associated with temporary worsening of diabetic retinopathy.3,16 The effect of long-term glycemic control with oral semaglutide has not been studied; however, patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. Renal function should be monitored when initiating and escalating doses of oral semaglutide. Adverse reactions The most common adverse reactions reported in ≥5% of patients treated with oral semaglutide in placebo-controlled trials are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation.3 The majority of gastrointestinal intolerances occurred during dose escalation of oral semaglutide. Hypoglycemia occurred more frequently when oral semaglutide was used with insulin secretagogues or insulin. Drug interactions Concomitant use of oral semaglutide with insulin or insulin secretagogues is associated with an increased risk of hypoglycemia.3 As such, when initiating oral semaglutide, consider decreasing the dose of insulin or insulin secretagogue to lower risk of hypoglycemia. Also, as slowing gastric motility is one of the mechanisms of action for oral semaglutide, caution must be taken when used with other oral medications. For example, levothyroxine exposure was increased 33% when administered with oral semaglutide in a drug interaction study. Increased monitoring should be considered for patients on medications with a narrow therapeutic index such as levothyroxine and warfarin. Special populations There are not enough available data to date to evaluate the drug-associated risk of major adverse maternal or fetal outcomes with use of oral semaglutide.3 As such, oral semaglutide should be used during pregnancy only if the potential benefit justifies any potential risk to the fetus. Breastfeeding is not recommended during treatment with oral semaglutide as there are alternate forms of semaglutide available on the market that can be used during lactation, which do not have the risk of salcaprozate sodium (an absorption enhancer in the tablet) accumulation. Switching to and from Ozempic® (semaglutide injection) Patients treated with once weekly Ozempic® 0.5 mg injection can be transitioned to oral semaglutide 7 mg or 14 mg.3 Patients can start oral semaglutide up to 7 days after their last injection of Ozempic®. There is no equivalent dose of oral semaglutide for Ozempic® 1 mg. Patients treated with oral semaglutide 14 mg daily can

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be transitioned to Ozempic® 0.5 mg injection once weekly. Patients can start Ozempic® the day after their last dose of oral semaglutide. Implications in pharmacy practice The availability of an oral, non-injectable GLP-1 agonist for glycemic control can prove to be a valuable asset for patients who may have disregarded glycemic management with injectable therapy because of a fear of needles. Since oral semaglutide requires titration, and the starting dose, 3 mg for 30 days, is not effective for glycemic control, oral semaglutide may not be optimal in patients who require rapid glycemic control. Strict administration of oral semaglutide, first thing in the morning, with plain water and no other oral medications further complicates administration of oral semaglutide in patients who may be on other oral medications that have unique dosing considerations, such as levothyroxine and bisphosphonates. Needing to wait 30 minutes to an hour in between dosing such medications when used with oral semaglutide may prove to be a barrier to adherence. Both the ADA and AACE recommend use of a GLP-1 agonist for management of T2DM in patients with established CVD, or at high risk for CVD.5,6 Although oral semaglutide was found to be noninferior to placebo for the primary composite outcome of MACE, as recommended by the ADA 2020 standards of care, the cardiovascular effects and benefits of oral semaglutide need to be further investigated in large, longer-term outcomes trials to establish its place in therapy. References

1. United States Food and Drug Administration. FDA approves first oral GLP-1 for type 2 diabetes. September 20, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes. Accessed December 8, 2019.

2. Novo Nordisk. Rybelsus® information for healthcare professionals only. Last update unknown. https://www.rybelsuspro.com/. Accessed December 8, 2019.

3. Rybelsus® [package insert]. Plainsboro, NJ: Novo Nordisk; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed December 8, 2019.

4. Garber A. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34(Suppl 2):S279-S284.

5. American Diabetes Association. Standards of medical care in diabetes – 2020. Diabetes Care. 2020;43(Suppl 1):S1-S212.

6. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary. Endocr Pract. 2020;26(1):107-139.

7. Avgerinos I, Michailidis T, Liakos A, et al. Oral semaglutide for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2020;22(3):335-345.

8. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019;42(9):1724-1732.

9. Rodbard HW, Rosenstock J, Canani LH, et al. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial. Diabetes Care. 2019;42(12):2272-2281.

10. Rosenstock J, Allison D, Birkenfeld AL, et al. Effects of additional oral semaglutide vs. sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 randomized clinical trial. JAMA. 2019;321(15):1466-1480.

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11. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomized, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50.

12. Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomized, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):515-527.

13. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841-851.

14. Pieber TR, Bode B, Mertens A, et al. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicenter, open-label, randomized, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):528-539.

15. Zinman B, Aroda VR, Buse JB, et al. Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial. Diabetes Care. 2019;42(12):2262-2271.

16. Wang T, Lu W, Tang H, Buse JB, Stürmer T, Gower EW. Assessing the association between GLP-1 receptor agonist use and diabetic retinopathy through the FDA Adverse Event Reporting System. Diabetes Care. 2019;42(2):e21-e23.

CDC and FDA Warn Against THC Vaping Products – Safety Update Troy Hoelzl, PharmD

Introduction Electronic cigarettes (e-cigarettes), also known as vapes, vape pens, and electronic nicotine delivery systems (ENDS), are inhaled aerosol devices used to deliver various substances.1,2 The first products, introduced to the United States (US) market in 2007, were designed to deliver nicotine and resembled conventional cigarettes. The available products have evolved to include rechargeable devices in the form of flash drives, pens, and other everyday items, and, in addition to nicotine, are used to deliver substances such as tetrahydrocannabinol (THC). E-cigarette, or vaping, product use-associated lung injury (EVALI) is a recently recognized severe respiratory illness.1 Since August 2019, the Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), and state health authorities have been investigating and characterizing the outbreak of EVALI. In October 2019, the FDA issued a consumer alert stating that a majority of samples tested by federal and state health officials related to this investigation had been identified as vaping products containing THC.3 Thus, they recommended that consumers not use vaping products containing THC, not use vaping products obtained off the street, illicitly, or socially, and to not modify or add any substances to vaping products. On January 17, 2020, the CDC released 2 reports, 1 involving details from cases of EVALI reported nationwide, including patient demographics and self-reported substance use characteristics, as well as a report describing characteristics of patients with EVALI in Illinois.4,5 The 2 reports are discussed below. Safety update Data from the first report were analyzed through the CDC’s National Syndromic Surveillance Program (NSSP).4 As of January 14, 2020, a total of 2,668 hospitalized cases were reported to the CDC, from all 50 states, the District of Columbia, Puerto Rico, and the US Virgin Islands. The outbreak began in June 2019 and peaked in September 2019 with an emergency department visit rate of 116 per million. The median patient age was 24

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years (range 13-85) and 66% were male. Most were non-Hispanic Caucasian (73%), and 15% were Hispanic. All patients had reported use of e-cigarettes or vaping products. Among them, 82% had used any THC-containing product and 33% had used exclusive THC-containing products; in contrast, 57% of patients reported using any nicotine-containing product, and 14% reported using exclusive nicotine-containing products. In a second report, the CDC described patients with EVALI in Illinois and compared characteristics of patients using only nicotine-containing products to those of patients using any THC-containing products.5 A total of 195 cases of EVALI had been reported to the Illinois Department of Public Health; 121 patients were interviewed. One-hundred and four (86%) patients reported using any THC-containing product. The remaining 17 (14%) reported using only nicotine-containing products, with 9 (7%) having no indication of any THC use based on self-reporting or toxicology testing. Among the 104 patients who had used any THC-containing products, 46 (44%) had confirmed EVALI; in contrast, 2 of the 17 (12%) patients who used only nicotine-containing products and none of the 9 patients (0%) with no indication of any THC use had confirmed EVALI (p=0.01 for both comparisons).5 When comparing groups, those who reported using any THC-containing product were more likely to be male compared to those with no indication of any THC use (75% vs. 22%; p=0.003).5 They were also more likely to be aged 13 to 24 years (63% vs. 22%, p<0.001). No statistically significant differences were found when comparing the frequency of use of nicotine-containing products, number of nicotine-containing products used, or source of nicotine product(s). In terms of clinical characteristics, 20% of patients using THC-containing products and 21% of patients using only nicotine-containing products had an existing respiratory condition, such as asthma, chronic obstructive pulmonary disease, and obstructive sleep apnea (p=1.0).5 Over 90% of patients in both groups reported experiencing shortness of breath, any cough and/or pleuritic chest pain (99% THC vs. 94% nicotine-only, p=0.3). Patients who reported using THC-containing products were more likely to meet the criteria for leukocytosis (white blood cell count >11,000/mm3; 91% THC vs. 56% nicotine-only, p=0.001). A lower likelihood of a severe outcome, defined as death or respiratory failure requiring endotracheal intubation and mechanical ventilation, was also found when comparing groups (21% THC vs. 41% nicotine-only, p=0.07), though this difference was not statistically significant. Additional updates Since the publication of the January reports, the CDC has posted updated data on their website regarding the number of hospitalizations and deaths related to EVALI.6 As of February 18, 2020, a total of 2,807 hospitalized cases or deaths have been reported to the CDC from all 50 states, the District of Columbia, Puerto Rico, and the US Virgin Islands. Sixty-eight deaths have been confirmed in 29 states and the District of Columbia. Notably, the CDC had announced in January that 50% of patients with EVALI who reported using THC-containing cigarettes or vaping devices provided information on the source of the product.1 Among these patients, 78% reported exclusive informal sources, such as family/friends, dealers, online, or other sources, while 16% reported commercial sources such as recreational and/or medical dispensaries, vape or smoke shops, stores, and pop-up shops. Six percent reported use of both informal and commercial sources.

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Though not well-described in the above reports, the CDC reported in December 2019 that laboratory analyses of samples from 51 cases of patients with EVALI have shown vitamin E acetate is strongly linked to the EVALI outbreak.1 Vitamin E acetate was found in bronchoalveolar lavage (BAL) fluid samples from 48 of the 51 patients but not in the BAL fluid from patients without EVALI. Vitamin E acetate is an additive in some THC-containing e-cigarettes or vaping products. Vitamin E is found in many foods and cosmetic products and usually does not cause harm when ingested or applied topically; however, inhalation of vitamin E acetate may impair lung function. Although a mechanism of action has not been confirmed, it is known that isomers of vitamin E can have regulatory effects on protein kinase C α in respiratory endothelial cells regulating leukocyte recruitment.7 This is an important part of the pathway leading to airway hyper-responsiveness and lung inflammation. Notably, the number of EVALI cases reported peaked in September 2019 but have since declined.8 Experts hypothesize the cause for the decline may be multifactorial.4 Some factors may include the FDA and CDC’s rapid response to the rise in EVALI cases and increased public awareness of the risk associated with THC-containing products, removal of vitamin E acetate from some products, and law enforcement actions related to some illicit products.1 Based on the continued decline in new EVALI cases since September 2019, as well as identification of vitamin E acetate as a primary cause of EVALI, the CDC announced on February 25, 2020, that the February 18 update would be their final update on the number of hospitalized EVALI cases and deaths nationally.6 Implications in pharmacy practice Concerned patients who have used or are currently using THC-containing e-cigarettes or vaping products may seek the advice of their local pharmacist. Pharmacists should advise these patients that the CDC and FDA recommend consumers not use those products, especially if from informal sources.8 Substances should not be added to e-cigarettes or vaping products unless intended by the manufacturer. If the products are being used for smoking cessation purposes, patients should not switch to smoking. The benefits and drawbacks of continuing e-cigarettes or vaping products and switching to FDA-approved smoking cessation medications should be considered. E-cigarettes or vaping products should not be used by children, pregnant women, and adults who do not currently use tobacco products. Patients should be counseled that EVALI usually presents with respiratory symptoms such as shortness of breath, cough, and/or chest pain, but patients can also experience gastrointestinal irritation, fever, chills, and/or fatigue.5 Patients experiencing any of these symptoms should contact their healthcare provider. Additional guidance for healthcare professionals may be found on the CDC website at cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease/healthcare-providers/. References

1. Centers for Disease Control and Prevention. Outbreak of lung injury associated with the use of e-cigarette, or vaping, products. Updated January 17, 2020. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html. Accessed January 17, 2020.

2. King BA, Jones CM, Baldwin GT, Briss PA. The EVALI and youth vaping epidemics — implications for public health. N Engl J Med. 2020;382(8):689-691.

3. U.S. Food and Drug Administration. Vaping illness update: FDA warns public to stop using tetrahydrocannabinol (THC)-containing vaping products and any vaping products obtained off the

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street. October 4, 2019. https://www.fda.gov/consumers/consumer-updates/vaping-illness-update-fda-warns-public-stop-using-tetrahydrocannabinol-thc-containing-vaping. Accessed February 10, 2020.

4. Krishnasamy VP, Hallowell BD, Ko JY, et al. Update: characteristics of a nationwide outbreak of e-cigarette, or vaping, product use–associated lung injury — United States, August 2019–January 2020. MMWR Morb Mortal Wkly Rep. 2020;69(3):90-94.

5. Ghinai I, Navon L, Gunn JKL, et al. Characteristics of persons who report using only nicotine-containing products among interviewed patients with e-cigarette, or vaping, product use–associated lung Injury — Illinois, August–December 2019. MMWR Morb Mortal Wkly Rep. 2020;69(3):84-89.

6. Centers for Disease Control and Prevention. Outbreak of lung injury associated with the use of e-cigarette, or vaping, products. Updated February 25, 2020. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html. Accessed February 29, 2020.

7. Cook-Mills JM, Abdala-Valencia H, Hartert T. Two faces of vitamin E in the lung. Am J Respir Crit Care Med. 2013;188(3):279-284.

8. Centers for Disease Control and Prevention. Most EVALI patients used THC-containing products as new cases continue to decline. January 17, 2020. https://www.cdc.gov/media/releases/2020/p0117-evali-cases-decline.html. Accessed January 17, 2020.

Risk of Hip Fracture in Older Adults as Related to Concurrent Use of Multiple Fracture-Associated Drugs

Amanda Foster, PharmD

Background The Centers for Disease Control and Prevention (CDC) reports that each year over 300,000 older people (≥65 years of age) are hospitalized for hip fractures, with over 95% of these fractures caused by falling.1 The CDC also states that women experience three-quarters of these hip fractures due to increased fall rates and increased prevalence of osteoporosis. In the United States (US), falls have not only led to hip fractures, but have led to death for many older adults.2 The CDC speculates that if the current fall-related death rate continues to increase as it has from 2007 to 2016, by 2030 there will be 7 fall-related deaths every hour. Falls are not only costly to a patient’s health, but they are costly to the healthcare system, with approximately $50 billion per year spent on non-fatal fall injuries and $754 million spent on fatal falls.3 One of the options the CDC recommends to help reduce hip fracture risk in older adults is to have a healthcare professional such as a physician or pharmacist review the patient’s medications, including over-the-counter products, for potentially inappropriate agents.1 The medications referred to by the CDC may be found in the 2019 American Geriatrics Society (AGS) Beers Criteria®,4 which is, “an explicit list of potentially inappropriate medications (PIMs) that are typically best avoided in older adults in most circumstances or under specific situations, such as certain diseases or conditions.” Table 1 lists the medications cited by the AGS Beers Criteria® as being associated with an increased risk of fracture in older adults. Overall, studies show that when 1 or more of these medications is/are taken by a geriatric patient, the risk of fracture increases significantly.

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Table 1. 2019 AGS Beers Criteria® List of Medications that May Increase Fracture Risk and Rationale.4

Fracture-Risk-Associated Medication or Medication Class

Rationale

BZDs Older adults have increased sensitivity to BZDs and decreased metabolism of long-acting agents; may cause ataxia, impaired psychomotor function, syncope, additional falls

Nonbenzodiazepine, BZD receptor agonist hypnotics (Z-drugs)

Older adults have increased sensitivity to Z-drugs and decreased metabolism of long-acting agents; may cause ataxia, impaired psychomotor function, syncope, additional falls

PPIs

Risk of bone loss and fracture. Avoid scheduled use for >8 weeks unless for high-risk patients (e.g., oral corticosteroids or chronic NSAID use), erosive esophagitis, Barrett’s esophagitis, pathological hypersecretory condition, or demonstrated need for maintenance treatment (e.g., because of failure of drug discontinuation trial or H2-receptor antagonists)

Skeletal muscle relaxants Anticholinergic adverse effects (drowsiness/sedation, blurred vision, dizziness, confusion); effectiveness at dosages tolerated by older adults questionable

Antiepileptics May cause ataxia, impaired psychomotor function, syncope, additional falls; should be avoided except for seizure and mood disorders

Antipsychotics

May cause ataxia, impaired psychomotor function, syncope, additional falls; avoid for behavioral problems of dementia and/or delirium unless nonpharmacological options have failed or are not possible and the older adult is threatening substantial harm to self or others

SNRIs, SSRIs, TCAs

May cause ataxia, impaired psychomotor function, syncope, additional falls; if 1 of the drugs must be used, consider reducing use of other CNS-active medications that increase risk of falls and fractures and implement other strategies to reduce fall risk; data for antidepressants are mixed but no compelling evidence that certain antidepressants confer less fall risk than others

Opioids May cause ataxia, impaired psychomotor function, syncope, additional falls; avoid except for pain management in the setting of severe acute pain

AGS=American Geriatrics Society; BZDs=benzodiazepines; CNS=central nervous system; H2=histamine-2; NSAID=non-steroidal anti-inflammatory drug; PPIs= proton-pump inhibitors; SSRIs=selective serotonin reuptake inhibitors; SNRI= serotonin-norepinephrine reuptake inhibitors; TCAs=tricyclic antidepressants. Study of interest A recent study by Emeny et al assessed the hip fracture risk associated with concurrent exposure to multiple fracture-associated drugs (FADs).5 A random 20% sample of Medicare fee-for-service administrative data for age-eligible Medicare beneficiaries aged ≥67 years from 2004 to 2014 was analyzed in this retrospective cohort study. Patients were excluded if they had a fragility fracture apparent during the 24-month pre-observation period, rationalized by the authors to “create a lower-risk cohort for exploration of FAD risk in the general, geriatric population.” Patients were also excluded if they received diagnoses or services during the study period for cancer (except nonmelanoma skin cancer), advanced renal disease, vertebral fracture, or hospice. The FADs targeted by the study were: inhaled steroids, oral steroids, proton pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), thiazolidinediones (TZDs), anticonvulsants, benzodiazepines (BZDs), barbiturates, opioids, muscle relaxants, histamine-1 (H1) receptor antagonists, anti-Parkinsonian agents, centrally-acting antihypertensives, antipsychotics, nitrates (not sublingual, oral and

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transdermal only), loop diuretics, thiazide and thiazide-like diuretics, and sedative hypnotics. It was determined that a patient was taking a FAD via prescription receipt from the Medicare Prescription Drug Event file and was determined to be exposed to the FAD from the date of prescription dispensing through the days supply of the prescription. If a patient taking a FAD was also taking a fracture-protective drug (systemic estrogen, selective estrogen receptor modulator, bisphosphonate, calcitonin, parathyroid hormone, denosumab, or beta-blocker) they were still included in the study, but were also analyzed for exposure using the same protocol as the FADs. The primary outcome of the study was hip fracture hospitalization (identified by a hip fracture diagnosis code on an inpatient claim) associated with current exposure to FAD(s). Cox regression models were applied to counting-process data for statistical analysis. The statistical tests were 2-sided and risk estimates with P<0.05 were considered significant. A total of 2,646,255 individuals were assessed during the 10-year analysis period, with a mean age of 77.2 years, more women (61.1%) than men (38.9%), and more Caucasian individuals (80.7%) than blacks/African Americans (8.3%).5 The following results were reported as fully adjusted models. For women, compared with receiving 0 FADs, receiving 1 FAD was associated with hazard ratio (HR) of 2.04 (95% confidence interval [CI], 1.99-2.11; P<0.001); receiving 2 FADs was associated with HR of 2.86 (95% CI, 2.77-2.95; P<0.001); and receiving ≥3 FADs was associated with HR of 4.50 (95% CI, 4.36-4.65; P<0.001). Among men, compared with receiving 0 FADs, receiving 1 FAD was associated with HR of 2.23 (95% CI, 2.11- 2.36; P<0.001); receiving 2 FADs was associated with HR of 3.40 (95% CI, 3.20-3.61; P<0.001); and receiving ≥3 FADs was associated with HR of 5.18 (95% CI, 4.87-5.52; P<0.001). The authors reported no association between increasing age and fracture risk associated with FAD count. Individual FAD risks for women were as follows: first-generation antipsychotics with HR of 1.54 (95% CI, 1.05-2.24; P<0.001), opioids with HR of 3.26 (95% CI, 3.04-3.49; P<0.001), and anti-Parkinsonian agents with HR of 3.29 (95% CI, 2.89-3.76; P<0.001).5 For women, muscle relaxants were not associated with an increased fracture risk when received alone. Also, combinations of FADs that met the population-level impact criteria for risk of fracture included: opioids plus sedative hypnotics with HR of 4.90 (95% CI, 3.98-6.02; P<0.001), opioids plus loop diuretics with HR of 4.48 (95% CI, 3.96-5.07; P<0.001), opioids plus PPIs with HR of 4.00 (95% CI, 3.56-4.49; P<0.001), SSRIs plus opioids with HR of 3.91 (95% CI, 3.46-4.43; P<0.001), SSRIs plus BZDs with HR of 4.50 (95% CI, 3.76-5.38; P<0.001), SSRIs plus loop diuretics with HR of 3.05 (95% CI, 2.75-3.37; P<0.001), and nitrates plus loop diuretics with HR of 3.25 (95% CI, 2.84-3.72; P<0.001). Individual FAD risks for men were as follows: sedative hypnotics with HR of 1.51 (95% CI, 1.17-1.95; P=0.002), opioids with HR of 3.83 (95% CI, 3.36-4.36; P<0.001), and anti-Parkinsonian agents with HR of 4.23 (95% CI, 3.57-5.01; P<0.001). For men, combinations of FADs that met the population-level impact criteria for risk of fracture included 5 that paralleled the women’s results (opioids plus loop diuretics, opioids plus PPIs, SSRIs plus opioids, SSRIs plus loop diuretics, nitrates plus loop diuretics). The riskiest combinations for men were opioids plus loop diuretics with HR of 6.93 (95% CI, 5.52-8.70; P<0.001) and opioids plus SSRIs with HR of 6.26 (95% CI, 4.83-8.12; P<0.001). The authors summarized that 20 out of 21 examined drug groups were associated with an average 2-fold higher relative risk of hip fracture.5 They also found that hip fracture risk increased 3-fold when 2 FADs were being taken and more than 4-fold when 3 FADs were being taken. Furthermore, they noted multiple limitations to their study, the first being that the study was observational, which may confer residual confounding “if FAD use is related to unobserved behavioral risk factors, unrecorded diseases, or disease severity beyond that controlled for.” The second limitation cited was that the exposure measure was based on prescription fills; thus the extent to which patients fill but do not take medications, take medications over periods distinct from days supply, or obtain medications through unobserved channels may bias the results. Third, the authors only observed for current exposure without considering dose, specific drugs within a drug class, cumulative exposure, or when the FAD was initiated. They predicted that ignoring these factors may have led to shifting the results toward favoring the null hypothesis. Fourth, another limitation was they only studied hip fractures, and therefore, the results cannot be confirmed for other fragility fractures with combined FAD use. Fifth, Medicare Part D coverage for BZDs was limited until 2013 and since this study analyzed patients from 2004 to

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2014, BZD exposure was likely underestimated. Overall, the authors concluded that their study was “hypothesis-generating” and additional studies should be performed to consider factors influencing use of FADs, FAD risk versus anticipated benefit in essential-use situations, and FAD pairs/combinations that increase risk more than others. This study demonstrates that as the number of FADs an older patient is taking increases, so does the likelihood of hip fracture.

Additional literature Correa-Pérez et al conducted a retrospective cohort study that aimed to estimate the prevalence of polypharmacy and fall risk-increasing drugs (FRIDs) in older patients discharged from an orthogeriatric unit in Switzerland after hip fracture surgery.6 Participants were included in the study if they were aged ≥80 years, consecutively discharged from the orthogeriatric unit in 2014 after admission for hip fracture, and able to walk (Functional Ambulation Categories Scale >1 before the fracture). They were excluded from the study if they were not allowed by the surgeon to put weight on the broken hip after surgery, received only end of life care, and/or did not have drug information at hospital discharge. Participants were involved in the study for a 2-year follow-up period from hospital discharge to 2 years post-discharge. The authors of this study classified FRIDs into 2 groups based on the Scottish Polypharmacy Guide: those with a low and moderate risk of falling (opioids, vasodilators used in cardiac diseases, antihypertensives, diuretics, beta blocking agents, calcium channel blockers, agents acting on the renin-angiotensin system, alpha-adrenoreceptor antagonists) and those with a high risk of falling (antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, and dopaminergic agents). They utilized hospital electronic records to collect the patients’ baseline variables before the hip fracture, total number of drugs prescribed at discharge, and FRIDs prescribed at discharge. A total of 282 patients were screened for the study with 54 patients not fulfilling the inclusion criteria. Power was set at 80% and a significance level of 95% if there were at least 193 patients involved in the study. Of the 228 patients enrolled in the study, all were using high-risk FRIDs and 56.6% were using both groups of FRIDs at discharge.6 When comparing baseline characteristics between patients with ≤3 FRIDs and patients with >3 FRIDs, the authors found no significant differences except for the Barthel Index (which measures baseline activities of daily living) and the Lawton Index (which measures instrumental activities of daily living). For the Barthel Index, patients taking ≤3 FRIDs had a mean score of 82.1 ± 23.9, while patients taking >3 FRIDs had a mean score of 76.0 ± 26.4 (P=0.049). For the Lawton Index, patients taking ≤3 FRIDs had a mean score of 4.3 ± 3.4 while patients taking >3 FRIDs had a mean score of 2.8 ± 2.8 (P=0.004). When comparing baseline characteristics between patients with polypharmacy (5-9 drugs) and those with extreme polypharmacy (≥10 drugs), there were no differences between both groups except for the Lawton Index, visual disturbance, and need of domestic help. For the Lawton Index, patients with polypharmacy had a higher score than patients with extreme polypharmacy (4.8 ± 3.5 vs. 3.3 ± 3.2, P=0.006). For visual disturbance, patients with polypharmacy had a lower prevalence than those with extreme polypharmacy (51.1% vs. 67.7%, P=0.041). For need of domestic help, patients with polypharmacy had a lower prevalence than those with extreme polypharmacy (42.2% vs. 63.9%, P=0.010). The authors found that the number of FRIDs was higher in the group of patients with extreme polypharmacy than in the group with polypharmacy (1.5 ± 1.0 vs. 3.4 ± 1.5, P<0.05). When a logistic regression was performed, patients who were independent in performing instrumental activities, as determined by the Lawton Index, had a lower risk of extreme polypharmacy or high FRIDs prevalence (>3 medications), after adjusting for age, with an odds ratio (OR) of 0.39 (95% CI, 0.18-0.83) and 0.41 (95% CI, 0.20-0.84), respectively. Living in a nursing home was only associated with high risk of FRIDs prevalence after adjusting for gender and age with an OR of 4.03 (95% CI, 1.12-14.53). It was also discovered that extreme polypharmacy increased the risk of high FRIDs prevalence with an OR of 15.57 (95% CI, 6.58-36.8), and high FRIDs prevalence increased the risk of extreme polypharmacy with an OR of 3.64 (95% CI, 2.51-5.3). The authors found that female gender and increased age was not associated with high risk of extreme polypharmacy or high FRIDs use. The authors asserted that the main limitation of the study was selection bias.6 In using routinely collected health data, limitations of a retrospective study design include bias in selection of patients at time of patient

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inclusion and quality of information recorded in the medical notes. Overall, the authors concluded that polypharmacy and functional status regarding daily living may be related to injurious falls. They will be using the study results to intervene in discharge medication planning to decrease the number of medications prescribed in general, and specifically target FRIDs in an attempt to decrease the risk of falling in the geriatric population. Discussion While the AGS Beers Criteria® cites individual drugs or drug classes and the dangers that may be posed to elderly patients who take them, it does not provide direct links between which PIM combinations may pose a higher risk than others for falls and fractures.4 Both reviewed studies demonstrated that those patients taking multiple FADs/FRIDs have an increased risk for hip fracture.5,6 While the authors of both studies noted the retrospective, observational study design as a limitation, the studies support deprescribing by identifying which combinations of FADs/FRIDs pose a greater risk of fracture to elderly patients than others. Emeny et al concluded that hip fracture risk increased 3-fold when 2 FADs were being taken and more than 4-fold when 3 FADs were being taken.5 In women, individual FADs associated with significant increases in hip fracture risk were first-generation antipsychotics, opioids, and anti-Parkinsonian agents. Combinations of FADs that met the population-level impact criteria for risk of fracture for women included: opioids plus sedative hypnotics, opioids plus loop diuretics, opioids plus PPIs, SSRIs plus opioids, SSRIs plus BZDs, SSRIs plus loop diuretics, and nitrates plus loop diuretics. In men, individual FADs associated with significant increases in hip fracture risk were sedative-hypnotics, opioids, and anti-Parkinsonian agents. Combinations of FADs that met the population-level impact criteria for risk of fracture in men included 5 that paralleled the women’s results (opioids plus loop diuretics, opioids plus PPIs, SSRIs plus opioids, SSRIs plus loop diuretics, nitrates plus loop diuretics). Correa-Pérez et al concluded that polypharmacy and functional status regarding daily living may be related to injurious falls.6 It was also discovered that extreme polypharmacy (≥10 drugs) increased the risk of high FRIDs prevalence, and high FRIDs prevalence increased the risk of extreme polypharmacy. Overall, while more research needs to be conducted, clinicians of older patients need to work together to deprescribe FRIDs and FADs. Further research should include identifying a deprescribing methodology that will result in reduced medication-related hip fractures in older adults. In conclusion, while studies demonstrated that there are specific FADs/FRIDs that are associated with an increased risk of fracture,5,6 the healthcare system now needs to develop, study, and adopt interventions to prevent these medications from being prescribed unnecessarily. References

1. Centers for Disease Control and Prevention. Hip fractures among older adults. Updated September 20, 2016. https://www.cdc.gov/homeandrecreationalsafety/falls/adulthipfx.html. Accessed January 20, 2020.

2. Centers for Disease Control and Prevention. Important facts about falls. Updated February 10, 2017. https://www.cdc.gov/homeandrecreationalsafety/falls/adultfalls.html. Accessed January 20, 2020.

3. Centers for Disease Control and Prevention. Falls data. Updated September 17, 2019. https://www.cdc.gov/homeandrecreationalsafety/falls/fallcost.html. Accessed January 20, 2020.

4. 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674-694.

5. Emeny RT, Chang CH, Skinner J, et al. Association of receiving multiple, concurrent fracture-associated drugs with hip fracture risk. JAMA Netw Open. 2019;2(11):e1915348.

6. Correa-Pérez A, Delgado-Silveira E, Martín-Aragón S, Rojo-Sanchis AM, Cruz-Jentoft AJ. Fall-risk increasing drugs and prevalence of polypharmacy in older patients discharged from an orthogeriatric unit after a hip fracture. Aging Clin Exp Res. 2019;31(7):969-975.

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Authors Merin Panthapattu, PharmD Dr. Panthapattu received her Doctor of Pharmacy degree from the UB SPPS. She is currently a PGY-1 pharmacy practice resident at Middleport Family Health Center. Her professional interests include transitions of care, primary care, and ambulatory care. Troy Hoelzl, PharmD Dr. Hoelzl received his Doctor of Pharmacy degree from the UB SPPS and completed a PGY-1 community pharmacy practice residency at Middleport Family Health Center. He is currently a PGY-2 ambulatory care pharmacy resident at Buffalo Medical Group. His professional interests include diabetes management, quality improvement, and precepting students. He plans to pursue a career in ambulatory care and/or academia. Amanda Foster, PharmD Dr. Foster received her Doctor of Pharmacy from D’Youville College School of Pharmacy. She is currently a PGY-1 pharmacy practice resident at Middleport Family Health Center. Her professional interests include transitions of care, geriatrics, precepting, and academia. She would like to become a Board-Certified Geriatric Pharmacist (BCGP), practicing in transitions of care with the geriatric population while precepting pharmacy students at her clinical practice site and teaching pharmacy classes related to her career interests. Editors Linda Catanzaro, PharmD Dr. Catanzaro received her PharmD from the UB SPPS and subsequently completed a specialty residency in HIV informatics. She also developed and directed the UB SPPS PGY-2 drug information residency program. She is currently a Clinical Assistant Professor at the UB SPPS and staffs the New York State Medicaid Drug Information Response Center. Holly Coe, PharmD Dr. Coe received her PharmD from the UB SPPS after receiving her BS in Neuroscience from the University of Rochester. She completed PGY-1 and PGY-2 residencies at the UB SPPS specializing in drug information/pharmacoinformatics. She is currently a Clinical Assistant Professor at the UB SPPS and she staffs the New York State Medicaid Drug Information Response Center. Terry Dunn, PharmD Dr. Dunn received both her BS in Pharmacy and PharmD from the UB SPPS. She also completed a hospital pharmacy residency at New England Medical Center in Boston. She has had extensive experience as a pharmacist in various settings, including practicing in a traditional role in hospitals as a Clinical Pharmacy Specialist. She has also served as a Science Specialist at a law firm, working with a team of lawyers defending pharmaceutical companies in product liability lawsuits. In addition, she has participated on an FDA contract updating and rewriting drug labels. She is currently a Clinical Assistant Professor at the UB SPPS and Coordinator for the Center for Health Outcomes, Pharmacoinformatics, and Epidemiology (HOPE). Irene Reilly, PharmD, BCPS Dr. Reilly received her PharmD from the University of Illinois at Chicago (UIC) College of Pharmacy after receiving her BA in Economics from the University of Chicago. She completed PGY-1 and PGY-2 residencies at the UIC College of Pharmacy, specializing in drug information. She is currently a Clinical Assistant Professor at the UB SPPS and she leads the New York State Medicaid Drug Information Response Center. Please address any comments or corrections to Dr. Reilly at irenehon@buffalo.edu.