By: Kristin Peterson, PharmD, BCPS, BCCP – MSHP Membership Committee Chair; Mercy Hospital Joplin
The Membership Committee is pleased to share some of the results from the 2020 MSHP Annual Survey. This year 64 members responded to the survey.
Reasons for Being Involved
Affiliate chapter activities and CE was selected by respondents as the primary reason for involvement in MSHP.
Top three reasons for being involved in MSHP:
Advocacy and leadership opportunities were also frequently ranked by responders as top three membership benefits.
Overall, responders felt that MSHP is doing a good job fulfilling most organization activities.
Most important MSHP activities per responders:
MSHP activities which the organization is best fulfilling:
1. Providing opportunities of organizational involvement (I.e. committee)
2. Providing leadership opportunities
3. Delivering high quality education
4. Delivering ongoing continuing education
Top Priorities for Coming Year:
Top Areas for Improvement:
The majority of members indicated that they feel they receive a good value for their membership dues.
We want to thank all the members that took the time to fill out the survey. These results will be used during the next strategic planning meeting to guide organization initiatives.
We are excited about all the changes that have been happening within MSHP over the past year and look forward to continuing to improve your membership experience!
By: Rachel Kiehne, PharmD; PGY2 Ambulatory Care Resident
Mentor: Justinne Guyton, PharmD, BCACP, PGY2 Ambulatory Care Residency Director, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis/St. Louis County Department of Public Health
Program Number: 2021-01-04
Approval Dates: February 3, 2021 to August 1, 2021
Approved Contact Hours: 1 hour
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There is a growing need for new and innovative drugs due to the significant prevalence, morbidity, and mortality of type 2 diabetes mellitus. In 2018, 32.6 million people in the United States had this disease, and diabetes mellitus was the seventh leading cause of death.1 The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in clinical practice for the treatment of type 2 diabetes mellitus has steadily increased over the past few years due to its unique mechanism of action, efficacy, and effect on major adverse cardiac events.
According to the 2020 American Diabetes Association (ADA) guidelines, first-line treatment of type 2 diabetes mellitus should be a combination of maximally titrated metformin and lifestyle modifications. The next medication used is then dependent upon clinical characteristics and patient preference. Some considerations include presence of atherosclerotic cardiovascular disease (ASCVD), heart failure, chronic kidney disease (CKD), minimizing hypoglycemia risk, minimizing weight gain/promoting weight loss, and cost. The GLP-1 RA class is a reasonable choice in most of these categories; an exception is cost concerns due to availability as brand name only. Additionally, some GLP-1 RAs provide benefit in reducing cardiovascular disease events (i.e. liraglutide, semaglutide and dulaglutide) and therefore are preferred in patients with established ASCVD. This class has not shown reduction in heart failure hospitalizations, but several agents have shown renal benefits. Additionally, in patients with significant hyperglycemia that require injectable therapy, GLP-1 RAs should be considered prior to insulin in most patients.2
One potential barrier to initiation of a medication in the GLP-1 RA class is administration. Until recently, these medications were only available as subcutaneous injections that ranged from twice daily to once weekly. However, in September 2019, the first oral GLP-1 RA was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.3 Of note, oral semaglutide is available as the brand name Rybelsus®, while subcutaneous semaglutide is available under the brand name Ozempic®. Availability of an oral formulation makes GLP-1 RAs more accessible to patients who are resistant or unable to perform self-administered injections. However, not all GLP-RAs have shown the same degree of A1c lowering, weight loss, or cardiovascular benefit. Therefore, this article will focus on reviewing the pharmacology, pharmacokinetics, and clinical trial data for oral semaglutide.
Semaglutide is an analogue with 94% sequence homology to the endogenous hormone, GLP-1. It therefore binds to and activates the GLP-1 receptor. Semaglutide has increased albumin binding compared to endogenous GLP-1, which extends the half-life significantly by reducing renal clearance and protecting the drug from metabolic degradation. Semaglutide is also stabilized against degradation by the DPP-4 enzyme.4
Semaglutide achieves blood glucose reduction by glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. It also slightly delays gastric emptying in the early phase after food intake, which reduces the rate at which postprandial glucose appears in blood circulation. Due to its long half-life, both fasting and post-prandial glucose levels are reduced with semaglutide. During induced hypoglycemia, semaglutide does not inhibit counter-regulatory increases in glucagon versus placebo.4
Oral semaglutide is co-formulated with salcaprozate sodium. This aids absorption after oral administration, which mainly occurs in the stomach. Maximum concentrations of oral semaglutide occur 1-hour post-dose, and steady state exposure is achieved after 4-5 weeks of administration. Bioavailability of oral semaglutide is 0.4%-1%.4
The volume of distribution of semaglutide is approximately 8 liters. Semaglutide is highly albumin-bound (>99%).4
The elimination half-life is approximately 1 week, and semaglutide will remain in circulation for approximately 5 weeks following the last dose. The primary method of semaglutide metabolism is proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain. The primary method of secretion is through the urine and feces. Approximately 3% of the absorbed dose is excreted in the urine unchanged.4
Oral semaglutide does not significantly inhibit or induce CYP enzymes or drug transporters. However, due to it’s ability to delay gastric emptying, there is some potential for increased drug absorption of other medications. A drug interaction study showed that oral semaglutide increased exposure of levothyroxine by 33%.4
Administration and dosing:
Semaglutide should be administered at 3 mg by mouth once daily for 30 days, then 7 mg by mouth once daily. If further glycemic control is needed after another 30 days, then the dose may be increased to a maximum dose of 14 mg by mouth once daily. In order to achieve full oral absorption, semaglutide should be administered on an empty stomach at least 30 minutes before the first food, beverages, or other oral medications and with a maximum of 4 ounces of plain water. Tablets should also be swallowed whole without splitting, chewing, or crushing.4
Clinical Trial Data:
Novo Nordisk funded a series of ten clinical trials to study the safety and efficacy of oral semaglutide. These trials make up the PIONEER (Peptide InnOvatioN for Early diabEtEs tReatment) series. This series compares oral semaglutide to placebo as well as other standard of care glucose-lowering medications.5-14
Common key inclusion criteria for the PIONEER trials include adults aged 18 and older with type 2 diabetes mellitus, an A1c between either 7.0% to 9.5% or 7.0 to 10.5%, and various background glucose-lowering medications. Common key exclusion criteria included eGFR less than 60 mL/min/1.73m2, history of pancreatitis, history of proliferative retinopathy or maculopathy requiring acute treatment, personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and any medication for diabetes or obesity within previous 90 days other than those meeting inclusion criteria or short-term insulin for less than 14 days.5-14
All trials also allowed for use of additional glucose-lowering medication (other than GLP-1 RAs or DPP-4 inhibitors) if the subject discontinued the trial product, or if rescue medication was required as add-on to the trial product due to unacceptable hyperglycemia or elevated A1c. Most of the trials performed two statistical tests using the treatment policy estimand and trial product estimand. The treatment policy estimand was an intention-to-treat analysis that included all subjects regardless of additional glucose-lowering medication use or trial product discontinuation. The trial product estimand was a per-protocol analysis that estimated results using data collected prior to premature discontinuation or initiation of rescue medication. Results will be listed for the treatment policy estimand unless otherwise specified.5-14
Oral semaglutide versus placebo
PIONEER 1 was a 26-week, randomized, double-blind clinical trial comparing the efficacy of daily oral semaglutide versus placebo as monotherapy for type 2 diabetes managed with diet and exercise alone. Patients were randomized in a 1:1:1:1 ratio to oral semaglutide 3 mg, 7 mg, or 14 mg and placebo. The dose of oral semaglutide was increased every 4 weeks until the randomize dose was achieved. Rescue medications could be used if fasting blood glucose levels were greater than 240 mg/dL from weeks 8-13 or greater than 200 mg/dL from week 14 onward. The primary endpoint was change in A1c from baseline to week 26, and the confirmatory secondary endpoint was change from baseline to week 26 in body weight. The estimated treatment differences (ETD) for A1c lowering for oral semaglutide 3 mg, 7 mg, and 14 mg versus placebo were -0.6%, -0.9%, and -1.1% respectively (p<0.001). All results significantly favored oral semaglutide. For change in bodyweight, only the 14 mg dose of oral semaglutide showed significantly more bodyweight reduction than placebo with an ETD of -2.3 kg (p<0.001). The ETDs for the 3 mg and 7 mg doses versus placebo were -0.1 kg (p = 0.87) and -0.9 kg (p = 0.09).5
PIONEER 5 was a 26-week, randomized, double-blind clinical trial to compare the efficacy of oral semaglutide versus placebo as add-on to metformin and/or a sulfonylurea, or basal insulin with or without metformin in patients with type 2 diabetes mellitus and moderate renal impairment (eGFR 30-59 mL/min/1.73m2). Patients were randomized in a 1:1 fashion to either once-daily oral semaglutide 14 mg or placebo. Semaglutide was titrated every 4 weeks until the target dose was reached. Rescue medications could be used if fasting blood glucose levels were greater than 240 mg/dL from weeks 12-16 or greater than 200 mg/dL at week 17 and later. The primary endpoint was change from baseline to week 26 in A1c, with the confirmatory secondary endpoint being change in bodyweight during this timeframe. The ETD for change in A1c for oral semaglutide versus placebo was -0.8%, with an ETD of -2.5 kg for change in body weight (p<0.0001). The eGFR remained unchanged throughout the trial period. This shows that oral semaglutide is safe and effective in patients with moderate renal impairment.6
Oral semaglutide versus placebo as add-on to insulin
PIONEER 8 was a 52-week, randomized, double-blind clinical trial comparing the efficacy of oral semaglutide to placebo as add-on to insulin with or without metformin for treatment of type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1 ratio to either semaglutide (3 mg, 7 mg, or 14 mg) or placebo. Oral semaglutide was titrated every 4 weeks until target dose was achieved. The baseline insulin dose was reduced by 20% at randomization and maintained until week 8. The dose of insulin could then be altered from weeks 8 to 26 without exceeding pre-trial dosing and was freely adjustable from weeks 26 to 52. The dose of insulin could be lowered at any time if deemed appropriate. Basal insulin doses were adjusted based on self-monitored blood glucose readings measured 3 days leading up to the visit. The recommended target fasting blood glucose was 71-99 mg/dL and A1c was less than 7.0%. Adjustments were made in 2-unit increments if fasting blood sugars were 100-126 mg/dL and up to 8 units if over 162 mg/dL. Increases in insulin doses met rescue medication criteria if the dose was increased by at least 20% and maintained for 2 visits. Other criteria for rescue medication were fasting blood glucose greater than 200 mg/dL at week 16 and later, and an A1c > 8.5% at week 26 and later. The primary endpoint was change in A1c from baseline to week 26, and the confirmatory secondary endpoint was change in bodyweight at week 26. Oral semaglutide was more effective for A1c lowering at week 26, with an ETD of -0.5%, -0.9%, and -1.2% for the 3 mg, 7 mg, and 14 mg doses respectively (p<0.0001). The 3 mg, 7 mg, and 14 mg doses of oral semaglutide had significantly larger reductions in bodyweight than placebo, with an ETD of -0.9 kg (p = 0.0.0392), -2.0 kg (p = 0.0001) and -3.3 kg (p = <0.0001). At 52 weeks, all three doses of oral semaglutide demonstrated significant decreases in total daily insulin dosage versus placebo, with an ETD of -8 units (p = 0.0450), -16 units (p<0.0001), and -17 units (p<0.0001) for the 3 mg, 7 mg, and 14 mg doses respectively.7
Oral semaglutide versus SGLT-2 Inhibitor
PIONEER 2 was a 52-week, randomized, open-label clinical trial comparing the efficacy of daily oral semaglutide versus empagliflozin as add-on to metformin for type 2 diabetes mellitus. Patients were randomized in a 1:1 ratio to oral semaglutide 14 mg daily versus oral empagliflozin 25 mg daily. Empagliflozin was titrated every 4 week until the treatment dose was achieved, while empagliflozin was started at 10 mg daily then increased to 25 mg daily at week 8. Rescue medications could be used if fasting blood glucose levels were above 260 mg/dL from weeks 8 to 13, greater than 240 mg/dL from weeks 14 to 25, and greater than 200 mg/dL or A1c greater than 8.5% weeks 26 and later. The primary outcome was change in A1c while the confirmatory endpoint was change in bodyweight, both from baseline to week 26. Oral semaglutide 14 mg significantly reduced A1c more than empagliflozin 25 mg at week 26, with an ETD of -0.4% (p<0.0001). However, there was no significant difference between the two groups for bodyweight lowering at 26 weeks, with an ETD of -0.1 kg (p = 0.7593).8
Oral semaglutide versus DPP-4 Inhibitor
PIONEER 3 was a 78-week, randomized, double-blind, double-dummy clinical trial comparing the efficacy of daily oral semaglutide versus sitagliptin as add-on to metformin with or without a sulfonylurea for treatment of type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1 ratio to daily oral semaglutide (3 mg, 7 mg, or 14 mg) or daily oral sitagliptin (100 mg). Oral semaglutide was titrated every 4 weeks until the treatment dose was achieved, while sitagliptin was initiated and maintained at 100 mg daily. The primary outcome was change in A1c while the confirmatory endpoint was change in bodyweight, both from baseline to week 26. Semaglutide 3 mg significantly reduced the A1c compared to oral sitagliptin at 26 weeks with an ETD of 0.2% (p = 0.008). However, the 7 mg and 14 mg doses demonstrated significantly more A1c lowering, with an ETD of -0.3% and -0.5% respectively (p<0.001). All three doses of oral semaglutide significantly reduced bodyweight, with ETDs of -0.6 kg (p = 0.02), -1.6 kg (p<0.001), and -2.5 kg (p<0.001) for the 3 mg, 7 mg, and 14 mg doses respectively when compared to sitagliptin 100 mg daily.9
PIONEER 7 was a 52-week, randomized, open-label clinical trial comparing the efficacy of flexibly dosed oral semaglutide versus sitagliptin as add-on to stable doses of one or two glucose-lowering medications (metformin, sulfonylureas, SGLT-2 inhibitors, or thiazolidinediones for treatment of type 2 diabetes. Patient were randomized in a 1:1 ratio to either flexibly dosed oral semaglutide or sitagliptin 100 mg daily. Oral semaglutide was started at 3 mg daily, then every 8 weeks the dose could be adjusted. The current dose was continued if the A1c was less than 7.0%, and increased if 7.0% or greater. However, if moderate-to-severe nausea or vomiting occurred 3 or more days during the week prior to the visit, oral semaglutide was maintained or decreased regardless of glycemic control. Rescue medication was offered to patients with an A1c of 8.5% or higher from week 32 onward. The primary outcome was achievement of an A1c target less than 7.0% at week 52. The confirmatory secondary endpoint was change in bodyweight during the same time period. The use of flexibly dosed oral semaglutide significantly increased the proportion of patients achieving an A1c of <7.0% versus sitagliptin, with an odds ratio (OR) of 4.40 (p<0.0001). Oral semaglutide also significantly reduced bodyweight at 52 weeks, with an ETD of -1.9 kg (p<0.0001).10
Oral semaglutide versus other GLP-1 RA
PIONEER 4 was a 52-week, randomized, double-blind, double-dummy clinical trial comparing the efficacy of daily oral semaglutide versus subcutaneous liraglutide as add-on to metformin with or without an SGLT-2 inhibitor. Patients were randomized in a 2:2:1 ratio to daily oral semaglutide (14 mg) versus daily subcutaneous liraglutide (1.8 mg) vs placebo. The dose of oral semaglutide was increased at 4 week intervals until the target dose was reached, while liraglutide was started at 0.6 mg daily, then increased to 1.2 mg daily at week 1, then increased and maintained at 1.8 mg daily at week 2. Rescue medication could be used if fasting blood glucose levels were above 240 mg/dL from weeks 8 to 13, greater than 200 mg/dL from weeks 14 and later, and an A1c greater than 8.5% weeks 26 and later. The primary outcome was change in A1c from baseline to week 26, while the confirmatory endpoint was change in bodyweight. The use of oral semaglutide 14 mg daily demonstrated no difference in A1c lowering at 26 weeks with an ETD of -0.1% (p = 0.0645), but had significantly more bodyweight lowering at 26 weeks versus liraglutide 1.8 mg daily with an ETD of -1.2 kg (p = 0.0003). There was significantly more A1c and bodyweight lowering with oral semaglutide compared to placebo, with ETDs of -1.1% and -3.3 kg respectively (p<0.0001).11
PIONEER 9 was a 52-week, randomized, double-blind clinical trial to study the efficacy of oral semaglutide versus subcutaneous liraglutide as monotherapy in Japanese patients with type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1:1 ratio to receive oral semaglutide daily (3 mg, 7 mg, or 14 mg) or subcutaneous liraglutide daily (0.9 mg) or placebo. The dose of oral semaglutide was titrated every 4 weeks. Subcutaneous liraglutide was started at 0.3 mg daily, then increased by 0.3 mg at weeks 1 and 2 to achieve the 0.9 mg dose, which is the maximum approved dose in Japan. The liraglutide injections were open-label, but all oral doses were blinded. Rescue medication could be added if patients had blood glucose levels above 240 mg/dL from weeks 8-13, or greater than 200 mg/dL from week 14 onwards. Rescue medication could also be given from week 26 and later if A1c was greater than 8.5%. The primary outcome was change in A1c from baseline to week 26. A secondary endpoint included change in bodyweight at week 26. At week 26, oral semaglutide demonstrated significantly more A1c reduction than placebo at all three doses, with ETDs of -1.1%, -1.5%, and -1.7% for the 3 mg, 7 mg, and 14 doses respectively (p<0.0001). Compared to liraglutide, oral semaglutide showed no difference in A1c reduction at the 3 mg and 7 mg doses, with respective ETDs of 0.3% (p = 0.0799) and -0.1% (p = 0.3942). However, there was more A1c lowering with oral semaglutide 14 mg than liraglutide with and ETD of -0.3% (p = 0.0272). At 26 week, oral semaglutide did not reduce bodyweight versus placebo at 3 mg and 7 mg doses. However, there was significantly more bodyweight reduction with the 14 mg dose, with an ETD of -1.2 (p = 0.0073). When compared to liraglutide, the 3 mg dose of oral semaglutide did not demonstrate more bodyweight reduction, but the 7 mg and 14 doses did, with respective ETDs of -0.4 kg (p = 0.3233), -0.9 kg (p = 0.0312), and -2.3 kg (p<0.0001).12
PIONEER 10 was a 52-week randomized, open-label clinical trial to compare the safety and efficacy of subcutaneous dulaglutide as add-on to monotherapy (sulfonylurea, glinide, TZD, alpha-glucosidase inhibitor, or SGLT-2 inhibitor) in Japanese patients with type 2 diabetes mellitus. Patients were randomized in a 2:2:2:1 ratio to receive either oral semaglutide (3 mg, 7 mg, or 14 mg) or subcutaneous dulaglutide weekly (0.75 mg). The dose of oral semaglutide was increased every 4 weeks until the target dose was reached. Subcutaneous dulaglutide was initiated and maintained at 0.75 mg once weekly, which is the maximum approved dose in Japan. Rescue medication could be added if fasting blood glucose levels were greater than 240 mg/dL during weeks 14-25, greater than 200 mg/dL after week 26, or an A1c greater than 8.5% at week 26 and later. The primary endpoint was number of treatment-emergent adverse events during exposure to the study drug (Table 3). Change in A1c and bodyweight from baseline to week 26 were also measured as secondary outcomes. Compared to dulaglutide, oral semaglutide 3 mg demonstrated less A1c lowering with an ETD of 0.4% (p = 0.0026), similar A1c lowering for the 7 mg dose with an ETD of -0.1% (p = 0.2710), and more A1c lowering at the 14 mg dose with an ETD of -0.4% (p = 0.0006). There was no significant difference in bodyweight lowering for the 3 mg dose of oral semaglutide, but there was significant decreases in bodyweight compared to dulaglutide for the 7 mg and 14 mg doses, with ETDs of -0.5 kg (p = 0.2632), -1.3 kg (p = 0.0023), and -2.5 kg (p<0.0001) respectively.13
Oral Semaglutide and Cardiovascular Outcomes
PIONEER 6 was an event-driven, randomized, double-blind, placebo-controlled clinical trial to investigate cardiovascular outcomes on treatment with once-daily oral semaglutide versus placebo as add-on to standard of care for patients with type 2 diabetes mellitus. Patients were included in this study if they were 50 years of age or older and had established cardiovascular disease (CVD) or CKD or if they were 60 years of age or older and had cardiovascular risk factors only. Key exclusion criteria were treatment with an GLP-1 RA, DPP-4 inhibitor, or pramlintide within 90 days prior to screening; New York Heart Association class 4 heart failure; planned coronary-artery, carotid-artery, or peripheral-artery revascularization; myocardial infarction, stroke, or hospitalization for unstable angina or transient ischemic attack within 60 days before screening; long-term or intermittent hemodialysis or peritoneal dialysis, or severe renal impairment (eGFR <30 mL/min/1.73 m2); and proliferative retinopathy or maculopathy resulting in active treatment. The primary outcome was time from randomization to the first occurrence of a major adverse cardiovascular event (composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The hazard ratio for the primary outcome was 0.79 (p<0.0001 for noninferiority, p = 0.17 for superiority). Therefore, oral semaglutide has shown cardiovascular safety, but has not demonstrated cardiovascular benefit.14 However, an additional trial is currently underway to further investigate the cardiovascular effects of oral semaglutide with a larger patient population for a longer follow-up period. This trial is titled “A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL).” However, the study completion is not expected until 2024.15
A summary of adverse effects is reported in table 3. The most common reported adverse events were consistent with those seen by the injectable GLP-1 RAs, including gastrointestinal upset (nausea, vomiting, diarrhea). Rates of severe or blood-glucose confirmed hypoglycemia were low, with most events occurring in trials where patients were receiving background glucose-lowering agents with known risk of hypoglycemia (sulfonylureas, insulin).2,5-14
Oral semaglutide benefits include A1c and bodyweight reduction, both in comparison to placebo and other standard of care treatment regimens. The reductions in A1c and bodyweight are dose-dependent, and based on the results of the PIONEER series, all patients should be titrated up to a minimum effective dose of 7 mg. Small benefit from the 3 mg may still be seen during the titration period, which is used to minimize GI side effects. The results of the PIONEER 7 trial also showed that based on tolerability and blood glucose control, flexible dosing of semaglutide is a reasonable treatment strategy.5-14
At 26 weeks, oral semaglutide at the maximum dose of 14 mg daily was more effective for A1c reduction than placebo, oral empagliflozin 25 mg daily, oral sitagliptin 100 mg daily, titration of current insulin regimen, subcutaneous liraglutide 0.9 mg daily in Japanese patients, and subcutaneous dulaglutide 0.75 mg weekly in Japanese patients. Oral semaglutide 14 mg daily had similar A1c lowering when compared to subcutaneous liraglutide 1.8 mg daily.5-14
Oral semaglutide 14 mg daily significantly reduced bodyweight at 26 weeks when compared to placebo, oral sitagliptin 100 mg daily, further titration of background insulin regimen, subcutaneous liraglutide 1.8 mg daily, subcutaneous liraglutide 0.9 mg daily in Japanese patients, and subcutaneous dulaglutide 0.75 mg weekly in Japanese patients. Similar bodyweight reductions were seen with oral semaglutide 14 mg daily and oral empagliflozin 25 mg daily at 26 weeks.5-14
One major limitation of implementation of this new dosage form is the lack of demonstrated cardiovascular benefit that has been seen in other injectable GLP-1 RAs, including injectable semaglutide.2 However, use may increase significantly if the SOUL trial shows cardiovascular benefit.15 Currently, oral semaglutide should be considered in patients who are averse to injectable formulations. While oral semaglutide demonstrated cardiovascular safety in the PIONEER 5 trial, the injectable GLP-1 RAs and oral SGLT-2 inhibitors that have demonstrated cardiovascular risk reduction would be preferred in patients with clinical ASCVD. Cost considerations are also important, as use is limited to patients with good insurance coverage or those that qualify for patient assistance programs. Patients started on oral semaglutide should be counseled on potential gastrointestinal side effects and its unique administration instructions.
*Exact results not reported for change in bodyweight or change in A1c
Abbreviations: AGI, alpha-glucosidase inhibitors; BAS, basal; BMI, body mass index; BOL, bolus; DUL, dulaglutide; EMP, empagliflozin; ETD, estimated treatment difference; FLEX, flexible-dosing; GLI, glinides; INS, insulin; LIR, liraglutide; MET, metformin; PLA, placebo; SEM, semaglutide; SGLT-2i, Sodium-glucose co-transporter-2 inhibitor; SIT, sitagliptin; SU, sulfonylureas; TZD, Thiazolidinediones; T2DM, type 2 diabetes mellitus
Abbreviations: MAX, maximally tolerated dose; PLA, placebo; SEM, semaglutide
Abbreviations: AGI, alpha-glucosidase inhibitors; BAS, basal; BMI, body mass index; BOL, bolus; DUL, dulaglutide; EMP, empagliflozin; ETD, estimated treatment difference; FLEX, flexible-dosing; GLI, glinides; INS, insulin; LIR, liraglutide; MET, metformin; PLA, placebo; SEM, semaglutide; SGLT-2i, Sodium-glucose co-transporter-2 inhibitor; SIT, sitagliptin; SU, sulfonylureas; TZD, Thiazolidinediones
By: Hannah Michael, PharmD, PGY1 Pharmacy Resident – University of Missouri Health Care
Current guideline therapy provided by the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes (ISPAD) highlights that type 1 diabetes accounts for most diabetic diagnoses for children and adolescents.1-3 Due to the pharmacokinetic differences of the available types of insulins and highly variable pharmacodynamics in the pediatric population, data on these regimens are not transferable from the adult population to pediatric patients. Knowing this, it is important to highlight effective insulin treatment for this population as well as the differences in administration considerations to provide the most appropriate therapeutic regimens for all age groups with diabetes.
As in the adult population, glycemic goals and targets are just as essential in effectively assessing control of diabetes in children and adolescents to prevent acute and long-term complications, including microvascular and macrovascular complications. Diabetic nephropathy is a known major contributor to morbidity and mortality risk, and although the advanced stages of this occurrence are rare in children and adolescents, alterations in renal function develop quickly after diabetes diagnosis and often progress during puberty.4 In addition, it has been demonstrated that adolescents are at a higher risk of developing vision-threatening retinopathy when compared with adults. These examples of physiologic and developmental differences stress the importance of early identification of diabetes in this patient population as well as effective initial and lifelong insulin therapy.
Hemoglobin A1c levels remains an essential tool to assess long-term glycemic control and to prevent chronic complications of diabetes. A goal of <154 mg/dL (<7.0%) is recommended for many children, however, a less stringent goal of <168 mg/dL (<7.5%) may be appropriate depending on the presence of the following factors: the ability to articulate symptoms of hypoglycemia, individuals who have hypoglycemia unawareness, patients that cannot obtain/use analog insulins or lack access to insulin-delivery technologies, patients who cannot check blood glucose levels regularly, or patients who have nonglycemic factors that increase A1c.5 To achieve a goal of <7.5%, blood glucose targets include a pre-meal of 90-130 mg/dL, post-meal of 90-180 mg/dL, and pre-bed range of 90-150 mg/dL. Effective monitoring for these patients includes frequent blood glucose checks up to six to ten times per day, including before meals and snacks, at bedtime, and as needed for exercise, driving, and/or presence of hypoglycemia symptoms. Notably, better glucose control for pediatric and adolescent populations has been demonstrated with multiple daily injections and insulin pumps when compared to a twice daily regimen. Use of newer technologies for insulin delivery and monitoring, such as sensor-augmented and/or automated insulin pumps and continuous glucose monitoring (CGM), in conjunction with insulin analogs, have all been shown to reduce the risk of hypoglycemia with associated lower A1c targets.
Other necessary considerations for the pediatric and adolescent population include distinctions in insulin absorption and insulin requirements. Insulin activity has particular variability in children, as young children with less subcutaneous fat will have faster absorption, and, inversely, a higher percentage of subcutaneous fat will result in slower absorption. Absorption has shown to be quick (~15 minutes) when administered in the abdomen, intermediate (~20 minutes) with lateral arm injection, and slow (~30 minutes) for both front/lateral position of the thigh and the lateral upper quadrant of the buttocks. Insulin requirements evolve as these patients continue to grow: In the partial remission phase, or the honeymoon phase, where endogenous insulin is produced following the initial introduction of insulin treatment, a total daily dose of <0.5 units/kg/day may be required, whereas for prepubertal children, insulin dosing requirements may be between 0.7 to 1 units/kg/day, and during puberty, requirements may reach up to 2 units/kg/day. It is also interesting to note that the mechanisms which invoke the dawn phenomenon, or a rise in morning blood glucose levels, including increased nocturnal growth hormone secretion and increased resistance to insulin, are even more significant in puberty. Because of this, it may be appropriate to utilize an intermediate acting insulin later in the evening or longer acting basal insulin at bedtime for patients who do not utilize an insulin pump.
For a comprehensive comparison, the various insulins with considerations for pediatrics and adolescents is provided in the table below.1,2,3,6
Diabetes represents a complex disease state which requires extensive knowledge and practice in the individualization of treatment. These special considerations are made even more apparent in the pediatric and adolescent population as the continued growth and development of these patients provides multiple opportunities for adjustments in insulin treatment. Furthermore, understanding the intricacies of insulin therapy management is a crucial step in ensuring safe and effective therapy when optimizing each patient’s regimen.
Diabetes represents a complex disease state which requires extensive knowledge and practice in the individualization of treatment. These special considerations are made even more apparent in the pediatric and adolescent population as the continued growth and development of these patients provides multiple opportunities for adjustments in insulin treatment. Furthermore, understanding the intricacies of insulin therapy management is a crucial step in ensuring safe and effective therapy when optimizing each patient’s regimen.
By: Abbey Jin, PharmD Candidate 2021, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Laura Challen, PharmD, MBA, BCPS, BCACP, Associate Professor, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Clinical Pharmacist, JFK Clinic Mercy Hospital-St. Louis
Severe hypoglycemia, a severe and potentially fatal event that requires intervention, has historically been treated with injectable glucagon that requires reconstitution prior to injection. Baqsimi® and Gvoke® are new United States Food and Drug Administration (FDA)-approved glucagon products for severe hypoglycemia that provide alternative preparations. Eli Lilly and Company’s Baqsimi® nasal powder is an intranasal glucagon delivery device, approved on July 24th, 2019.1 It is the first non-injectable glucagon therapy for emergency treatment in severe hypoglycemia.1 Xeris Pharmaceutical’s Gvoke® is a glucagon injection for treatment of severe hypoglycemia, approved on September 10th, 2019.2
Hypoglycemia can be differentiated into three classifications: levels 1, 2, and 3. Level 1 (mild hypoglycemia) is defined as blood glucose levels greater than or equal to 54 mg/dL up to 69 mg/dL. Level 2 (moderate hypoglycemia) is defined as blood glucose levels less than 54 mg/dL. Level 3 (severe hypoglycemia) is defined as hypoglycemia that results in altered physical and/or mental state and needing intervention. It is recommended that any patients who experience level 2 or 3 hypoglycemia travel with a glucagon device3 for administration by a caregiver in case the patient becomes unresponsive.4 If the patient is conscious, glucose can be self-administered orally.4
Indication, Dosage, Administration, Storage and Cost
Baqsimi® is indicated for severe hypoglycemia treatment in patients with diabetes who are 4 years of age and older. It is designed to be absorbed via the nasal mucosa and does not need to be reconstituted prior to intranasal administration.3 The recommended dosage and route for all patients is 3 mg (one actuation) intranasally (in one nostril).5 A caretaker should insert the tip of the device into one nostril and press the plunger. After the dose is administered, the caregiver should call emergency medical services. If the patient does not respond to the first 3 mg dose, then another 3 mg dose from an un-used Baqsimi® device can be administered after 15 minutes.5 Baqsimi® is available as a carton containing one or two devices of a single 3 mg dose. It is recommended to store Baqsimi® devices at temperatures up to 86oF.3 Per Micromedex® Red Book, the wholesale acquisition cost (WAC) package price is $280.80 for the Baqsimi® One PackTM.6
Gvoke® is indicated for the treatment of severe hypoglycemia in patients with diabetes who are 2 years of age and older. Two Gvoke® products are available for use: Gvoke® pre-filled syringe (PFS) 0.5 mg/0.1 mL or 1 mg/0.2 mL and Gvoke® HypoPen 0.5 mg/0.1 mL or 1 mg/0.2 mL autoinjectors.7 Gvoke® products are dispensed as single doses and do not require reconstitution prior to administration.4 The recommended dose and route for patients 2 to under 12 years of age and who weigh less than 45 kg is 0.5 mg subcutaneously. The recommended dose and route for pediatric patients who weigh 45 kg and over or who are 12 years of age and older is 1 mg subcutaneously. Areas recommended for injection are the outer, upper arm, outer thigh, or lower abdomen. Similar to Baqsimi®, following a dose, emergency medical services should be called. If a patient is unresponsive after one dose, a second dose can be administered 15 minutes later.4 Gvoke® is to be stored at room temperatures ranging from 68oF to 77oF.7 Per Micromedex® Red Book, the WAC package price for the Gvoke® HypoPen and Gvoke® PFS 1 packs are both $280.80, the same price as Baqsimi®.8,9
Drug Interactions, Adverse Drug Events, Contraindications, Use in Pregnancy and Lactation
Gvoke® and Baqsimi® may interact with indomethacin, interfering with their ability to increase blood glucose. They also have potential drug interactions with beta-blockers, which can lead to increases in blood pressure and pulse. Gvoke® and Baqsimi® can increase warfarin’s anticoagulation effects.3,7
For Baqsimi®, the most common potential side effects include headache; vomiting and nausea; nasal discomfort and congestion; watery, itchy, or red eyes, and itchy throat.5 Gvoke®’s most common side effects for adults include headache, nausea, vomiting, and injection site edema. Gvoke®’s most common side effects for pediatric patients include headache, nausea, vomiting, pain in the abdomen, injection site reaction and discomfort, urticaria, and hypo- and hyperglycemia.10 Both are contraindicated in patients with a medical history of pheochromocytoma, insulinoma, and glucagon hypersensitivity.5,10
From case reports and observational studies, there has not been a reported link between administration of glucagon in pregnant women and risk of miscarriage, defects, or other negative outcomes for the fetus and mother.5,10 There is currently no data on glucagon being present in breast milk, but glucagon is hypothesized to be of no danger to infants since it can be broken down in their gastrointestinal tracts.3,7
Baqsimi® Clinical Trials Review
Intranasal glucagon has been studied in three clinical trials. In an open-label, randomized, crossover, and two-period trial, Suico et al. showed that all of the 66 type I diabetes mellitus (T1DM) patients who were administered intramuscular and nasal glucagon experienced a rise in the plasma glucose to at least 70 mg/dL or a rise of at least 20 mg/dL from baseline in 30 minutes of administration. The results showed that 3 mg nasal glucagon was non-inferior to 1 mg intramuscularly administered glucagon with a 0.0% treatment difference (-1.52%, 1.52%).11
Rickels et al. conducted a randomized, crossover, non-inferiority trial with 75 adult T1DM patients. The study showed that 98.7% of the 3 mg intranasal and 100% of the 1 mg intramuscular glucagon visits had a rise in plasma glucose to 70 mg/dL or greater or an increase by 20 mg/dL or greater from baseline within 30 minutes of administration (98.7% vs. 100%; CI 4.0%).12
Sherr et al. conducted a randomized, crossover trial studying the rise in blood glucose of T1DM patients (4 to less than 8 years of age and 8 to less than 12 years of age) who received either 2 or 3 mg intranasal glucagon at two different times vs. one weight-based dose of intramuscular glucagon. Children under 25 kg received a 0.5 mg dose. Children weighing at least 25 kg received a 1 mg dose. Sherr et al. also studied patients 12 to less than 17 years of age. They were administered a 1 mg intramuscular dose of glucagon during one time and a 3 mg intranasal glucagon at another time. The results showed that 58 out of 59 intranasal and all 24 intramuscular glucagon administrations resulted in a glucose rise greater than or equal to 25 mg/dL from baseline within 20 minutes of administration. The study supported use of 3 mg intranasal glucagon for pediatric patients ranging from 4 to less than 17 years. Intramuscular and intranasal glucagon administrations reported nausea at 67% and 42%, respectively (p=0.05).13
Gvoke® Clinical Trials Review
Gvoke® has been studied in 2 multicenter crossover studies of adult T1DM populations (18 to 74 years). One study was double-blinded with 80 participants. The other study was single blinded with 81 participants. A single-arm trial of 31 T1DM pediatric patients from 2 to under 18 years of age was also conducted. Nearly all (98.7%) of the adult patients that were administered Gvoke® and all (100% ) of the adult patients that were administered a Glucagon Emergency Kit® had a rise in blood glucose to more than 70 mg/dL or an increase of 20 mg/dL or more from baseline 30 minutes post administration. Gvoke®’s mean time to the aforementioned outcomes was 13.8 minutes while the Glucagon Emergency Kit® was 10 minutes. In the pediatric arm, 30 out of 30 (100%) of the evaluated patients experienced a rise of greater than or equal to 25 mg/dL in blood glucose.10
From the total of 154 adult patients who were administered Gvoke®, the most common adverse reactions were nausea, vomiting, edema at injection area, and headache. For the pediatric population (n=31), most common adverse reactions experienced by all age groups were nausea, hypoglycemia, and vomiting.10
Comparison with Previous Glucagon Products
Unlike previous glucagon injections, both Gvoke® and Baqsimi® do not require reconstitution prior to administration.3,4 This can result in saving precious minutes during the event of a severe hypoglycemic attack. This may also be easier for a caretaker to administer compared to GlucaGen® and Eli Lilly and Company’s glucagon due to lack of reconstitution. Preparation and administration of Gvoke® was also shorter by 60-70 seconds versus the Glucagon Emergency Kit®.4 Novo Nordisk’s GlucaGen® HypoKit®’s WAC package price is $293.05 each, slightly costlier than Baqsimi® and Gvoke®.14 Fresenius’s Glucagon Emergency Kit®’s WAC package price is $279.80 while Eli Lilly and Company’s Glucagon Emergency Kit®’s WAC package price is $280.80, comparable to Gvoke® and Baqsimi®.15
Gvoke® and Baqsimi® are new glucagon devices with shorter preparation time and comparable pricing to those currently available on the market.3-10,14,15 However, as with all new products, time will gauge their popularity and preference amongst patients with diabetes.
By: Miriam Bisada, PharmD Candidate 2021 and Yostena Khalil, PharmD Candidate 2022; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis.
Mentor: Erica F. Crannage, Pharm.D., FCCP, BCPS, BCACP; Associate Professor, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Clinical Pharmacist Mercy Clinic-Family Medicine
Diabetes mellitus is a disease of abnormal carbohydrate metabolism related to relative or absolute impairment in insulin secretion. Pharmacogenomics, the study of drug responses impacted by genes, is a drastically growing field especially after the Human Genome Project (HGP) mapped DNA for the entire human genome in 2000. However, the clinical utilization of pharmacogenomics has been limited to severe idiosyncratic adverse drug reactions, variations in drug metabolism, and chemotherapy interventions.1 The International Diabetes Foundation estimated 463 million in the world were diagnosed with diabetes in 2019 and predicted 578 million by 2030.2 Through the efforts of the Genome-Wide Association Study (GWAS), 50 genetic loci were found associated with various glycemic traits and at least 90 loci with type 2 diabetes.3 Over the past 20 years, many monogenic forms of diabetes have been identified which have great response to targeted treatments. However, diabetes remains a complex polygenic disease with many variants contributing to the risk and prevalence.
Type 1 diabetes mellitus (T1DM) is likely to be triggered at an early age by the development of autoantibodies against islet cells, insulin, and/or glutamic acid decarboxylase.4 The greater the number of types of beta cell autoantibodies, the higher the risk of progression of diabetes.5 There are several genetic mutations that have been identified which increase a patient’s likelihood of developing type 1 diabetes mellitus. A patient is more likely to develop type 1 diabetes mellitus if they have variants of the HLA-DQA1, HLA-DQB1, and HLA-DRB1 genes.6 These genes belong to the human leukocyte antigen (HLA) complex which is a group of proteins encoded by the MHC gene complex, a large locus of vertebrate DNA, in humans. These proteins are responsible for the regulation of the immune system, which aids our immune system to recognize foreign substances and differentiate them from our own. Along with genetics, environmental factors, such as a virus, can also trigger the progression of type 1 DM.7
Unlike T1DM, diet and exercise can significantly decrease the development of diabetes type 2 (T2DM), but these measures alone have not been effective at curtailing the increase in prevalence of T2DM, especially with the growing obesity pandemic.8 T2DM is an insulin resistant disease and patients with a first-degree diagnosed relative are three times likely at risk for T2DM. Genes that are candidates for disease susceptibility involve pancreatic β cell function, insulin action/glucose metabolism, or other metabolic conditions that increase T2DM risk. There are more than 50 candidate genes affecting T2DM, but only few are promising for future use in clinical practice; PPARγ, ABCC8, KCNJ11, and CALPN10 mutations are associated with T2DM. CALPN10, encodes intracellular calcium dependent cysteine protease, has been linked with T2DM diagnosis.
Metformin is the first-line treatment of T2DM but causes gastrointestinal (GI) effects in about 10% of patients. Patients had better response to metformin with reduced GLUT2 transport (up to 0.5% HbA1c); however, side effects were more pronounced in patients with reduced function of SLC22A1 genes had 2.4 times higher odds (95% confidence interval (CI) =1.48–3.93, P=0.001) of developing GI side effects.9 There was also a 0.33% greater reduction in HbA1c for patients taking metformin that carried an C allele for SLC2A2 single-nucleotide polymorphism rs8192675 (reduces the expression of GLUT2 that alters metformin action) than patients that didn’t.8 SLC22A1 (encodes OCT1 transporter), SLC29A4 (encodes PMAT transporter), and SLC6A4 (encodes serotonin transporter) genes are expressed in human gut responsible for transporting of metformin. The GWAS found that patients with three or more alleles of these genes affect their tolerance of metformin with odds of 2.15 (95% CI, 1.2–4.12).8 However, current metformin pharmacogenomics data has a 3 evidence level which means it is not clinically practical yet as the results have not been replicated or have a clear evidence based association.12 Patients with loss-of-function variants in CYP2C9 have higher exposure to sulfonylureas and thus experience a greater glycemic response.10 ATP binding cassette, subfamily C, member 8 (ABCC8), has a high affinity for sulfonylurea receptors along with KCNJ11 as both regulate hormones released like insulin and glucagon in beta cells. Peroxisome proliferator-activated receptor-γ (PPARγ) is widely studied because of its adipocyte and lipid metabolism effects as one form can decrease insulin sensitivity and increase T2DM risk. PPARγ is the therapeutic target of thiazolidinediones (TZD) class of medications. Variants in PPARγ where patients carry alleles experienced an increased glycemic response to TZDs with odds of 2.32 ([95% CI = 1.10–4.87] P = 0.03).9 Patients with altered CYP2C8 and SLCO1B1 activity have a different response to pioglitazone and rosiglitazone in glycemic response and side effects that might be driven from genotype-based differential drug responsiveness.13 Overall, TZD have a grade C level of evidence on the CPIC guidelines and a 3 PharmGKB level of evidence so there are no prescribing actions because dosing based on PGX data has weak evidence or unclear.12 Unlike T1DM, T2DM has defined genes linked to drug mechanisms like ABCC8, which encodes the high-affinity sulfonylurea receptor, and KCNJ11, both of which are known to be ATP-sensitive potassium channels to regulate insulin and glucagon release.
An uncommon subtype of T2DM known as Maturity Onset Diabetes of the Young (MODY) occurs before the age of 25 and accounts for <5% of all the T2DM cases.7 Currently, there are six forms of MODY which are caused by mutations in GCK, HNF, and NEURODI genes involved in metabolism of glucose, regulation of insulin, glucose transport, and development of fetal pancreas.8 It was thought that MODY3 severe diabetes, to be T1DM, but changed to T2DM diagnosis once realized that the mutations in MODY3 are sensitive to sulfonylureas. Given the autosomal dominant inheritance of MODY, early genetic diagnosis may reduce long-term complications. Revealing genetic mutations could help us better diagnose and personalize treatments.
With a growing focus on genetic studies and pharmacogenomics, our understanding is expanding to where we could match treatments based on a patient's genomic makeup in the near future. A world of personalized medicine practice through global research and data-based medicine could reduce healthcare cost with more rapid identification of needed preventative strategies and/or ideal treatments. The Type 1 Diabetes TrialNet has a strategy to gene test high risk patients and use preventive measures to avoid onset of disease since T1DM is not curable.8 Early findings remain promising; however, we are not at a point where the benefits of using genetic information for diabetes is robust enough to be generalizable to all patients and is outweighed by the cost.8 Although genetic links to diseases, drug mechanisms and effects have been reported in literature, more comprehensive robust studies are needed before pharmacogenomics for diabetes can be utilized in routine clinical disease management. Pharmacists, as interprofessional team members with a goal to optimize medications, should continue to contribute to and monitor future pharmacogenomic research efforts to fulfill the promise of the Human Genome Project and find consistent results across populations for genetic conclusion to better our patient outcomes.
By: Bridgette McCauley, PharmD; PGY-2 Psychiatry Pharmacy Practice Resident
Mentor: O. Greg Deardorff, PharmD, BCPP; Clinical Pharmacy Manager, Fulton State Hospital – Fulton, MO
Program Number: 2021-01-03
Postpartum depression (PPD) is classified as a major depressive disorder occurring “during pregnancy or within four weeks following delivery.”1 In the United States, the prevalence of PPD is estimated to be 11.5% and is the leading cause of maternal mortality.2-5 Within the first-year after giving birth, one in seven deaths is a result of suicide.6 Those at highest risk of developing PPD are those with a history of depression, history of or current tobacco use, have experienced domestic violence, fear childbirth, are of lower socioeconomic status, have gestational diabetes, ≥40 years old, adolescents, unintentional pregnancy, or maternal anxiety.7-12 While the etiology is not clear, there are a few theories thought to cause PPD.
The exact pathophysiology is unknown, but thought to be related to neurotransmitter abnormalities, genetic predisposition, decreased estrogen, hypothalamic dysfunction, thyroid dysfunction, and alterations of reproductive hormones.13-21 One reproductive hormone in particular, allopregnanolone (a progesterone neurosteroid metabolite), is thought to have a role in PPD.18-21 Allopregnanolone is a positive allosteric modulator of GABAA and in animal models has been linked to anxiety and depression.21,24-26 During pregnancy, progesterone rises and is at its highest plasma concentration during the third trimester.22 The concentrations quickly decrease after childbirth.23 If the GABAA receptors do not adapt to the changes in allopregnanolone at child birth, it may trigger PPD.27
Overview of Brexanolone28
Brexanolone (Zulresso®) is a positive allosteric modulator of GABAA receptors, which was approved in 2019 for the treatment of PPD. This was the first medication approved by the FDA for PPD. This medication is given as a continuous infusion over 60 hours and must be administered in a healthcare facility. It is given as 30 µg/kg/h (0-4h), 60 µg/kg/h (4-24h), 90 µg/kg/h (24-52h), 60 µg/kg/h (52-56h), and 30 µg/kg/h (56-60h). If the patient does not tolerate the 90 µg/kg/h infusion, a dose of 60 µg/kg/h may be used instead. Due to the prolonged infusion, all patients are required to have childcare for the time of the infusion.
The most common adverse effects are sedation/somnolence (13-21%), dizziness/presyncope (12-13%), loss of consciousness (3-5%), and flushing/hot flush (2-5%). Due to the loss of consciousness/sedation risk, this medication does have a REMS program. This ensures that patients are monitored with pulse oximetry and physical assessment by staff.
While brexanolone has no contraindications, it should not be used in those with end stage renal disease (ESRD) with an eGFR of <15 mL/min/1.73m2 due to the solubilizing agent, betadex sulfobutyl ether sodium. This agent can accumulate in severe renal impairment. This medication does not require dose adjustments in patients with hepatic impairment.
During the administration of brexanolone, breast feeding is not recommended, but was found to be safe at 36 hours post-infusion. At 36 hours, the concentration in the breast milk was <10 ng/mL in at least 95% of women. Exposure to the medication in breast milk is not expected to be high as the oral bioavailability is low. Therefore, breastfeeding 36 hours post-infusion should be acceptable as relative infant dose is low.
Evidence Supporting Brexanolone29
Two phase 3 studies were performed. In the studies, there were two different brexanolone infusion rates compared (Table 1). Study 1 looked at both the brexanolone 60 µg/kg/h and 90 µg/kg/h infusion groups. This study showed that at 60 h, the least squares mean reduction in Hamilton Depression Rating Scale (HAM-D) scores were 19.5 points (SE 1.2) in brexanolone 60 µg/kg/h, 14.0 points (SE 1.2) in brexanolone 90 µg/kg/h, and 14.0 points (SE 1.1) in placebo group. The second study of the phase 3 trials, looked at brexanolone 90 µg/kg/h versus placebo and found the least squares mean reduction in HAM-D scores was 14.6 points (SE 0.9) in brexanolone 90 µg/kg/h vs 12.1 points (SE 0.8) in placebo. The phase 3 trial did show that brexanolone was superior to placebo in treatment of postpartum depression at 60 h and showed responses were sustained up to 30 days. Of those that responded to treatment at 60 h, 94% of patients did not relapse at 30 days post-infusion.
Prior to the approval of brexanolone, the mainstay of treatment for PPD was antidepressants.30-32 Most commonly, selective serotonin reuptake inhibitors (SSRIs) were the treatment of choice for PPD. SSRIs do not have a rapid onset of action and may take up to 6-12 weeks to see the full resolution of symptoms.33 A matching-adjusted indirect comparisons and network meta-analysis of brexanolone with SSRIs by Cooper et al demonstrated that brexanolone 90 µg/kg/h showed a greater change from baseline than SSRIs when looking at both HAM-D and Edinburgh Postnatal Depression Scale.34
Eldar-Lissai et al, estimated the average cost of a course of brexanolone to be $34,000, while SSRIs are relatively cheap.35 They estimated that direct maternal medical costs for brexanolone treated patients was $65,908 vs $73,653 for SSRIs over 11 years. This study showed the incremental cost effectiveness ratio of brexanolone was $106,662 per quality adjusted life years over 11-years versus SSRIs. In addition, women treated with brexanolone averaged 6.230 quality adjusted life years vs 5.979 for SSRIs. This study showed that while brexanolone is expensive, it is cost-effective for the treatment of PPD.
Brexanolone is a novel treatment for PPD and has shown promising results. While the long-term effects are not yet known, it has shown itself to be effective for the treatment of PPD and is a viable option for patients suffering with PPD.
By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
We are in the People Business.
Every day, we go to work to take care of people. Pharmacists are in the business of protecting, educating, persuading, and serving people. It’s what we do, as we interact with patients, nurses, doctors, and other health care professionals. Today I’d like to ask for your help in educating, persuading, and serving a different group of people: Lawmakers!
Politicians Are People Too
As I have written in other articles, pharmacists, technicians and interns have to play according to the rules, and those rules have their foundation in the laws that are passed in Jefferson City. Part of MSHP’s 2021 strategic plan is to increase the amount of education and guidance we provide to the lawmakers who are working hard to create good laws that keep the Missouri public safe. That takes time, and it takes focus, and it takes effort. We can’t do it by ourselves. Will you help?
Three Ways to Help
We have a Public Policy committee that meets monthly to provide updates and discuss our options for getting engaged. We are also forming work groups to focus on provider status, reimbursement for cognitive services, and MSHP advocacy and education on legislative topics. If you would like to add your listening ear and your voice, please email me so that you can join our committee.
We are getting ready for the annual Legislative Day, which will be 3/30. This is a time for Jefferson City to focus on pharmacy, and it provides an opportunity for the Missouri Pharmacy Association and Missouri Society of Health System Pharmacists to come together with one voice to remind our lawmakers of the important role we play in caring for patients. It is a Tuesday, and usually there are events scattered throughout the day, so you will need to make a plan in order to be able to participate. Of course the event will look different this year, so stay tuned. We are not ready for signups, but if you are interested in receiving updates, please email me and I will keep you informed.
If you are not available on 3/30, that is no problem at all! There are 51 other weeks this year where you can reach out to your senator or representative and begin the process of building relationships with them and educating them on pharmacy-related topics. With the COVID vaccine in the news, all eyes are on pharmacy right now. This is a great time to begin the process of meeting the person who represents you so that you can provide them with important information when they need it. Don’t know who your lawmakers are? You can find them here in less than a minute. Send them an email to get on their email list. Don’t feel equipped to speak on behalf of Missouri Pharmacy? Email me and I will provide you with some talking points and agenda items to discuss.
Caring For Lawmakers
Remember, we are in the people business, and our lawmakers are people who need our expertise and care. Let’s make 2021 the year when we start making a difference in our patients by caring for our lawmakers!
Don’t Miss What the Public Policy Committee Has Done!
Advocacy 101 Webinar:
This is a 1 hour webinar that gives the basics about advocating for our patients at the legislative level and at the regulatory level. It is a brief tutorial of ‘how things work.’ Link
Public Policy Updates:
By: Jackie Harris, PharmD, BCPS; Executive Director, MSHP Research and Education Foundation; Christian Hospital
MSHP R&E Foundation is currently accepting submissions and nominees for several awards.
MSHP R&E Best Practice Award
The Best Practice Award program recognizes innovation and outstanding performance in a pharmacy directed initiative. The theme for the 2021 award focuses on Adapting to New Circumstances. Submission deadline is January 11, 2021.
A poster of the program will be highlighted during the Spring Meeting Poster Session. The award recipient will be honored at a Reception during the Spring Meeting and have the opportunity to provide a brief podium presentation detailing the implementation and impact of the project to the attendees.
Applicants will be judged on their descriptions of programs and practices currently employed in their health system based on the following criteria:
Applicants must be active MSHP members practicing in a health-system setting such as a large or small hospital, home health, ambulatory clinic or other health care system. More than one successful program from a health system may be submitted for consideration.
Award recipient will receive half off their meeting registration, a plaque and a $250 honorarium.
Submission Instructions: A program summary not to exceed 400 words must be submitted with the application and include the following information.
MSHP R&E Best Residency Project Award
The Best Residency Project Award recognizes innovation and outstanding performance in a pharmacy residency project. A poster of the program will be highlighted during the Spring Meeting Poster Session. The award recipient will be honored at a Reception during the Spring Meeting and have the opportunity to provide a brief podium presentation detailing the implementation and impact of the project to the attendees. Submission deadline is January 11, 2021
Applicants will be judged based on the following criteria:
Applicants must be active MSHP members completing a residency in a health-system setting such as a large or small hospital, home health, ambulatory clinic or other health care system.
Email your submission to firstname.lastname@example.org with Best Residency Project Award Submission in the subject line.
The Garrison award was established in 1985, named after Thomas Garrison for his long standing support of MSHP (past-president 1974-1976), ASHP (past-president 1984) and numerous professional and academic contributions to Pharmacy.
The Garrison Award is presented each year to a deserving candidate who has been nominated in recognition of sustained contributions in multiple areas:
Email your nomination to email@example.com with Garrison Award Submission in the subject line.
Submission Deadline for Garrison Award is January 11, 2021.
Tonnies Preceptor Award
MSHP R&E Foundation is pleased to honor a health system pharmacist for outstanding service to the profession as a preceptor to pharmacy students and/or residents. Below are the Criteria and Procedures to nominate a preceptor for the award.
The Tonnies Preceptor award was established in 2020, named after Fred Tonnies, Jr. for his long standing support of MSHP (past-president 1976-1978), Mid-Missouri Society of Hospital Pharmacists (MMSHP) (past-president 1988) and numerous professional and academic contributions to Pharmacy. He was one of the founding members of MSHP and MMSHP, and has over 35 years of precepting experience.
The Tonnies Preceptor Award is presented each year to a deserving candidate who has been nominated in recognition of sustained contributions in multiple areas:
The award will be presented to a health system pharmacist that consistently exemplifies the core values (Professionalism, Desire to educate and share knowledge with students, Willingness to mentor, Willingness to commit the time necessary for precepting, Respect for others, Willingness to work with a diverse student population) and the following characteristics:
Each letter of nomination must include:
Support for Nomination: Please briefly explain (in no more than 500 words) the ways in which the nominee models these core values. The winner will be selected by the Board of Directors of the MSHP Research and Education Foundation. Email your submission to firstname.lastname@example.org with Tonnies Preceptor Award Submission in the subject line.
Submission Deadline for Tonnies Preceptor Award is January 11, 2021.
Best Practices Award Winner – A Pharmacist-Driven Penicillin Allergy Overhaul
Becca Nolen, Infectious Diseases and Antimicrobial Stewardship Pharmacist at SSM Health-St. Mary’s Hospital received the Best Practices Award during the Virtual KCHP/MSHP Spring Meeting for her project entitled “A Pharmacist-Driven Penicillin Allergy Overhaul.”
One of the most commonly reported allergies in the United States is to penicillin. Historically, cross-reactivity between penicillin and other beta-lactam antibiotics has been estimated at 10%, but recent literature has shown that the beta-lactam ring does not confer cross-reactivity, and the true likelihood of cross-reactivity is significantly lower than previously reported (approximately 1%).
This program consists of pharmacist-led interventions at SSM Health St. Mary’s Hospital – St. Louis, including education of providers when beta-lactams may be appropriate in penicillin-allergic patients, beta-lactam allergy questionnaires, and penicillin skin testing in patients who have penicillin allergies and are not on a penicillin or cephalosporin for treatment of infection. A real-time best-practice alert (BPA) that identifies patients for the Antimicrobial Stewardship pharmacist to review and assess which of the aforementioned interventions would be most appropriate. Patients are excluded if they are on antibiotics for surgical prophylaxis, duration of antibiotics is <48 hours, or if they are on appropriate antibiotics that were not a penicillin or cephalosporin. Data were collected during a pilot of the project from November 2018 to February 2019, though the project is still on-going.
During the study period, 297 BPAs were generated and 214 patients were excluded, mostly for being on antibiotics less than 48 hours. 83 patients were on appropriate antibiotics that were not a penicillin or cephalosporin. Recommendations to switch antibiotics were made on 30 patients, and one penicillin skin test was completed during the study period. Interventions were accepted in 90% of patients, and no patients had adverse drug reactions or required supportive care after switching to a penicillin or cephalosporin. Since the study time period, 12 penicillin skin tests have been performed.
This project has helped educate our providers on the appropriate management of infected patients with reported penicillin allergy, as well as to expand the role of pharmacist. The utilization of unnecessary broad-spectrum antibiotics has been reduced, which could potentially lead to shorter hospital stays and less repeated use of broad-spectrum antibiotics in penicillin -allergic patients.
If you have any questions about this project, please contact Becca Nolen at Rebecca.Nolen@ssmhealth.com.
Mentor: Alexandria Wilson, Pharm.D., BCPS (AQ-ID); Associate Professor, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Clinical Pharmacy Specialist, Infectious Diseases, Washington University Infectious Disease Clinic
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread rapidly across the world since the first known cases arose out of Wuhan, China in late 2019.1 Coronavirus disease 2019 (COVID-19) was declared a pandemic on March 11th, 2020.2,3 As of the writing of this paper, there have been over 43 million confirmed cases of COVID-19 worldwide, with over 1 million deaths.4 Patients with underlying health conditions may have different outcomes than patients without comorbidities.5,6 In particular, people living with Human Immunodeficiency Virus (PLHIV) have been labelled as a COVID-19 high-risk group due to immunosuppression.7 In a report from Kanwugu et al., published on July 21st 2020, there have been 378 reported cases of COVID-19 among PLHIV worldwide.8 This review will summarize the clinical characteristics, HIV management, and outcomes of PLHIV who are infected with SARS-CoV-2.
Epidemiology of COVID-19 in PLHIV
The first published case of HIV and SARS-CoV-2 coinfection was reported in Wuhan, China in early 2020.8 Mirazaei et al. published a systematic review of 252 cases of HIV and SARS-CoV-2 infections in July 2020.2 The majority of those cases were male (80.9%) with a mean age of 52.7 years on antiretroviral therapy (ART) (98%).2 Many patients also had other chronic health conditions known to increase the risk of COVID-19, such as hypothyroidism, asthma, hyperlipidemia, hypertension, obesity, diabetes, and lung disease. 2,5 Slightly over 20% of the patients in the systematic review were smokers. 2
Clinical Features and Courses of COVID-19 in PLHIV
Upon admission, coinfected patients presented with similar signs and symptoms of COVID-19 to HIV- uninfected patients. Many coinfected patients had upper or lower respiratory infections, fever, cough, headache, dyspnea, malaise, sore throat, arthralgia, gastrointestinal upset, myalgia, lymphopenia, and lung changes, i.e. opacities upon X-ray imaging.2,5,9,10
The following table compares the results of Mirazaei et al.’s systematic review of COVID-19 in PLHIV (percentages calculated from available data) to the largest COVID-19 cohort available as of November 3rd, 2020 (>44,000 patients) and United States (US) COVID-19 case surveillance data of hospitalization and intensive care unit (ICU) admission rates from January 22, 2020 to May 30, 2020. 2,11-13
This data suggests that PLHIV who develop COVID-19 have more severe and critical illnesses, hospitalizations, and ICU admissions than HIV negative patients. A majority (86.9% of 176) of patients had high CD4 counts of at least 200 cells/mm.3 Similarly, a HIV-1 RNA of no more than 1000 copies/mL was seen in a majority (99.1% of 233) of patients with viral load data.2 There have also been some reports of PLHIV presenting with Pneumocystis jirovecii pneumonia and COVID-19.14
Findings from Specific Cohorts
There have been conflicting outcomes concerning the survival rates of PLHIV with COVID-19 compared to the general COVID-19 population. For instance, in the United Kingdom, a cohort of patients from the OpenSAFELY platform reported 14,882 COVID-19 deaths with 25 cases among PLHIV. The study included a total of 17.3 million patients with 27,480 cases among PLHIV who were three times more likely to have a COVID-19-related death compared to HIV negative patients (Hazard Ratio (HR) 2.90, 95% Confidence Interval (CI) 1.96-4.30). The association was even greater in patients of African ethnicity (HR 3.80, 2.15-6.74, vs. HR 1.64, 0.92-2.90, p-interaction=0.045).15 Similarly, in a study from Western Cape, South Africa with a patient repository of 3,460,932, 16% were PLHIV. Of this 16%, 3,978 PLHIV were diagnosed with COVID-19, and 115 PLHIV with COVID-19 died. It was shown that HIV was associated with COVID-19 mortality. The risk was similar across different levels of immunosuppression and viral loads. Standardized mortality ratio for COVID-19-related deaths in PLHIV was 2.39 (95% CI 1.96-2.86).16 Another multicenter cohort study with 286 patients found that PLHIV and COVID-19 with CD4 count below 200 cells/mm3 had a higher risk for death, ICU admission, mechanical ventilation or hospitalization, regardless of viral suppression.17
However, a large scale study of 7,576 patients conducted by the US Veterans Aging Cohort Study, showed no difference in mortality (adjusted HR (aHR) 1.08, 95% CI 0.66-1.75), hospital admission (aHR 1.09, 95% CI 0.85-1.41), intubation (aHR 0.89, 95% CI 0.49-1.59), or ICU admission (aHR 1.08, 95% CI 0.72-1.62) between PLHIV and HIV negative patients with COVID-19. This study matched PLHIV and HIV negative patients to account for potential confounders.18 Another study in New York with a cohort of 100 PLHV and 4,513 HIV negative patients also supported no difference in mortality rates.19 All of these studies were not included in Mirazaei et al.’s systematic review which reported deaths in 14.3% of 252 coinfected patients.2
HIV Management in COVID-19
For PLHIV, the National Institutes of Health (NIH) guidelines for COVID-19 treatment recommend patients continue taking their ART unchanged, including investigational agents, and medications for opportunistic infections (OI) prophylaxis.14
The Guidelines recommend against changing ART regimens to treat or prevent COVID-19.20 However, clinicians are advised to consult with a HIV specialist if the ART needs to be adjusted or if the patient is on a feeding tube. For PLHIV not on ART, it is currently unknown when is best to start taking the ART. Overall, clinical recommendations for management of coinfected patients do not differ from the general population.14
Cohorts that assessed specific ARTs patients were taking at the time of COVID-19 included combination nucleoside reverse transcriptase inhibitors with an integrase inhibitor, nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with protease inhibitors (PIs), or combination therapy with nonnucleoside reverse transcriptase inhibitors (NNRTIs).5,21
There have also been studies of outcomes in coinfected populations on ARTs. A cohort study of 77,590 PLHIV in which 236 were diagnosed with COVID-19, in Spain looked at outcomes of PLHIV receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC) and other ARTs (3TC in two-drug therapies or NNRTI with PI monotherapy). The results of the study are summarized in the table below. 21
The results of this study suggest a benefit in COVID-19-related outcomes of PLHIV on TDF/FTC compared to other ARTs. The study also suggested ARTs have a protective effect in PLHIV, lessening the risk for serious COVID-19 cases.21 There have been other studies looking at ARTs, like lopinavir/ritonavir and darunavir/cobicistat, for treatment of COVID-19, but have shown no clinical benefit compared to the standard of care or need further investigation, respectively.22,23
Current cases of infection with SARS-CoV-2 in PLHIV present with similar clinical features to HIV uninfected people. Different studies have suggested varied outcomes in PLHIV.15-19 Current COVID-19 treatment guidelines offer the same management recommendations for PLHIV and HIV-patients.14 In PLHIV, there are guidelines for HIV management, which state ARTs should not be changed. In one cohort, the combination of ARTs TDF/FTC showed some benefit compared to other ARTs in COVID-19-related outcomes of PLHIV, but more data is needed.21 Differences in the outcomes observed in the cohorts may be attributed to the retrospective nature of some studies, the differing designs, size of cohort, etc. Due to the novelty of COVID-19, there are still many unanswered questions, including whether CD4 count or viral load in PLHIV are associated with severity of COVID-19, and the impact of different ARTs.2 To make accurate conclusions, there needs to be more data on COVID-19 in PLHIV.