By: Jacklyn Harris, PharmD, BCPS, Christian Hospital/St. Louis College of Pharmacy
We had another great virtual Spring Meeting this year! We hope that you enjoyed the programming as much as we did and hope that you were able to view this year’s posters. Our poster presenters did not disappoint- they did a great job completing their research and recording a short 5-minute video review of their poster. Our poster winners this year are listed below.
If you were not able to view the posters, check them out here http://www.moshp.org/mshp-posters-2021/.
This year’s MSHP R&E Foundation Best Practice theme was ‘Adapting to New Circumstances’. This year’s Best Practice award was presented to Kat Lincoln for her project entitled “Daptomycin-weight-based dose optimization”. Look for a review of her project in the next newsletter!
This year’s Best Residency Project Award was presented to Sara Lauterwasser for her project entitled “Safety comparison of heparin and enoxaparin for venous thrombosis prophylaxis in traumatic brain injury”. We will be scheduling a special webinar for Dr. Lauterwasser to present her project.
The 2nd annual Tonnies Preceptor Award was given out at this year’s meeting. The Tonnies awards was established in honor of Fred Tonnies, Jr for his longstanding support of MSHP, MMSHP, and numerous professional and academic contributions to Pharmacy, including over 35 years of dedicated service to student learners. The award recognizes a pharmacist for their sustained contribution to precepting learners in health-system pharmacy, mentoring students/residents in the research process, activity with pharmacy students throughout the state, and service to the profession through ASHP, MSHP, and/or local affiliates. This year’s Tonnies Preceptor Award was presented to Austin Campbell. Dr. Campbell is Clinical Pharmacy Specialist in Psychiatry at the Missouri Psychiatric Center at the University of Missouri Health Care. His investment in developing future practitioners has been evident for many years.
Our final award was the Garrison Award. The Garrison Award recognizes an individual who demonstrates outstanding accomplishments in health-system pharmacy practice, demonstrates teaching through involvement with pharmacy students and contributions to the professional of pharmacy through involvement with MSHP, ASHP, or local affiliates. This year’s award was presented to Diane McClaskey. Diane is the Assistant Director of Experiential Education and Clinical Assistant Professor for the University of Missouri Kansas City, School of Pharmacy at MSU. She embodies the spirit of the Garrison Award in her continuous efforts in student involvement, research and publications, and leadership. We were honored to award this year’s Garrison Award to Diane! Congratulations!!
Please congratulate each of our award winners!! We look forward to when we can present these awards to each of you in person. Thanks for another great Spring Meeting and continue to push the practice of pharmacy in Missouri!
By: Amanda Bernarde, PharmD; PGY1 Pharmacy Resident, University of Missouri Health Care
Uncontrolled pain in the trauma patient population can lead to a variety of long-term, debilitating effects.1,2 Most prominently, patients experience impaired healing due to additional production of inflammatory factors, increased risk of infection, and psychological disorders persisting well past the initial injury.3 Due to the subjectivity of pain assessments and confounding factors, including sedating medications that can mask uncontrolled pain, recent exposure to opioids, and chronic versus acute pain etiologies, pain management remains a challenge in all patient populations.
Opioids continue to be the mainstay in pain management for trauma patients. However, due to their adverse effect profile, potential for misuse and abuse, and the ever-evolving drug shortage issues facing health care institutions, additional approaches to medication management are necessary to adequately control patients’ pain.2 Multimodal analgesia (MMA) is the concomitant use of both opioid and non-opioid pain medications for synergistic mechanisms of action in an effort to minimize opioid-related adverse effects. This approach combats the two sides of pain patients experience: nociceptive and neuropathic.2,4 Nociceptive pain is caused by mechanical harm to the body, which is the traditional sense of trauma-related pain and commonly managed by opioids, while neuropathic pain is an effect of inappropriate stimuli to the sensory system and not well controlled by opioids.
In a quasi-experimental study completed by Hamrick et al., investigators demonstrated the positive effects of MMA on cumulative oral morphine equivalents (OME) in critically ill trauma patients.5 Patients with three or more mechanisms of medication pain management had an average OME of 116.3 mg, while patients without MMA had an average OME of 479 mg spanning the first five days after injury. Beyond the overall reduction of opioid requirements when using a multimodal pain approach, use of non-opioids in addition to traditional regimens have significantly reduced intubation time and intensive care unit length of stay with a reduction of 2.64 and 4.25 days, respectively.6 This impact on both short-term and long-term outcomes can drastically alter a patient’s disease course and management beyond the acute setting.
There are a number of specific medication classes that have been explored in conjunction with opioids, including traditional over-the-counter pain medications, gabapentinoids, α-adrenergic agonists, and ketamine. Trauma patients given scheduled oral acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) in addition to opioids had an average OME reduction 6.34 mg and 10.18 mg, respectively, in the 24-hour period post-MMA.4 Though reduction in opioid requirements may have been a natural disease progression, several studies have found similar results in non-trauma patients.2,7,8 Gabapentin and pregabalin mitigate neuropathic pain and help prevent chronic pain, while α-adrenergic agonists, like dexmedetomidine and clonidine, work both peripherally and centrally to provide analgesia, anxiolysis, and sedation.2 Both medication classes have demonstrated effective reduction of OME and coinciding pain scores in non-trauma surgical patients, yet no studies have been conducted in critically ill trauma patients to illustrate the effects in this patient population. Lastly, in a recent systematic review and meta-analysis, ketamine administration in the pre-hospital setting was not found to be less effective at managing pain compared to opioids.9 This non-opioid analgesic has proven efficacious in decreasing pain scores and OME for both intranasal administration and intravenous administration in a variety of trauma population subsets.10,11 Each MMA approach, though successfully protocolized at many institutions, should be individualized to the patient, including end organ function, comorbid conditions precluding use, and baseline use of these medications which may reduce their efficacy in treating the acute pain needs of the patient.
In addition to the non-opioid medication therapies, there are nonpharmacologic approaches that can facilitate to both the physical progress and emotional aspects for trauma patients. One such nonpharmacologic therapy is early initiation of physical therapy. From a physical standpoint, assisted movement restores range of motion, promotes healing of injured tissues, and decreases long-term activation of inflammatory responses.12 Early mobilization has demonstrated a reduction of pulmonary, vascular, and cardiovascular complications, including pneumonia, pulmonary embolism, acute respiratory distress syndrome, deep vein thromboses, myocardial infarctions, and cardiovascular shock.12,13 Additionally, a statistically significant decrease in hospital length of stay by 2.4 days was shown when comparing early mobility to the control group (p=0.02). Though ICU length of stay was reduced by 1.5 days, these findings were not statistically significant, attributing the decrease in total length of stay to fewer complications when patients reached the general care floors. The positive effect of early physical therapy have prompted additional research in nonpharmacologic approaches to pain management, including mobilization in the emergency department and use of virtual reality.
The limitations and risks associated with long-term, high-dose opioid use remain a concern in practitioners’ minds in treating critically ill trauma patients. Despite the limited data in this patient population, literature from other non-traumatic surgeries has been extrapolated to trauma patients due to their similar pain management needs. In the studies available and those extrapolated, MMA has shown to significantly decrease opioid and overall analgesic requirements, intubated days, and intensive care unit and hospital length of stay, in addition to minimizing misuse and abuse of opioids by setting the same precedent in the outpatient world.
By: Emily Lammers, PharmD, MSLD; PGY2 Ambulatory Care/Academia Resident
Mentor: Lisa Cillessen, PharmD, BCACP; Clinical Assistant Professor, UMKC School of Pharmacy at MSU
Program Number: 2021-03-02
Approval Dates: April 7, 2021 to October 1, 2021
Approved Contact Hours: 1 hour
Diabetes mellitus is a chronic disease that affects over 34 million children and adults in the United States alone and 422 million people worldwide. This equates to a global presence of diabetes in people aged 18 years and older of 8.5%.1 In the United States specifically, 10.5% of the population are diagnosed with diabetes which equates to 1 in 10 Americans. Of the people in the United States diagnosed with diabetes, about 5% of the population, or 1.4 million, are diagnosed with Type 1 Diabetes Mellitus (T1DM) and 90- 95% are diagnosed with Type 2 Diabetes Mellitus (T2DM).2 These statistics show that diabetes mellitus is a common disease state that healthcare providers will encounter in their patients regardless of the environment in which they work.
Type 1 diabetes mellitus, which typically presents in adolescents and young adults, is characterized by the immune system destroying insulin producing cells in the pancreas causing the pancreatic beta cells completely stop producing insulin. This leaves the patient without an insulin supply. Insulin is responsible for binding to cells to allow glucose into the cells. If you think of a lock and key, insulin is the key that unlocks the cells and allows glucose to enter the cell. If the cells cannot take up glucose, the body cannot use this glucose for energy and the patient will be in a hyperglycemic state. Due to the lack of insulin in the body, patients with T1DM are indicated for insulin therapy as the treatment of choice. This patient population will require two to four injections per day of insulin. In combination with insulin injections, patients with T1DM need to monitor their blood sugar levels multiple times a day.3
Type 2 diabetes mellitus, which typically presents in older, overweight patients, is characterized by decreased beta cell function, insulin secretion and insulin sensitivity. The body still produces some insulin, but cells are not responding to the insulin to allow glucose into the cells. This is what leads to hyperglycemia in these patients and the diagnosis of T2DM. Patients with T2DM can be treated with both oral and injectable medications based on the severity of their disease. Some patients will not require injections, and some will require up to six injections per day. In combination with this, T2DM patients will need to monitor their blood sugars between one to four times daily depending on their treatment regimen and progression of disease.
Whether the patient has T1DM or T2DM, diabetes puts any patient at an increased risk of complications in the future. These complications can include cardiovascular disease, retinopathy, neuropathy, nephropathy, and others. One of the best ways to mitigate these risks is to have good management of the patient's diabetes and blood glucose levels. This includes staying at or below an A1c of 7% and maintaining blood sugars within the fasting (80-130 mg/dL) and postprandial (<180 mg/dL) goals as outlined by the American Diabetes Association. Based on the UKPDS 35 trial, every 1% reduction in A1c is correlated with a 21% decreased risk of diabetic complications.4 This trial and other evidence highlight the importance of maintaining proper control of blood glucose. One of the best ways for a patient to know the status of their blood sugars is to test, but many times patients are limited on the amount of times they can test in a day based on their insurance coverage and not wanting to continuously have finger sticks. This is an area where continuous glucose monitors (CGM) can come into play.
In 2016, the Endocrine Society appointed task force created recommendations and guidelines surrounding CGM use for patients with T1DM and T2DM. The task force recommends the use of CGMs in adult patients with T1DM who have A1c levels above target and who are willing and able to use these devices on a nearly daily basis. Secondly, the task force recommends CGM devices for adult patients with well-controlled T1DM who are willing and able to use these devices on a nearly daily basis. Thirdly, the task force recommends short-term, intermittent CGM use in adult patients with T2DM (not on prandial insulin) who have A1c levels 7% or higher and are willing and able to use the device. These recommendations indicate that CGMs place in therapy is growing and patients are benefiting from using CGMs.5
Continuous Glucose Monitors (CGM):
A continuous glucose monitor is a device a patient wears externally on either their abdomen or arm or is implanted. The device has a small sensor that will be inserted under the skin and automatically tracks a patient's interstitial blood glucose throughout the day and night. Interstitial fluid is part of the extracellular fluid between a patient’s cells and interstitial glucose values are determined by the rate of glucose diffusion from plasma to the interstitial fluid and the rate of glucose uptake by subcutaneous tissue cells.6 Interstitial glucose values can have a delay compared to blood glucose levels, so if a patient is experiencing signs of hypoglycemia, but the CGM device is not showing a hypoglycemic reading, the patient should verify with a blood glucose fingerstick.
CGMs have different components to them that include a sensor, transmitter, and receiver. The sensor is a small wire inserted subcutaneously and is responsible for measuring interstitial blood glucose levels every one to five minutes. The transmitter is a wireless component of the sensor that will transmit blood glucose levels to a receiver, reader, or application (app) on a smartphone.7 The sensor and transmitter are combined into a small, compact device that is attached externally to the body for most devices. There is one implantable CGM device on the market. Lastly, the receiver is a device that is separate from the sensor and transmitter. The receiver, which can be a small device or a compatible smart device, will display the transmitted data from the sensor. Different CGM devices are on the market and may have small differences from each other like where to place the sensor or the amount of time before each reading, but each device will have a sensor, transmitter, and receiver. Having the CGM device continuously track blood glucose levels allows patients and providers to see trends throughout the day and night and utilize these numbers to make medication or lifestyle changes.8
In recent trials completed in T1DM and T2DM patients, CGM have been shown to decrease hypoglycemic events. The IMPACT trial from 2016, showed patients with T1DM had a 38% reduction of time in hypoglycemia and a 40% nighttime reduction of hypoglycemia (<70 mg/dL)9. The REPLACE trial in 2017, showed that patients with T2DM had a 43% reduction of time in hypoglycemia and a 54% nighttime reduction of hypoglycemia (<70 mg/dL).10 This reduction provides a safer environment for patients and reduces worry for providers and patients regarding patients experiencing hypoglycemic events.
How many CGMs are on the market?
Pharmacists may have noticed that CGM devices have gained more popularity in recent years with the Freestyle Libre and Freestyle Libre 2 coming to market, but this was not the first CGM to be approved for use in patients with diabetes. Dexcom G6, Guardian Connect with the Guardian Sensor 3, and Senseonics Eversence are other continuous glucose monitors that are available to patients and have been since the early 2000’s.
The Dexcom G6 is the most current model that is available to patients and is equipped with a 10-day wearable sensor and transmitter. A patient will place the sensor and transmitter on their abdomen. The sensor and transmitter device are water-resistant and easy to insert with an auto-applicator. The Dexcom G6 transmitter wirelessly provides a glucose reading every five minutes, or up to 288 times per day to the receiver or a compatible smart device. These readings can be shared with up to ten others via the Dexcom Share feature. If a patient wishes to share data from their device with their healthcare provider, the information can be shared via the Dexcom Clarity software which allows providers to review CGM data at any time. The G6 is also equipped with an alert system for critically low blood sugars. The device monitors glucose trends and if glucose is trending downward, the device will alert a patient with a 20-minute advanced warning of a severe hypoglycemic event (<55 mg/dL). A patient will also have the option to set a “Low Alert” and “High Alert” for when their blood glucose readings are below or above target range. These alerts can be set, changed, or discontinued at any time by the patient. The alert for critically low blood sugars cannot be changed or stopped. The G6 is FDA permitted to make diabetes treatment decisions without confirmatory finger sticks or calibration needed, but if a patient is experiencing symptoms that are not in line with the readings they are receiving, fingerstick blood sugar should be taken to confirm.11
Guardian Connect and Guardian Sensor 3
The Guardian Connect CGM is powered by the Guardian Sensor 3, which can be worn up to seven days and is water-resistant for up to 30 minutes. The sensor measures interstitial blood glucose levels every five minutes. The transmitter will then automatically transfer these readings to the Guardian Connect app. The Guardian Connect app allows patients to set predictive high and low glucose values ranging from 10-60 minutes prior to predicted events happening. With the predictive alerts turned on to 30 minutes before a low, the Guardian Connect system had a 98.5% rate of detecting hypoglycemic events by evaluating if the patient’s glucose is trending downward. This system also allows patients to connect with their healthcare providers via the CareLink system platform. This platform enables providers virtual, remote monitoring of their patient’s glucose levels and trends. Another feature of the Guardian Connect system is the Sugar.IQ Diabetes Assistant cognitive app. This app uses IBM Watson analytics to identify patterns in diabetes data. The app continually analyzes how a patient’s glucose levels respond to their food intake, insulin dosages, and daily routines. This helps patients discover any hidden reasons for highs or low and gives a daily summary of glucose levels to allow patients to see how their blood sugar levels are trending.12
Eversence is the world’s first and only long-term, implantable CGM device. The sensor will be professionally placed by a healthcare provider every 90 days directly under the skin in a patient’s arm. The sensor is 3.5mm x 18.3mm. The sensor remains accurate if compressed and during exercise. The transmitter will sit right above the sensor on a patient’s arm and is removable, rechargeable, and water-resistant up to 30 minutes. A benefit of the transmitter being removable is patients can remove the device for a special occasion and they will not waste a sensor because the sensor and transmitter are not attached. The transmitter will send data to a patient’s smart device every five minutes via Bluetooth. The transmitter will provide on-the-body vibration alerts when a patient’s blood glucose is too high or too low in addition to alerts the patient can see and hear. Eversence is the only CGM on the market that includes vibration alerts. Blood glucose levels are automatically sent to a patient’s smart device from the transmitter, the patient’s smart device will track the real-time glucose measurements with no need for a different receiver. The patient can also track exercise and meals to see them on the graph and aid in identifying trends. The data sent to the smart device can be shared with up to five people of the patient’s choosing and could include members of the healthcare team.13
Freestyle Libre 14-day
Freestyle Libre is a 14-day sensor that a patient wears on the upper part of the back of their arm. The sensor filament is less than 0.4mm thick and is water- resistant. The receiver is a separate device that patients can use to scan the sensor to obtain their glucose readings. A patient can also use their smart device with the LibreLink app if preferred. Patients may scan the transmitter as often as they want while they are wearing the sensor and a new reading is available every minute to view with the system storing glucose readings every 15 minutes. It is required that patients do scan the sensor at least once every eight hours or data will be lost for that time period. Each scan will show the patient’s current blood sugar reading, direction sugars are trending, and a trend graph showing the last eight hours of glucose history. The reader will hold up to 90 days of glucose history including daily patterns, time in target, low glucose levels, and 7, 14 and 30-day averages. This data is available to be shared with up to 20 people like family members or healthcare providers via the LibreLinkUp app. Freestyle Libre 2, which was approved Summer 2020, is the most recent version of the Freestyle Libre devices. The Libre 2 has all the features of the previous versions and includes alerts for high and low blood sugars for the patient. Along with that, the Libre 2 has an online portal called LibreView that can be accessed by patients and healthcare providers to share CGM data. The Libre 2 is not currently approved to be used with the LibreLink app, so patients will need to have the receiver accessible to scan the sensor at least once every 8 hours. The receiver can double as a glucose meter if the patient needs to perform a fingerstick blood sugar check.14
Comparison of Continuous Glucose Monitors
How do I interpret the numbers?
The glucose readings, trend lines, averages, and alerts from a continuous glucose monitor can seem daunting as a healthcare provider trying to figure out what to do with all the information. From a figure used in an article written by Dr. Bergenstal, this article will go through how to interpret all the information from a CGM report.
This figure is from a FreeStyle Libre device, but many of the CGMs on the market will produce similar data to what is in the image above. The average glucose has a high correlation with A1c, but not as much with glycemic variability or hypoglycemia. If a healthcare provider were to only utilize this number when making a treatment decision it does not give much information around glucose patterns. The glucose management index is a substitution for estimated A1c. This number is calculated from the mean CGM glucose over a specified period of time. The next item to take a look at is the time in range (TIR). This graph shows the time a patient is in target range, above and below. As healthcare providers, we want to try to maximize our patient’s time in range and minimize the time above and below. The image above shows the TIR as a percentage, but some data will show it in minutes or hours in range per day averaged over the allotted time period. TIR will automatically set up to 70-180 mg/dL, but if a patient or provider wants to alter the target levels that is available to do. The time in hypo- and hyperglycemia have specified values and then beyond that will have critical values. These are shown above with <70 mg/dL considered below target range, but then it also specifies what percentage of that time the patient spent <54 mg/dL. These values can be extremely useful for healthcare providers to identify how often a patient is below or above goal. Using this information paired with the graph on time to see when exactly the patient is experiencing the time above or below can aid the provider in making very informed, specific medication regimen changes. The coefficient of variation (CV) is a value that is used to mark glucose variability. It has been studied that a CV of <36% represents low glucose variability and a stable glucose profile and ≥ 36% is vice versa. Standard deviation (SD) highly correlates with mean glucose and A1c. If the SD is less than the mean glucose divided by three, a provider can assume low glucose variability and a stable glucose profile. Lastly, the ambulatory glucose profile with the dark blue line being the median with 50% of glucose levels above and 50% below. The dark blue shading is indicative of 50% of all glucose readings and the light blue is 80% of readings for the specified time. This graph is a visual that healthcare providers can quickly look at to identify how often and at what times a patient is in target range. It is also a great tool to use to identify what times a day a patient is at risk for a hypoglycemic event and can alter medication regimens to mitigate chances of hypoglycemia.15
A CGM report may seem daunting at first but breaking down each part and understanding what it means in the big picture could be helpful. While this article discussed specifically FreeStyle Libre, this information is transferable to any CGM report that a provider may be interpreting with some small differences present.
What monitor is right for my patient?
Insurance companies play a huge part in identifying which monitor may be right for a patient. Insurance companies issue preferred drug lists that indicate which medications and devices are preferred for that specific insurance company. This does not mean that non-preferred medications will not be covered to some extent but may have a higher copay or require a prior authorization. It is more common that insurance companies will provide coverage for continuous glucose monitor devices for patients with T1DM as these patients typically require more daily finger sticks and are treated solely with insulin which may put them at an increased risk for hypoglycemic episodes.
Each company with a CGM on the market will also have a team available for patients or providers to help with coverage. The pharmaceutical companies want patients using their products, so they offer many resources to help with the processing of paperwork and finding coverage opportunities for patients. Below is a list of insurance coverage and criteria that must be met for common insurances that pharmacists in Missouri may encounter. Commercial insurance companies have similar criteria, so only one has been listed below.
Missouri Medicaid covers Dexcom G6 for patients who meet certain criteria including:16
Blue Cross Blue Shield of Missouri
Blue Cross Blue Shield of Missouri covers Freestyle Libre 14 and Dexcom G6 at a tier 2 and ST. The step therapy qualifications are listed below for FreeStyle Libre 14 Day and similar steps are required for Dexcom G6:17
The Medicare National Coverage Determinations Manual has released the following information regarding coverage of a CGM for patients with Medicare insurance.18
Considering the different eligibility criteria for commonly seen insurance plans in Missouri, it can be hard for patients to gain approval for continuous glucose monitoring devices. There is always the option for patients to pay out of pocket, but that can be a considerable expense for patients. Continuous glucose monitors are great devices that have proven to decrease times in hypoglycemia and overnight hypoglycemia for patients. There is also the benefit of information sharing with friends, family, and the healthcare team. For healthcare providers, it makes our decision-making process more exact when we can identify trends in glucose over time instead of a moment in time blood sugar. With all those benefits being mentioned, cost and eligibility are the largest barriers. To increase accessibility to patients, there needs to be a reduction in cost or loosened eligibility criteria for patients with T1DM and T2DM.
By: Jamie Prashek, PharmD, PGY1 Pharmacy Resident, University of Missouri Health Care
Status epilepticus broadly refers to a seizure with prolonged activity; historically this was defined as a duration of at least 30 minutes.1-3 Lowenstein et al. further specified this definition as convulsive seizures with at least five minutes of continuous seizure activity or intermittent seizures without recovery of consciousness in-between.4,5 Current recommendation is for prompt initiation of treatment once activity has reached five-minutes.2 A delay in initiation increases the chance for prolonged activity and risk for neuronal injury. Morbidity and mortality increases as seizure time lengthens, with seizures lasting greater than 30 minutes having an increased risk for worse outcomes.2,5-7
Approximately 150,000 individuals develop epilepsy yearly, with 15% experiencing status epilepticus at some point.8 Since “time is brain”, status epilepticus is a medical emergency with immediate and effective treatment being imperative. Benzodiazepines have historically been the agents of choice as first line options.1,3 However, the exact agent, dose, and route of administration has been up for debate. Different routes of administration include intravenous (IV), intramuscular (IM), rectal, buccal, and intranasal. In addition, another question is which second line treatment agent is appropriate when status epilepticus is refractory to benzodiazepine treatment. The following will review key literature and guidelines to outline recommended and effective treatment in those with status epilepticus.
In 2016, the American Epilepsy Society released a guideline recommending treatment for convulsive status epilepticus in both children and adults.3 As mentioned previously benzodiazepines remain the initial treatment of choice, however, with various benzodiazepines and routes of administration, it is imperative to consider the feasibility of administration when making a selection. Intravenous benzodiazepines have been widely used, but obtaining access during active convulsions is not always feasible and another route must be available. Two pivotal studies discussed below, have helped to guide treatment with benzodiazepines.
The pre-hospital treatment for status epilepticus (PHTSE) study was a randomized, double blind, placebo controlled trial evaluating the safety of intravenous benzodiazepines by emergency medical service (EMS) providers.9,10 Study intervention included 2mg IV lorazepam, 5mg IV diazepam, or placebo, with the allowance of a one-time repeated dose if necessary. The primary outcome was cessation of status epilepticus prior to arrival to the emergency department (ED). Termination of status was evident in 59.1% in those who received IV lorazepam, 42.6% who received IV diazepam, and 21.1% who received placebo (p=0.001).
Silbergleit et al. compared the use of IM midazolam to IV lorazepam for pre-hospital treatment in those with active status epilepticus.11 The rapid anticonvulsant medication prior to arrival trial (RAMPART) was a randomized, double blind, non-inferiority trial designed to find an alternate efficacious agent.11 Treatment was as follows, patients weighing 40 kg or more received 10 mg IM midazolam followed by IV placebo, or they received IM placebo followed by 4 mg IV lorazepam. With dose adjustments for those between 13 to 40 kg, active drug doses at 5 mg IM midazolam and 2 mg IV lorazepam. The primary outcome of cessation of convulsions prior to ED arrival was evident in 73% of the IM midazolam group compared to 63.4% in the IV lorazepam group (p<0.001).11 Importance for this study was to provide EMS providers an alternative agent to IV lorazepam that was comparable in safety and efficacy. Limitations for IV lorazepam included the potential difficulty in obtaining IV access, along with the limited shelf life of unrefrigerated lorazepam solution.12
At the time of the 2016 guidelines, a gap in evidence existed for deciding the best secondary agent when status is refractory to benzodiazepine therapy. Chamberlain et al. with the established status epilepticus treatment trial (ESETT) set out to answer this exact question. ESETT was a double blind, randomized, Bayesian response trial comparing levetiracetam, fosphenytoin, and valproate in those after adequate benzodiazepine administration.13 Treatment randomization was in a 1:1:1 ratio with levetiracetam 60 mg/kg (max of 4500 mg), fosphenytoin 20 mg PE/kg (max of 1500 mg PE), or valproate 40 mg/kg (maximum 3000 mg) infused over 10 minutes. The primary outcome was for cessation of clinical seizures and improved responsiveness at 60 minutes without the need for additional anti-seizure medications or endotracheal intubation. Across the different age groups efficacy was evident in roughly half of the patients treated with each agent. Although, the ESETT did not answer the question of which agent is preferred, it does give more reassurance that utilizing levetiracetam, fosphenytoin, or valproate should be effective if dosed accurately.
The 2016 guidelines developed a treatment algorithm helping providers decide what agent is ideal at specific time intervals. See Figure 1 for a modified algorithm and Table 1 for treatment agents and dosing. IV lorazepam dosed at 4 mg is an ideal first line agent. In those without IV access IM midazolam is an appropriate alternative agent. After treatment with benzodiazepines, a plan for immediate treatment with a second phase agent is just as important, with appropriate choices including levetiracetam, fosphenytoin, and valproate.
By: Hannah Michael, PGY1 Pharmacy Resident, University of Missouri Health Care
As adults age, observed changes occur in their sleep patterns, resulting in a higher prevalence of insomnia in the older patient population, or those aged 65 years and older. In normal physiologic sleep processes, sleep is divided into non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. NREM sleep is then further divided into three different stages: N1, N2, and N3. N1 and N2 are categorized into light sleep with N2 accounting for around 48% of sleep time when brain waves begin to slow. N3 sleep is composed of very slow brain waves, also referred to as slow wave sleep.1 As patients age, nightly sleep begins to naturally shorten, however, there are other notable sleep changes that develop in older adults. There tends to be a decrease in total sleep time, a decrease in sleep efficiency, or the ratio of time asleep to time spent in bed, a lower percentage of both slow-wave sleep and REM sleep, and lastly, a decrease in REM latency, which is an important measure in sleep quality as it is the time from sleep onset to the first epoch of REM sleep.2 The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines insomnia as a sleep disturbance that causes significant clinical distress or functional impairment and occurs at least three nights a week for three months.3 The International Classification of Sleep Disorders 3rd Edition goes on to further divide each type into either primary, further categorized into idiopathic, paradoxical, and inadequate sleep hygiene, or secondary, which is attributed to medical conditions and mental disorders.4 Similar to the DSM-5 classification, chronic insomnia disorder includes all subtypes that occur at least three nights a week for at least three months.
Insomnia, if left untreated, may lead to increased rates of depression, cognitive impairment, as well as other medical conditions such as diabetes, cancer, or hypertension.5 Another important factor to keep in mind with this patient population is the disruption in standard time cues that otherwise develop with a consistent and regular schedule. The geriatric population is often retired, so fixed work schedules and mealtimes may change, and this may contribute to the development of insomnia when the homeostatic process that drives the need to sleep or stay awake is not regulated as it was prior to these daily adjustments. Understanding these developmental changes is essential in order to appropriately identify therapy modifications and recommendations for such a commonly encountered sleep disorder.
Prior to the consideration of pharmacological agents, sleep hygiene and other non-pharmacological approaches to treating insomnia should always be implemented. Important factors of sleep hygiene specifically include the incorporation of regular exercise and meals during the day; avoidance of stimulants, large meals, and electronic usage close to bedtime; limiting daytime naps; and optimizing one’s sleep environment, which includes maintaining cooler room temperatures and other physical bed considerations to maximize sleep comfort. Other non-pharmacological approaches include the use of cognitive behavioral therapy for insomnia (CBT-I), which is highlighted by the American Academy of Sleep Medicine (AASM) as a standard of treatment for insomnia.6 CBT-I is centered on identifying incorrect thoughts, beliefs, or knowledge about sleep and behaviors related to sleep. Additional methods include sleep restriction, which, with the help of a sleep diary, aims to make small adjustments each week to build back sleep drive. Lastly, stimulus control is another approach to train the brain to associate bed with sleep only; in doing this, patients are advised to leave their bed and complete a relaxing activity if unable to sleep, only to return to bed when sleepy.1
There are notable challenges when considering incorporating pharmacological agents for older adults when non-pharmacological approaches alone are insufficient. Prolonged use of different pharmacotherapies is associated with tolerance issues, dependence, and other related challenges, such as residual daytime sedation and cognitive impairment, both of which increase the risk for motor incoordination and resultant falls. The American Geriatrics Society 2019 Beers Criteria offers recommendations to reduce exposure to potentially inappropriate medication use in patients 65 years and older. For example, the guideline recommends avoiding benzodiazepines and nonbenzodiazepine hypnotics in older adults due to potential for adverse events, such as delirium, falls, fractures, and motor vehicle accidents.7 In addition, older patients often require dose adjustments due to changes in muscle mass and renal function, as well as increased sensitivity to adverse effects. These patients are also more likely to be taking additional medications for concomitant disease states, which increases their risk for drug interactions. The AASM provides general recommendations for insomnia depending on the different types, including sleep onset insomnia (difficulty initiating sleep), sleep maintenance insomnia (an inability to stay asleep throughout the night), or a combination of both. With these considerations in mind, understanding the available agents and their common adverse effects and pharmacokinetic profiles may guide appropriate therapy selection. A selected list of therapy agents and their specific characteristics are provided in the table below when considering these sleep aids in the geriatric population.6,8,9
Select review articles provide additional guidance for elderly patients and offer recommendations regarding preferred pharmacotherapy for sleep onset insomnia, including ramelteon, which works as a melatonin receptor agonist, short-acting nonbenzodiazepines (i.e., zaleplon or zolpidem), or melatonin.2,9 Caution is advised with melatonin products due to the varying formulations and inconsistent efficacy for each patient.
For sleep maintenance insomnia, beneficial pharmacotherapy agents may include suvorexant, which was approved in 2014 as a first-in-class insomnia drug that antagonizes both orexin type 1 and type 2 receptors, or low-dose doxepin, a tricyclic antidepressant. Of note, antidepressants may have more value in older patients with comorbid depression.
Lastly, for sleep maintenance or sleep onset insomnia, non-benzodiazepines, which agonize the benzodiazepine receptors at varying GABA subunits, may be useful with careful consideration of the pharmacokinetic properties. For example, eszopiclone may offer additional benefit for sleep maintenance insomnia due to its longer half-life. Each of these agents is advised to be prescribed for short-term use only, and benzodiazepines are generally suggested to be avoided in the elderly due to increased likelihood of falls, cognitive disruption, dependence, and difficulty with discontinuation.
Sleep status and quality of sleep remain important concerning the older population, as a natural decline in normal physiologic sleep processes is likely to be observed in these patients. Recognizing the challenges that are associated with drug therapy for the treatment of insomnia in the elderly is essential when deciding to incorporate pharmacological agents. Older patients are more likely to be on interacting drug therapies and may require dose adjustments when considering declines in renal function and increased sensitivity to the available treatments. Most importantly, non-pharmacological approaches should always be at the forefront of therapy and be incorporated into each patient-specific plan, as the development and continuation of improved sleep habits benefits all types of insomnia no matter a patient’s age.
By: Garrett Shobe; PharmD Candidate 2021
Mentor: Leigh Anne Nelson, PharmD, BCPP; Associate Professor of Pharmacy/Psychiatry, UMKC School of Pharmacy
Schizophrenia is a chronic disabling thought disorder resulting in severe detrimental effects to a person’s health, social, and occupational status. Individuals with schizophrenia can present with hallmark symptoms of psychosis (delusions, hallucinations, disorganized speech), negative symptoms (avolition, anhedonia), catatonic behavior, and cognitive dysfunction. People with schizophrenia have significantly higher rates of mortality as compared to the general population, especially in the presence of other psychiatric or substance use disorders and unfortunately, approximately 10% die of suicide. The American Psychiatric Association (APA) developed a new practice guideline in 2020 focused on the treatment of schizophrenia. The APA recommendations for use of first-generation antipsychotics (FGA), second-generation antipsychotics (SGA), treatment resistant schizophrenia, long-acting injectable antipsychotics (LAIA), and first-episode psychosis will be reviewed.
The APA practice guidelines recommend patients with schizophrenia be treated with an antipsychotic medication. Contrary to other treatment guidelines, it is difficult to take an algorithmic approach when selecting an antipsychotic medication for schizophrenia. Selection of an antipsychotic medication should be based upon patient specific characteristics and antipsychotic adverse effects. Efficacy of antipsychotics are similar with the exception of clozapine. Clozapine is the only antipsychotic medication to demonstrate superiority over other antipsychotics in clinical trials but is recommended for use only after failure of two antipsychotic trials. Additionally, its use is restricted to patients through the REMS program and mandates monitoring of absolute neutrophil counts due to the boxed warning for potential risk of developing life-threatening agranulocytosis. Metabolic disorders and cardiovascular disease are common in patients with schizophrenia and can be worsened by the use of antipsychotic medications. APA recommends working along-side the patient, and/or caregiver to assess for past treatment failures, tolerability issues, and future treatment preferences. As a healthcare practitioner, identifying target symptoms such as anxiety, insomnia, hallucinations, and delusions can help guide decision making when differentiating between antipsychotic medications.
FGA such as chlorpromazine, fluphenazine, haloperidol, loxapine, thiothixene, and others work by antagonizing dopamine (D2) receptors and are associated with a higher risk of extrapyramidal symptoms (EPS) (i.e. pseudoparkinsonism, dystonia, and akathisia and most concerning and stigmatizing, tardive dyskinesia (TD). Due to the higher risk for EPS and TD, FGA are usually reserved for patients who are unable to tolerate, or who have failed trials with a SGA. However, APA suggests that if a patient is prescribed an antipsychotic medication (FGA or SGA) and their symptoms have improved, they should continue taking the same medication and have movement disorder assessments for EPS and TD be conducted on a scheduled basis. FGA fall into the treatment guideline as primarily second line therapy to treat positive symptoms such as delusions and hallucinations.
SGA are used first line in schizophrenia. The undesirable side effect profile of FGA led to the development of SGA. Most SGA (clozapine, olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, lurasidone, asenapine) work by blocking both dopamine (D2) and serotonin (5-HT2A) receptors. These agents are associated with significant metabolic disturbances (weight gain, hyperlipidemia, hyperglycemia). Olanzapine and clozapine exhibit the highest risk for metabolic side effects. Risperidone, paliperidone and quetiapine are considered to possess moderate risk, while ziprasidone and aripiprazole are lowest risk. Newer SGA also fall into the lower risk category for metabolic side effects. Aripiprazole, brexpiprazole, and cariprazine have a unique mechanism of action acting as dopamine (D2) partial agonists and also antagonize serotonin (5-HT2A) receptors. Overall, SGA are associated with a lower risk of EPS and TD as compared with FGA. When selecting a SGA, it important to understand the activity of each drug at the histamine (H1), muscarinic (M1) and alpha1/2 receptors, and review labeling for common side effects that can affect adherence.
Treatment resistant schizophrenia (TRS) is defined as having persistent symptoms of psychosis despite receiving adequate treatment with antipsychotic medications. Patients classified with TRS will have shown no or partial response to antipsychotic treatment (<20% decrease in symptoms) over the course of six weeks to two antipsychotic trials. APA recommends patients with TRS to be treated with clozapine. In addition to TRS, patients with schizophrenia who are at risk for suicide and/or display aggressive behavior despite receiving treatment with other antipsychotics should be evaluated for treatment with clozapine. To initiate clozapine, baseline ANC must be greater than 1500/mm3. After initiation, ANC should be monitored weekly for 6 months, then every 2 weeks for 6 months, then monthly thereafter. Clozapine therapy should be stopped if a patients ANC drops below 1000/mm3, develop suspected myocarditis, or experiences a cardiomyopathy.
APA practice guidelines recommend utilizing LAIA for patients who prefer LAI formulation, or have a history of poor or uncertain medication adherence. LAIA can improve medication adherence, are predicted to decrease hospitalizations, and improve outcomes for patients with schizophrenia. FGA medications available in a LAI formulation include fluphenazine decanoate and haloperidol decanoate. SGA medications available in LAI formulations include aripiprazole (Abilify Maintena, Aristada Initio, Aristada), olanzapine (Relprevv), paliperidone (Invega Sustenna, Invega Trinza), and risperidone (Risperdal Consta, Perseris). It is important to understand that these medications have unique formulations, loading capabilities, titration patterns, pharmacokinetics, and adverse effects. For example, FGA LAI have sesame oil-based vehicles while SGA LAI are water-based. Many of the LAIA require oral antipsychotic overlap when initiating therapy, so it is important to individualize treatment plans to your patient, and their circumstances.
For individuals experiencing their first episode of psychosis, APA recommends being treated in a coordinated specialty care (CSC) program. CSC programs were developed to provide evidence-based interventions, including antipsychotic medication, and to help patients recover after an initial schizophrenia episode. CSC programs provide individual resiliency training, employment and education assistance which allows them to feel a sense of accomplishment while developing autonomy. CSC programs utilize a collaborative, team-based approach, incorporating family involvement and education into a patient’s treatment plan. In combination with antipsychotic medication and cognitive-behavioral therapy for psychosis, CSC programs have been associated with a reduction in mortality, improved quality of life, and a greater likelihood of being able to return to work or school after receiving up to two years of treatment. Once again, selection of an antipsychotic is based on patient characteristics and antipsychotic medication adverse effects with SGA being more commonly tolerated and prescribed than FGA.
To improve the quality of care and treatment outcomes for patients with schizophrenia, APA developed this updated practice guideline for the treatment of schizophrenia as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). This guideline provided new recommendations for TRS, use of LAIA and first episode psychosis.
By: Sarah Lothspeich, PharmD, MPH; PGY2 Ambulatory Care Resident, CoxHealth - Springfield
Program Number: 2021-03-03
According to the Centers for Disease Control and Prevention (CDC), more than an estimated 6.2 million adults were diagnosed with heart failure in the United States between 2013 and 2016.1 This number has grown and is predicted to continue to grow. In fact, between 2009 and 2012, the estimated number of adults with heart failure was around 5.7 million.1 The growth is especially concerning considering the significant healthcare costs associated with caring for patients with heart failure. In 2012, it was estimated that heart failure alone cost the nation $30.7 billion dollars.1,2
The National Institute of Health (NIH) defines heart failure simply as the inability of the heart to pump effectively enough to meet the needs of the body. Right-sided heart failure results in the heart not being able to pump enough blood to the lungs to become oxygenated, while left-sided heart failure results in the heart being unable to effectively pump oxygen-rich blood throughout the body. A person can have one or both types of heart failure. Heart failure is a progressive disease and typically occurs due to the progression of heart damage or weakening over time. Common causes of heart failure are ischemic heart disease, uncontrolled diabetes, and hypertension. Specifically, ischemic heart disease causes a build-up of plaque in the arteries limiting blood flow to the heart, thus weakening it. In uncontrolled diabetes, elevated blood sugars contribute to blood vessel and heart damage. Hypertension causes heart failure because increases in the force of blood flow on the artery walls weakens the heart and can lead to additional plaque build-up. Other conditions, such as arrythmias and congenital heart defects can also progress to heart failure. Common risk factors for heart failure include age 65 years or older, African American race, being overweight and a previous myocardial infarction (MI). Symptoms associated with heart failure are largely due to fluid overload. The most common manifestations are shortness of breath, fatigue and swelling in ankles, legs, or abdomen. Jugular vein distention (JVD) can also occur in right-sided heart failure.3
Heart failure is categorized into two groups for the purposes of treatment - heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). An echocardiogram is performed to estimate the left ventricular ejection fraction (LVEF). HFrEF is defined as a LVEF ≤40%. HFpEF is defined as a LVEF ≥ 50%. Borderline HFpEF is defined as LVEF 41 to 49%. There is currently no cure for heart failure, however the American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend drug therapies that have been shown to increase left ventricular ejection fraction, decrease symptoms/improve quality of life and decrease morbidity and/or mortality.4 Treatment recommendations within the ACC/AHA guideline are based on ACC/AHA stage and New York Heart Association (NYHA) function class. This is depicted in Table 1.
Table 1: ACC/AHA Staging and NYHA Function Class from 2017 ACC/AHA/HFSA Focused Update
Heart Failure Therapies
Before diving into heart failure treatments, it is important to review goals of care for these patients. Common goals include modifying or controlling risk factors, managing structural heart disease, reducing morbidity and/or mortality, eliminating or minimizing symptoms, and lastly, slowing progression of worsening cardiac function. Additionally, nonpharmacological treatments also have an important role in heart failure management. These include smoking cessation, weight optimization, decreasing alcohol and sodium intake and treating sleep apnea. Adequately treating and controlling diseases contributing to heart failure, such as diabetes and hypertension is also recommended.3 As previously mentioned, the ACC/AHA Heart Failure guideline separate therapy recommendations based on whether a patient has HFrEF or HFpEF. HFpEF guideline recommendations are limited. In general, the goal for those patients is to target symptoms, comorbidities and risk factors that could potentially worsen cardiovascular disease.4
For patients with HFrEF, it is recommended that all patients are on an Angiotensin-Converting Enzyme Inhibitor (ACE-I) or Angiotensin II Receptor Blocker (ARB) or Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and beta blocker therapy if they are able. It is also noted in the ACC/AHA Heart Failure guideline that while a specific ACE-I is not singled out as being the more effective, there is limited evidence for the use of fosinopril and quinapril. The preferred beta blockers listed in the guideline are bisoprolol, carvedilol, and metoprolol succinate as they have been specifically studied in this population. ACE-I, ARB, ARNI and beta blockers have all been shown to decrease mortality and hospitalizations in HFrEF patients. Aldosterone receptor antagonists (spironolactone and eplerenone) have also been shown to decrease mortality and hospitalizations and are recommended for patients with NYHA class II-IV who have an LVEF ≤ 35%. This class of medications is also recommended in patients after a MI if they have an LVEF ≤ 40% with heart failure symptoms or an LVEF ≤ 40% with diabetes. Ivabradine, an inhibitor of hyperpolarization-activated cyclic nucleotide-gated channels in the sinoatrial node, has also been shown to decrease mortality and hospitalizations and is beneficial for patients who are symptomatic (NYHA class II and III) with stable, chronic HFrEF and are currently on evidence-based therapies. Clinically the use of ivabradine may be limited as it requires a baseline heart rate of at least 70 beats per minute to initiate. Thiazide and loop diuretics are recommended for symptom management in patients with fluid retention. Digoxin can be used to decrease hospitalizations in HFrEF patients who are on other appropriate guideline-recommended therapies. It is important to note that when digoxin is used in HFrEF patients, it does not require a loading dose and the target level is 0.5 to 0.9 ng/mL. Lastly, hydralazine and isosorbide dinitrate decrease mortality and are recommended in addition to ACE-I and beta blockers for African American patients who have NYHA Class III or IV HFrEF. These medications may also be useful for symptomatic HFrEF patients who are unable to tolerate ACE-I/ARB therapy.4
Review of SGLT2 Inhibitor Indications and cardiovascular outcomes trials in diabetic patients
There are currently four sodium-glucose cotransporter-2 (SGLT2) inhibitors that are Food and Drug Administration (FDA) approved for the treatment of Type II Diabetes. These include: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Three of these four medications underwent trials in diabetic patients to evaluate cardiovascular outcomes with the intent to demonstrate no increased risk of cardiovascular harm. The names of the trials are listed in Table 2. Brief summaries of the cardiovascular outcome trials are detailed below. These studies are significant because the benefit they showed led to the evaluation of SGLT2 inhibitors for heart failure in patients without diabetes.
Table 2: SGLT2 inhibitor diabetes cardiovascular outcome trials
EMPA‐REG OUTCOME investigated the effect of empagliflozin on cardiovascular outcomes in patients with type II diabetes. The study included 7,020 participates with type II diabetes and established atherosclerotic disease. The results of this study showed empagliflozin significantly reduced the risk of heart failure hospitalization compared to placebo with a relative risk reduction (RRR) of 35% and an absolute risk reduction (ARR) of 1.4% in the exploratory end point.5 After the successful EMPA‐REG OUTCOME trial, CANVAS program trials evaluated canagliflozin in 6,656 patients with type II diabetes and established atherosclerotic disease and 3,486 patients with type II diabetes and at high risk for cardiovascular events. Canagliflozin significantly reduced heart failure hospitalization versus placebo with a RRR of 33% and an ARR of 3.2% in the exploratory end point.6 The DECLARE‐TIMI 58 trial investigated dapagliflozin versus placebo in 17,160 patients with type II diabetes who had either multiple cardiovascular risk factors or established atherosclerotic disease. Dapagliflozin showed a statistically significant reduction in heart failure hospitalization or cardiovascular death versus placebo, primarily due to decreased heart failure hospitalization which was associated with an ARR of 0.8% and a RRR of 27%. The heart failure hospitalization benefit was consistent regardless of recognized atherosclerotic disease and history of heart failure.7
Literature Supporting SGLT2 Inhibitors in Heart Failure without Diabetes
After the positive results in the cardiovascular outcome trials for diabetic patients, further evaluation regarding the use of SGLT2 inhibitors in heart failure patients without diabetes was warranted. In 2019, DAPA-HF was published after evaluating dapagliflozin in heart failure patients without diabetes and, nearly a year later in October 2020, EMPEROR-REDUCED was published evaluating empagliflozin in heart failure patients without diabetes.8,9 The full titles of these studies are listed in Table 3.
Table 3: SGLT2 inhibitor heart failure trials
DAPA-HF was a multicenter, double-blind, parallel-group, randomized controlled trial. This study took place in 410 centers in 20 countries. Enrollment occurred from 2017 to 2018 and a total of 4,744 patients with HFrEF (LVEF ≤ 40%) and NYHA II-IV symptoms were included with 2,373 in the dapagliflozin group versus 2,371 in the placebo group. Once patients were enrolled, there was a 14-day screening period after which patients were randomly assigned to receive dapagliflozin 10 mg once daily or placebo. Median follow-up for this study was 18.2 months. The primary outcome was worsening heart failure (hospitalization or urgent visit resulting in intravenous therapy for heart failure) or cardiovascular mortality. Baseline characteristics for the study population showed the following: 42% had type II diabetes, mean age was 66 years old, mean BMI was 28 kg/m2, 24% of patients were female, mean LVEF was 31% and mean estimated glomerular filtration rate (eGFR) 66 mL/min/1.73 m2. Additionally, 68% of participants were NYHA class II, 32% were NYHA class III, and 1% were NYHA class IV. A majority of the patients were on guideline-directed therapy including: 93% were on ACE-I/ARB/ARNI, 96% were on a beta blocker, 71% were on an aldosterone antagonist, and 93% were on diuretic therapy. The primary outcome of worsening heart failure (hospitalization or urgent visit resulting in IV therapy for HF) or cardiovascular mortality was significantly lower occurring in 16.3% in the dapagliflozin group versus 21.2% in the placebo group (hazard ratio 0.74, 95% confidence interval 0.65 to 0.85, P < 0.001). The authors of the study concluded that dapagliflozin use was associated with a lower risk of worsening heart failure or death from cardiovascular causes in patients with and without diabetes.8 This study led to the FDA approval of dapagliflozin to decrease hospitalizations and mortality in heart failure patients without diabetes.10
EMPEROR-REDUCED was a multicenter, double-blind, parallel-group, randomized controlled trial. This study took place in 520 centers in 20 countries. Enrollment occurred from 2017 to 2019 and a total of 3,730 patients with HFrEF (LVEF ≤ 40%) and NYHA II-IV symptoms were included with 1,863 in the empagliflozin group versus 1,876 in the placebo group. Once patients were enrolled, there was a 4 to 28-day screening period after which patients were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Median follow-up for this study was 16 months. The primary outcome was composite of adjudicate cardiovascular death or hospitalization for heart failure. Baseline characteristics for the study population showed the following: 50% had type II diabetes, mean age was 67 years old, mean BMI was 28 kg/m2, 24% of patients were female, mean LVEF was 27% and 48% of patients had a eGFR < 60 mL/min/1.73 m2. Additionally, 75% of participants were NYHA class II, 24% were NYHA class III, and 0.6% were NYHA class IV. A majority of the patients were on guideline-directed therapy including: 70% were on ACE-I/ARB, 19% ARNI, 94% were on a beta blocker, and 71% were on an aldosterone antagonist. The composite outcome of cardiovascular death or hospitalization for heart failure was significantly lower occurring in 19.4% in the empagliflozin group versus 24.7% in the placebo group (hazard ratio 0.75, 95% confidence interval 0.65 to 0.86, P < 0.001). The authors of the study concluded that empagliflozin use was associated with a lower risk of cardiovascular death or hospitalization compared to placebo for heart failure patients with and without diabetes.9
It is important to note that in both studies outlined above, approximately 90% of the patients were on ACE-I/ARB or ARNI and approximately 95% of the patients were on a beta-blocker. It is not known, however, if they were on the max tolerated doses targeted in heart failure. While both studies include patients in NYHA class II through IV, a majority of patients were in class II. There was also no difference in adverse events between SGLT2 inhibitor use and placebo.8,9 The positive outcomes for heart failure patients shown in DAPA-HF and EMPEROR-REDUCED led to the 2021 update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment. This update does include the recommendation to consider an SGLT2 inhibitor for patients with HFrEF and NYHA class II to IV after initiation of beta-blocker and angiotensin antagonist.11
Mechanism of SGLT2 Inhibitors in Heart Failure
SGLT2 is responsible for 90% of glucose and sodium reabsorption in the proximal convoluted tubules of the kidney. The mechanism of SGLT2 inhibitors in heart failure is unknown likely because it involves many different mechanisms. The three proposed hypotheses include the diuretic hypothesis, the thrifty substrate hypothesis and the NHE hypothesis.12
The diuretic mechanism of SGLT2 inhibitors differs from that of loop or thiazide diuretics because of the osmotic diuresis that results from glucose and sodium reabsorption. This leads to more fluid clearance from the interstitial fluid than the circulation preserving blood volume, organ perfusion and arterial filling. Additionally, SGLT2 inhibitors exert their activity in the proximal tubule where they activate tubuloglomerular feedback by increasing fluid and electrolyte delivery to the macula densa. By acting at different sites of the nephron SGLT2 inhibitors are able to produce greater electrolyte-free water clearance, resulting a more potent diuresis and natriuresis compared to thiazide and loop diuretics.12
The thrifty substrate hypothesis is related to increased oxidation of beta-hydroxybutyrate (BHOB) by the heart and kidneys which produces ATP more efficiently than fatty acids and glucose. This results from hyperketonaemia caused by increased hepatic synthesis and decreased urinary excretion of ketones by SGLT2 inhibitors. Utilizing a more energy-efficient fuel leads to improved cardiac and renal function.12
Lastly, the NHE hypothesis refers to the sarcolemmal sodium-hydrogen exchanger NHE1, which is in the heart and vascular and NHE3, which functionally interacts with SGLT2 at the apical surface of renal epithelial cells. Heart failure patients have increased activity of NHE1 and NHE3. Although SGLT2 is not expressed in the heart, it is thought that SGLT2 are able bind to and inhibit NHE1. Reducing NHE1 decreases the concentrations of intracellular sodium and calcium and increases the concentration of mitochondrial calcium. This improves systolic heart function by activating ATP production and reviving mitochondrial function.12
Heart failure affects over 6 million adults in the United States and that number is only expected to grow in the coming years.1,2 Current therapy is well-established, but heart failure is still associated with significant morbidity and mortality and thus accounts for a significant portion of healthcare spend. The potential benefits of SGLT2 inhibitors in heart failure patients stems from the cardiovascular outcome studies that were completed to show no additional cardiovascular harm in diabetic patients. The exact mechanism by which SGLT2 inhibitors provide benefit in heart failure patients is unknown but likely is a combination of multiple mechanisms. Randomized controlled trials in which only 40 to 50% of the patients had diabetes still resulted in significant heart failure benefits.8,9 The updated 2021 ACC Expert Consensus Decision Pathway does now include the consideration of SGLT2 inhibitors in patients with HFrEF and NYHA Class II to IV symptoms who are already on guideline-directed therapy with ACE-I/ARB/ARNI and beta blocker.11 It is worthy to note that much like in diabetic patients, the use of SGLT2 inhibitors in heart failure patients will be limited by the cost of the medication. If a patient is able and willing to take an SGLT2 inhibitor, the safety profile, limited drug-drug interactions, and therapeutic benefits shown in clinical trials favor its use.
By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
Quick Question: Are you compliant with the Board of Pharmacy rule that establishes the minimum size for the pharmacist’s photo that is posted in a pharmacy?
Next Questions: If you are noncompliant with this rule, will patients be negatively impacted? If you are compliant with the rule, will patients benefit?
Most Important Question: Why is this rule in place?
As you know, the Board of Pharmacy and the Department of Health have a simple goal: Protect the safety of the public. This important goal is the reason that their employees go to work each day, and it is the reason that the board members read and meet and debate and decide. This goal is noble, and the public trusts them to carry it out. Pharmacists are trusted professionals, and I believe that our diligent regulators share some of this credit. Because of their oversight, patients can trust the pharmacy profession.
How Best to Achieve Safety?
For many years, the favored approach to achieving public safety has been to create a system of robust rules that make it very clear what the pharmacists and technicians must do. These rules are detailed, and they spell out what is allowed and especially what is not allowed. This could be called the “Restrictive Approach.” The beauty of this approach is clarity: every pharmacist-in-charge can read the rules and know what is expected. Every inspector can give a clear answer about most questions, because everything is written down. The detail provides clarity and consistency, and the detail provides firm and irrefutable justification for an inspector to hold a pharmacy accountable when it is putting their patients at risk. (And trust me, there are some pharmacies out there that are not operating at the level that you and I would expect.)
At What Cost?
But is that still the best approach to patient safety? A potential unintended consequence of this approach is that the reason for the rule is obscured by the regulatory burden from the rule. In other words, the rules were written with good intentions to create a certain safe outcome, but sometimes the end result is that the complicated and detailed rules actually get in the way of safe care. Sometimes these inflexible rules limit the creative solutions that a pharmacy team has developed, or they divert so much time and energy to ‘checking the box’ that it is no longer feasible to offer cutting edge services that the patients really need. And sometimes a pharmacy can be following the specific ‘letter of the law’ and meeting the minimum standards, but are still clearly not providing good care.
Start with Why
These pharmacy rules can be very specific in “What” they require, but it is easy to forget “Why” they exist. For example, it is important for patients to know and trust their pharmacists, and so there is a requirement to post the pictures of the pharmacists. Obviously those pictures need to be large enough that the public can actually see them. And so, 20 CSR 2220-2.010 specifies the minimum size of the photo: 2” by 2”. This is a great example of a very specific rule to achieve an important “Big Picture” (sorry for the dad joke) goal. But is there another way?
Standards Based Regulation: This Changes Everything
Because of these gaps in our current approach, the Board of Pharmacy is beginning to shift towards an innovative concept called Standards Based Regulation. At a recent Board of Pharmacy webinar, Executive Director Kim Grinston gave a great description of the Board’s new approach to rule-making that they have been adopting over the past 2 years. I highly recommend that you click on the link and listen to it. It is a brief, 5 minute explanation, from 3:25 to 8:00 on the recording, and you will get a very clear understanding of the Board’s position on this exciting new approach. Some of her quotes are as follows:
“The goal of standards based regulation is to encourage professionals to use their professional judgment instead of listing very restrictive requirements that may not accommodate all scenarios.”
“The goal of standards-based regulation is to clearly identify what the safety standard is…and then allowing licensees to determine how to best meet that standard.”
“We want to get out of your way and let you be the experts that you are, and the standards based approach allows us to do that.”
This is an excellent summary of an exciting new approach. I believe that it will allow the pharmacy profession to modernize and advance. As barriers are removed, we will be able to provide our patients with the care that they need, and we will be able to focus our attention on solving the right problems and creating the right solutions to keep our patients safe.
Fill the Gap: Freedom Requires Responsibility
This is a new way of thinking! How will we handle it? Will we be able to continue to provide safe care to our patients as we are given more freedom and flexibility? This won’t be an overnight change, but as rules are changed and more flexibility is granted, I believe there are 2 things that we need to do. First, we need to raise the bar for ourselves, and make sure we are thinking about the best way to provide excellent care to our patients. Not just the bare minimum. Second, MSHP needs to step in and provide clear best practice guidance about areas where the rules have given us professional flexibility. Our Tech Check Tech guidance document is a recent example of this. We must continue to partner with our members and leaders from other organizations to paint the picture of ‘what good looks like.’
Remember, our patients trust us, and the Board of Pharmacy trusts us. Let’s rise to the occasion and demonstrate that their trust is well-placed. If we keep patient safety at the forefront of every decision that we make, I believe that we will do just that!
March 2021 Board of Pharmacy Webinar: https://vimeo.com/52010547520 CSR 2220-2.010 (Page 4 of the pdf)
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
2021 Public Policy Updates
January/February: Advocacy: Caring For Lawmakers
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
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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