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
Approval Dates: April 7, 2021 to October 1, 2021
Approved Contact Hours: 1 hour
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
Take CE Quiz
There is a growing need for new and innovative drugs due to the significant prevalence, morbidity, and mortality of type 2 diabetes mellitus. In 2018, 32.6 million people in the United States had this disease, and diabetes mellitus was the seventh leading cause of death.1 The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in clinical practice for the treatment of type 2 diabetes mellitus has steadily increased over the past few years due to its unique mechanism of action, efficacy, and effect on major adverse cardiac events.
According to the 2020 American Diabetes Association (ADA) guidelines, first-line treatment of type 2 diabetes mellitus should be a combination of maximally titrated metformin and lifestyle modifications. The next medication used is then dependent upon clinical characteristics and patient preference. Some considerations include presence of atherosclerotic cardiovascular disease (ASCVD), heart failure, chronic kidney disease (CKD), minimizing hypoglycemia risk, minimizing weight gain/promoting weight loss, and cost. The GLP-1 RA class is a reasonable choice in most of these categories; an exception is cost concerns due to availability as brand name only. Additionally, some GLP-1 RAs provide benefit in reducing cardiovascular disease events (i.e. liraglutide, semaglutide and dulaglutide) and therefore are preferred in patients with established ASCVD. This class has not shown reduction in heart failure hospitalizations, but several agents have shown renal benefits. Additionally, in patients with significant hyperglycemia that require injectable therapy, GLP-1 RAs should be considered prior to insulin in most patients.2
One potential barrier to initiation of a medication in the GLP-1 RA class is administration. Until recently, these medications were only available as subcutaneous injections that ranged from twice daily to once weekly. However, in September 2019, the first oral GLP-1 RA was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.3 Of note, oral semaglutide is available as the brand name Rybelsus®, while subcutaneous semaglutide is available under the brand name Ozempic®. Availability of an oral formulation makes GLP-1 RAs more accessible to patients who are resistant or unable to perform self-administered injections. However, not all GLP-RAs have shown the same degree of A1c lowering, weight loss, or cardiovascular benefit. Therefore, this article will focus on reviewing the pharmacology, pharmacokinetics, and clinical trial data for oral semaglutide.
Semaglutide is an analogue with 94% sequence homology to the endogenous hormone, GLP-1. It therefore binds to and activates the GLP-1 receptor. Semaglutide has increased albumin binding compared to endogenous GLP-1, which extends the half-life significantly by reducing renal clearance and protecting the drug from metabolic degradation. Semaglutide is also stabilized against degradation by the DPP-4 enzyme.4
Semaglutide achieves blood glucose reduction by glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. It also slightly delays gastric emptying in the early phase after food intake, which reduces the rate at which postprandial glucose appears in blood circulation. Due to its long half-life, both fasting and post-prandial glucose levels are reduced with semaglutide. During induced hypoglycemia, semaglutide does not inhibit counter-regulatory increases in glucagon versus placebo.4
Oral semaglutide is co-formulated with salcaprozate sodium. This aids absorption after oral administration, which mainly occurs in the stomach. Maximum concentrations of oral semaglutide occur 1-hour post-dose, and steady state exposure is achieved after 4-5 weeks of administration. Bioavailability of oral semaglutide is 0.4%-1%.4
The volume of distribution of semaglutide is approximately 8 liters. Semaglutide is highly albumin-bound (>99%).4
The elimination half-life is approximately 1 week, and semaglutide will remain in circulation for approximately 5 weeks following the last dose. The primary method of semaglutide metabolism is proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain. The primary method of secretion is through the urine and feces. Approximately 3% of the absorbed dose is excreted in the urine unchanged.4
Oral semaglutide does not significantly inhibit or induce CYP enzymes or drug transporters. However, due to it’s ability to delay gastric emptying, there is some potential for increased drug absorption of other medications. A drug interaction study showed that oral semaglutide increased exposure of levothyroxine by 33%.4
Administration and dosing:
Semaglutide should be administered at 3 mg by mouth once daily for 30 days, then 7 mg by mouth once daily. If further glycemic control is needed after another 30 days, then the dose may be increased to a maximum dose of 14 mg by mouth once daily. In order to achieve full oral absorption, semaglutide should be administered on an empty stomach at least 30 minutes before the first food, beverages, or other oral medications and with a maximum of 4 ounces of plain water. Tablets should also be swallowed whole without splitting, chewing, or crushing.4
Clinical Trial Data:
Novo Nordisk funded a series of ten clinical trials to study the safety and efficacy of oral semaglutide. These trials make up the PIONEER (Peptide InnOvatioN for Early diabEtEs tReatment) series. This series compares oral semaglutide to placebo as well as other standard of care glucose-lowering medications.5-14
Common key inclusion criteria for the PIONEER trials include adults aged 18 and older with type 2 diabetes mellitus, an A1c between either 7.0% to 9.5% or 7.0 to 10.5%, and various background glucose-lowering medications. Common key exclusion criteria included eGFR less than 60 mL/min/1.73m2, history of pancreatitis, history of proliferative retinopathy or maculopathy requiring acute treatment, personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and any medication for diabetes or obesity within previous 90 days other than those meeting inclusion criteria or short-term insulin for less than 14 days.5-14
All trials also allowed for use of additional glucose-lowering medication (other than GLP-1 RAs or DPP-4 inhibitors) if the subject discontinued the trial product, or if rescue medication was required as add-on to the trial product due to unacceptable hyperglycemia or elevated A1c. Most of the trials performed two statistical tests using the treatment policy estimand and trial product estimand. The treatment policy estimand was an intention-to-treat analysis that included all subjects regardless of additional glucose-lowering medication use or trial product discontinuation. The trial product estimand was a per-protocol analysis that estimated results using data collected prior to premature discontinuation or initiation of rescue medication. Results will be listed for the treatment policy estimand unless otherwise specified.5-14
Oral semaglutide versus placebo
PIONEER 1 was a 26-week, randomized, double-blind clinical trial comparing the efficacy of daily oral semaglutide versus placebo as monotherapy for type 2 diabetes managed with diet and exercise alone. Patients were randomized in a 1:1:1:1 ratio to oral semaglutide 3 mg, 7 mg, or 14 mg and placebo. The dose of oral semaglutide was increased every 4 weeks until the randomize dose was achieved. Rescue medications could be used if fasting blood glucose levels were greater than 240 mg/dL from weeks 8-13 or greater than 200 mg/dL from week 14 onward. The primary endpoint was change in A1c from baseline to week 26, and the confirmatory secondary endpoint was change from baseline to week 26 in body weight. The estimated treatment differences (ETD) for A1c lowering for oral semaglutide 3 mg, 7 mg, and 14 mg versus placebo were -0.6%, -0.9%, and -1.1% respectively (p<0.001). All results significantly favored oral semaglutide. For change in bodyweight, only the 14 mg dose of oral semaglutide showed significantly more bodyweight reduction than placebo with an ETD of -2.3 kg (p<0.001). The ETDs for the 3 mg and 7 mg doses versus placebo were -0.1 kg (p = 0.87) and -0.9 kg (p = 0.09).5
PIONEER 5 was a 26-week, randomized, double-blind clinical trial to compare the efficacy of oral semaglutide versus placebo as add-on to metformin and/or a sulfonylurea, or basal insulin with or without metformin in patients with type 2 diabetes mellitus and moderate renal impairment (eGFR 30-59 mL/min/1.73m2). Patients were randomized in a 1:1 fashion to either once-daily oral semaglutide 14 mg or placebo. Semaglutide was titrated every 4 weeks until the target dose was reached. Rescue medications could be used if fasting blood glucose levels were greater than 240 mg/dL from weeks 12-16 or greater than 200 mg/dL at week 17 and later. The primary endpoint was change from baseline to week 26 in A1c, with the confirmatory secondary endpoint being change in bodyweight during this timeframe. The ETD for change in A1c for oral semaglutide versus placebo was -0.8%, with an ETD of -2.5 kg for change in body weight (p<0.0001). The eGFR remained unchanged throughout the trial period. This shows that oral semaglutide is safe and effective in patients with moderate renal impairment.6
Oral semaglutide versus placebo as add-on to insulin
PIONEER 8 was a 52-week, randomized, double-blind clinical trial comparing the efficacy of oral semaglutide to placebo as add-on to insulin with or without metformin for treatment of type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1 ratio to either semaglutide (3 mg, 7 mg, or 14 mg) or placebo. Oral semaglutide was titrated every 4 weeks until target dose was achieved. The baseline insulin dose was reduced by 20% at randomization and maintained until week 8. The dose of insulin could then be altered from weeks 8 to 26 without exceeding pre-trial dosing and was freely adjustable from weeks 26 to 52. The dose of insulin could be lowered at any time if deemed appropriate. Basal insulin doses were adjusted based on self-monitored blood glucose readings measured 3 days leading up to the visit. The recommended target fasting blood glucose was 71-99 mg/dL and A1c was less than 7.0%. Adjustments were made in 2-unit increments if fasting blood sugars were 100-126 mg/dL and up to 8 units if over 162 mg/dL. Increases in insulin doses met rescue medication criteria if the dose was increased by at least 20% and maintained for 2 visits. Other criteria for rescue medication were fasting blood glucose greater than 200 mg/dL at week 16 and later, and an A1c > 8.5% at week 26 and later. The primary endpoint was change in A1c from baseline to week 26, and the confirmatory secondary endpoint was change in bodyweight at week 26. Oral semaglutide was more effective for A1c lowering at week 26, with an ETD of -0.5%, -0.9%, and -1.2% for the 3 mg, 7 mg, and 14 mg doses respectively (p<0.0001). The 3 mg, 7 mg, and 14 mg doses of oral semaglutide had significantly larger reductions in bodyweight than placebo, with an ETD of -0.9 kg (p = 0.0.0392), -2.0 kg (p = 0.0001) and -3.3 kg (p = <0.0001). At 52 weeks, all three doses of oral semaglutide demonstrated significant decreases in total daily insulin dosage versus placebo, with an ETD of -8 units (p = 0.0450), -16 units (p<0.0001), and -17 units (p<0.0001) for the 3 mg, 7 mg, and 14 mg doses respectively.7
Oral semaglutide versus SGLT-2 Inhibitor
PIONEER 2 was a 52-week, randomized, open-label clinical trial comparing the efficacy of daily oral semaglutide versus empagliflozin as add-on to metformin for type 2 diabetes mellitus. Patients were randomized in a 1:1 ratio to oral semaglutide 14 mg daily versus oral empagliflozin 25 mg daily. Empagliflozin was titrated every 4 week until the treatment dose was achieved, while empagliflozin was started at 10 mg daily then increased to 25 mg daily at week 8. Rescue medications could be used if fasting blood glucose levels were above 260 mg/dL from weeks 8 to 13, greater than 240 mg/dL from weeks 14 to 25, and greater than 200 mg/dL or A1c greater than 8.5% weeks 26 and later. The primary outcome was change in A1c while the confirmatory endpoint was change in bodyweight, both from baseline to week 26. Oral semaglutide 14 mg significantly reduced A1c more than empagliflozin 25 mg at week 26, with an ETD of -0.4% (p<0.0001). However, there was no significant difference between the two groups for bodyweight lowering at 26 weeks, with an ETD of -0.1 kg (p = 0.7593).8
Oral semaglutide versus DPP-4 Inhibitor
PIONEER 3 was a 78-week, randomized, double-blind, double-dummy clinical trial comparing the efficacy of daily oral semaglutide versus sitagliptin as add-on to metformin with or without a sulfonylurea for treatment of type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1 ratio to daily oral semaglutide (3 mg, 7 mg, or 14 mg) or daily oral sitagliptin (100 mg). Oral semaglutide was titrated every 4 weeks until the treatment dose was achieved, while sitagliptin was initiated and maintained at 100 mg daily. The primary outcome was change in A1c while the confirmatory endpoint was change in bodyweight, both from baseline to week 26. Semaglutide 3 mg significantly reduced the A1c compared to oral sitagliptin at 26 weeks with an ETD of 0.2% (p = 0.008). However, the 7 mg and 14 mg doses demonstrated significantly more A1c lowering, with an ETD of -0.3% and -0.5% respectively (p<0.001). All three doses of oral semaglutide significantly reduced bodyweight, with ETDs of -0.6 kg (p = 0.02), -1.6 kg (p<0.001), and -2.5 kg (p<0.001) for the 3 mg, 7 mg, and 14 mg doses respectively when compared to sitagliptin 100 mg daily.9
PIONEER 7 was a 52-week, randomized, open-label clinical trial comparing the efficacy of flexibly dosed oral semaglutide versus sitagliptin as add-on to stable doses of one or two glucose-lowering medications (metformin, sulfonylureas, SGLT-2 inhibitors, or thiazolidinediones for treatment of type 2 diabetes. Patient were randomized in a 1:1 ratio to either flexibly dosed oral semaglutide or sitagliptin 100 mg daily. Oral semaglutide was started at 3 mg daily, then every 8 weeks the dose could be adjusted. The current dose was continued if the A1c was less than 7.0%, and increased if 7.0% or greater. However, if moderate-to-severe nausea or vomiting occurred 3 or more days during the week prior to the visit, oral semaglutide was maintained or decreased regardless of glycemic control. Rescue medication was offered to patients with an A1c of 8.5% or higher from week 32 onward. The primary outcome was achievement of an A1c target less than 7.0% at week 52. The confirmatory secondary endpoint was change in bodyweight during the same time period. The use of flexibly dosed oral semaglutide significantly increased the proportion of patients achieving an A1c of <7.0% versus sitagliptin, with an odds ratio (OR) of 4.40 (p<0.0001). Oral semaglutide also significantly reduced bodyweight at 52 weeks, with an ETD of -1.9 kg (p<0.0001).10
Oral semaglutide versus other GLP-1 RA
PIONEER 4 was a 52-week, randomized, double-blind, double-dummy clinical trial comparing the efficacy of daily oral semaglutide versus subcutaneous liraglutide as add-on to metformin with or without an SGLT-2 inhibitor. Patients were randomized in a 2:2:1 ratio to daily oral semaglutide (14 mg) versus daily subcutaneous liraglutide (1.8 mg) vs placebo. The dose of oral semaglutide was increased at 4 week intervals until the target dose was reached, while liraglutide was started at 0.6 mg daily, then increased to 1.2 mg daily at week 1, then increased and maintained at 1.8 mg daily at week 2. Rescue medication could be used if fasting blood glucose levels were above 240 mg/dL from weeks 8 to 13, greater than 200 mg/dL from weeks 14 and later, and an A1c greater than 8.5% weeks 26 and later. The primary outcome was change in A1c from baseline to week 26, while the confirmatory endpoint was change in bodyweight. The use of oral semaglutide 14 mg daily demonstrated no difference in A1c lowering at 26 weeks with an ETD of -0.1% (p = 0.0645), but had significantly more bodyweight lowering at 26 weeks versus liraglutide 1.8 mg daily with an ETD of -1.2 kg (p = 0.0003). There was significantly more A1c and bodyweight lowering with oral semaglutide compared to placebo, with ETDs of -1.1% and -3.3 kg respectively (p<0.0001).11
PIONEER 9 was a 52-week, randomized, double-blind clinical trial to study the efficacy of oral semaglutide versus subcutaneous liraglutide as monotherapy in Japanese patients with type 2 diabetes mellitus. Patients were randomized in a 1:1:1:1:1 ratio to receive oral semaglutide daily (3 mg, 7 mg, or 14 mg) or subcutaneous liraglutide daily (0.9 mg) or placebo. The dose of oral semaglutide was titrated every 4 weeks. Subcutaneous liraglutide was started at 0.3 mg daily, then increased by 0.3 mg at weeks 1 and 2 to achieve the 0.9 mg dose, which is the maximum approved dose in Japan. The liraglutide injections were open-label, but all oral doses were blinded. Rescue medication could be added if patients had blood glucose levels above 240 mg/dL from weeks 8-13, or greater than 200 mg/dL from week 14 onwards. Rescue medication could also be given from week 26 and later if A1c was greater than 8.5%. The primary outcome was change in A1c from baseline to week 26. A secondary endpoint included change in bodyweight at week 26. At week 26, oral semaglutide demonstrated significantly more A1c reduction than placebo at all three doses, with ETDs of -1.1%, -1.5%, and -1.7% for the 3 mg, 7 mg, and 14 doses respectively (p<0.0001). Compared to liraglutide, oral semaglutide showed no difference in A1c reduction at the 3 mg and 7 mg doses, with respective ETDs of 0.3% (p = 0.0799) and -0.1% (p = 0.3942). However, there was more A1c lowering with oral semaglutide 14 mg than liraglutide with and ETD of -0.3% (p = 0.0272). At 26 week, oral semaglutide did not reduce bodyweight versus placebo at 3 mg and 7 mg doses. However, there was significantly more bodyweight reduction with the 14 mg dose, with an ETD of -1.2 (p = 0.0073). When compared to liraglutide, the 3 mg dose of oral semaglutide did not demonstrate more bodyweight reduction, but the 7 mg and 14 doses did, with respective ETDs of -0.4 kg (p = 0.3233), -0.9 kg (p = 0.0312), and -2.3 kg (p<0.0001).12
PIONEER 10 was a 52-week randomized, open-label clinical trial to compare the safety and efficacy of subcutaneous dulaglutide as add-on to monotherapy (sulfonylurea, glinide, TZD, alpha-glucosidase inhibitor, or SGLT-2 inhibitor) in Japanese patients with type 2 diabetes mellitus. Patients were randomized in a 2:2:2:1 ratio to receive either oral semaglutide (3 mg, 7 mg, or 14 mg) or subcutaneous dulaglutide weekly (0.75 mg). The dose of oral semaglutide was increased every 4 weeks until the target dose was reached. Subcutaneous dulaglutide was initiated and maintained at 0.75 mg once weekly, which is the maximum approved dose in Japan. Rescue medication could be added if fasting blood glucose levels were greater than 240 mg/dL during weeks 14-25, greater than 200 mg/dL after week 26, or an A1c greater than 8.5% at week 26 and later. The primary endpoint was number of treatment-emergent adverse events during exposure to the study drug (Table 3). Change in A1c and bodyweight from baseline to week 26 were also measured as secondary outcomes. Compared to dulaglutide, oral semaglutide 3 mg demonstrated less A1c lowering with an ETD of 0.4% (p = 0.0026), similar A1c lowering for the 7 mg dose with an ETD of -0.1% (p = 0.2710), and more A1c lowering at the 14 mg dose with an ETD of -0.4% (p = 0.0006). There was no significant difference in bodyweight lowering for the 3 mg dose of oral semaglutide, but there was significant decreases in bodyweight compared to dulaglutide for the 7 mg and 14 mg doses, with ETDs of -0.5 kg (p = 0.2632), -1.3 kg (p = 0.0023), and -2.5 kg (p<0.0001) respectively.13
Oral Semaglutide and Cardiovascular Outcomes
PIONEER 6 was an event-driven, randomized, double-blind, placebo-controlled clinical trial to investigate cardiovascular outcomes on treatment with once-daily oral semaglutide versus placebo as add-on to standard of care for patients with type 2 diabetes mellitus. Patients were included in this study if they were 50 years of age or older and had established cardiovascular disease (CVD) or CKD or if they were 60 years of age or older and had cardiovascular risk factors only. Key exclusion criteria were treatment with an GLP-1 RA, DPP-4 inhibitor, or pramlintide within 90 days prior to screening; New York Heart Association class 4 heart failure; planned coronary-artery, carotid-artery, or peripheral-artery revascularization; myocardial infarction, stroke, or hospitalization for unstable angina or transient ischemic attack within 60 days before screening; long-term or intermittent hemodialysis or peritoneal dialysis, or severe renal impairment (eGFR <30 mL/min/1.73 m2); and proliferative retinopathy or maculopathy resulting in active treatment. The primary outcome was time from randomization to the first occurrence of a major adverse cardiovascular event (composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The hazard ratio for the primary outcome was 0.79 (p<0.0001 for noninferiority, p = 0.17 for superiority). Therefore, oral semaglutide has shown cardiovascular safety, but has not demonstrated cardiovascular benefit.14 However, an additional trial is currently underway to further investigate the cardiovascular effects of oral semaglutide with a larger patient population for a longer follow-up period. This trial is titled “A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL).” However, the study completion is not expected until 2024.15
A summary of adverse effects is reported in table 3. The most common reported adverse events were consistent with those seen by the injectable GLP-1 RAs, including gastrointestinal upset (nausea, vomiting, diarrhea). Rates of severe or blood-glucose confirmed hypoglycemia were low, with most events occurring in trials where patients were receiving background glucose-lowering agents with known risk of hypoglycemia (sulfonylureas, insulin).2,5-14
Oral semaglutide benefits include A1c and bodyweight reduction, both in comparison to placebo and other standard of care treatment regimens. The reductions in A1c and bodyweight are dose-dependent, and based on the results of the PIONEER series, all patients should be titrated up to a minimum effective dose of 7 mg. Small benefit from the 3 mg may still be seen during the titration period, which is used to minimize GI side effects. The results of the PIONEER 7 trial also showed that based on tolerability and blood glucose control, flexible dosing of semaglutide is a reasonable treatment strategy.5-14
At 26 weeks, oral semaglutide at the maximum dose of 14 mg daily was more effective for A1c reduction than placebo, oral empagliflozin 25 mg daily, oral sitagliptin 100 mg daily, titration of current insulin regimen, subcutaneous liraglutide 0.9 mg daily in Japanese patients, and subcutaneous dulaglutide 0.75 mg weekly in Japanese patients. Oral semaglutide 14 mg daily had similar A1c lowering when compared to subcutaneous liraglutide 1.8 mg daily.5-14
Oral semaglutide 14 mg daily significantly reduced bodyweight at 26 weeks when compared to placebo, oral sitagliptin 100 mg daily, further titration of background insulin regimen, subcutaneous liraglutide 1.8 mg daily, subcutaneous liraglutide 0.9 mg daily in Japanese patients, and subcutaneous dulaglutide 0.75 mg weekly in Japanese patients. Similar bodyweight reductions were seen with oral semaglutide 14 mg daily and oral empagliflozin 25 mg daily at 26 weeks.5-14
One major limitation of implementation of this new dosage form is the lack of demonstrated cardiovascular benefit that has been seen in other injectable GLP-1 RAs, including injectable semaglutide.2 However, use may increase significantly if the SOUL trial shows cardiovascular benefit.15 Currently, oral semaglutide should be considered in patients who are averse to injectable formulations. While oral semaglutide demonstrated cardiovascular safety in the PIONEER 5 trial, the injectable GLP-1 RAs and oral SGLT-2 inhibitors that have demonstrated cardiovascular risk reduction would be preferred in patients with clinical ASCVD. Cost considerations are also important, as use is limited to patients with good insurance coverage or those that qualify for patient assistance programs. Patients started on oral semaglutide should be counseled on potential gastrointestinal side effects and its unique administration instructions.
*Exact results not reported for change in bodyweight or change in A1c
Abbreviations: AGI, alpha-glucosidase inhibitors; BAS, basal; BMI, body mass index; BOL, bolus; DUL, dulaglutide; EMP, empagliflozin; ETD, estimated treatment difference; FLEX, flexible-dosing; GLI, glinides; INS, insulin; LIR, liraglutide; MET, metformin; PLA, placebo; SEM, semaglutide; SGLT-2i, Sodium-glucose co-transporter-2 inhibitor; SIT, sitagliptin; SU, sulfonylureas; TZD, Thiazolidinediones; T2DM, type 2 diabetes mellitus
Abbreviations: MAX, maximally tolerated dose; PLA, placebo; SEM, semaglutide
Abbreviations: AGI, alpha-glucosidase inhibitors; BAS, basal; BMI, body mass index; BOL, bolus; DUL, dulaglutide; EMP, empagliflozin; ETD, estimated treatment difference; FLEX, flexible-dosing; GLI, glinides; INS, insulin; LIR, liraglutide; MET, metformin; PLA, placebo; SEM, semaglutide; SGLT-2i, Sodium-glucose co-transporter-2 inhibitor; SIT, sitagliptin; SU, sulfonylureas; TZD, Thiazolidinediones
By: Hannah Michael, PharmD, PGY1 Pharmacy Resident – University of Missouri Health Care
Current guideline therapy provided by the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes (ISPAD) highlights that type 1 diabetes accounts for most diabetic diagnoses for children and adolescents.1-3 Due to the pharmacokinetic differences of the available types of insulins and highly variable pharmacodynamics in the pediatric population, data on these regimens are not transferable from the adult population to pediatric patients. Knowing this, it is important to highlight effective insulin treatment for this population as well as the differences in administration considerations to provide the most appropriate therapeutic regimens for all age groups with diabetes.
As in the adult population, glycemic goals and targets are just as essential in effectively assessing control of diabetes in children and adolescents to prevent acute and long-term complications, including microvascular and macrovascular complications. Diabetic nephropathy is a known major contributor to morbidity and mortality risk, and although the advanced stages of this occurrence are rare in children and adolescents, alterations in renal function develop quickly after diabetes diagnosis and often progress during puberty.4 In addition, it has been demonstrated that adolescents are at a higher risk of developing vision-threatening retinopathy when compared with adults. These examples of physiologic and developmental differences stress the importance of early identification of diabetes in this patient population as well as effective initial and lifelong insulin therapy.
Hemoglobin A1c levels remains an essential tool to assess long-term glycemic control and to prevent chronic complications of diabetes. A goal of <154 mg/dL (<7.0%) is recommended for many children, however, a less stringent goal of <168 mg/dL (<7.5%) may be appropriate depending on the presence of the following factors: the ability to articulate symptoms of hypoglycemia, individuals who have hypoglycemia unawareness, patients that cannot obtain/use analog insulins or lack access to insulin-delivery technologies, patients who cannot check blood glucose levels regularly, or patients who have nonglycemic factors that increase A1c.5 To achieve a goal of <7.5%, blood glucose targets include a pre-meal of 90-130 mg/dL, post-meal of 90-180 mg/dL, and pre-bed range of 90-150 mg/dL. Effective monitoring for these patients includes frequent blood glucose checks up to six to ten times per day, including before meals and snacks, at bedtime, and as needed for exercise, driving, and/or presence of hypoglycemia symptoms. Notably, better glucose control for pediatric and adolescent populations has been demonstrated with multiple daily injections and insulin pumps when compared to a twice daily regimen. Use of newer technologies for insulin delivery and monitoring, such as sensor-augmented and/or automated insulin pumps and continuous glucose monitoring (CGM), in conjunction with insulin analogs, have all been shown to reduce the risk of hypoglycemia with associated lower A1c targets.
Other necessary considerations for the pediatric and adolescent population include distinctions in insulin absorption and insulin requirements. Insulin activity has particular variability in children, as young children with less subcutaneous fat will have faster absorption, and, inversely, a higher percentage of subcutaneous fat will result in slower absorption. Absorption has shown to be quick (~15 minutes) when administered in the abdomen, intermediate (~20 minutes) with lateral arm injection, and slow (~30 minutes) for both front/lateral position of the thigh and the lateral upper quadrant of the buttocks. Insulin requirements evolve as these patients continue to grow: In the partial remission phase, or the honeymoon phase, where endogenous insulin is produced following the initial introduction of insulin treatment, a total daily dose of <0.5 units/kg/day may be required, whereas for prepubertal children, insulin dosing requirements may be between 0.7 to 1 units/kg/day, and during puberty, requirements may reach up to 2 units/kg/day. It is also interesting to note that the mechanisms which invoke the dawn phenomenon, or a rise in morning blood glucose levels, including increased nocturnal growth hormone secretion and increased resistance to insulin, are even more significant in puberty. Because of this, it may be appropriate to utilize an intermediate acting insulin later in the evening or longer acting basal insulin at bedtime for patients who do not utilize an insulin pump.
For a comprehensive comparison, the various insulins with considerations for pediatrics and adolescents is provided in the table below.1,2,3,6
Diabetes represents a complex disease state which requires extensive knowledge and practice in the individualization of treatment. These special considerations are made even more apparent in the pediatric and adolescent population as the continued growth and development of these patients provides multiple opportunities for adjustments in insulin treatment. Furthermore, understanding the intricacies of insulin therapy management is a crucial step in ensuring safe and effective therapy when optimizing each patient’s regimen.
Diabetes represents a complex disease state which requires extensive knowledge and practice in the individualization of treatment. These special considerations are made even more apparent in the pediatric and adolescent population as the continued growth and development of these patients provides multiple opportunities for adjustments in insulin treatment. Furthermore, understanding the intricacies of insulin therapy management is a crucial step in ensuring safe and effective therapy when optimizing each patient’s regimen.
By: Abbey Jin, PharmD Candidate 2021, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Laura Challen, PharmD, MBA, BCPS, BCACP, Associate Professor, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Clinical Pharmacist, JFK Clinic Mercy Hospital-St. Louis
Severe hypoglycemia, a severe and potentially fatal event that requires intervention, has historically been treated with injectable glucagon that requires reconstitution prior to injection. Baqsimi® and Gvoke® are new United States Food and Drug Administration (FDA)-approved glucagon products for severe hypoglycemia that provide alternative preparations. Eli Lilly and Company’s Baqsimi® nasal powder is an intranasal glucagon delivery device, approved on July 24th, 2019.1 It is the first non-injectable glucagon therapy for emergency treatment in severe hypoglycemia.1 Xeris Pharmaceutical’s Gvoke® is a glucagon injection for treatment of severe hypoglycemia, approved on September 10th, 2019.2
Hypoglycemia can be differentiated into three classifications: levels 1, 2, and 3. Level 1 (mild hypoglycemia) is defined as blood glucose levels greater than or equal to 54 mg/dL up to 69 mg/dL. Level 2 (moderate hypoglycemia) is defined as blood glucose levels less than 54 mg/dL. Level 3 (severe hypoglycemia) is defined as hypoglycemia that results in altered physical and/or mental state and needing intervention. It is recommended that any patients who experience level 2 or 3 hypoglycemia travel with a glucagon device3 for administration by a caregiver in case the patient becomes unresponsive.4 If the patient is conscious, glucose can be self-administered orally.4
Indication, Dosage, Administration, Storage and Cost
Baqsimi® is indicated for severe hypoglycemia treatment in patients with diabetes who are 4 years of age and older. It is designed to be absorbed via the nasal mucosa and does not need to be reconstituted prior to intranasal administration.3 The recommended dosage and route for all patients is 3 mg (one actuation) intranasally (in one nostril).5 A caretaker should insert the tip of the device into one nostril and press the plunger. After the dose is administered, the caregiver should call emergency medical services. If the patient does not respond to the first 3 mg dose, then another 3 mg dose from an un-used Baqsimi® device can be administered after 15 minutes.5 Baqsimi® is available as a carton containing one or two devices of a single 3 mg dose. It is recommended to store Baqsimi® devices at temperatures up to 86oF.3 Per Micromedex® Red Book, the wholesale acquisition cost (WAC) package price is $280.80 for the Baqsimi® One PackTM.6
Gvoke® is indicated for the treatment of severe hypoglycemia in patients with diabetes who are 2 years of age and older. Two Gvoke® products are available for use: Gvoke® pre-filled syringe (PFS) 0.5 mg/0.1 mL or 1 mg/0.2 mL and Gvoke® HypoPen 0.5 mg/0.1 mL or 1 mg/0.2 mL autoinjectors.7 Gvoke® products are dispensed as single doses and do not require reconstitution prior to administration.4 The recommended dose and route for patients 2 to under 12 years of age and who weigh less than 45 kg is 0.5 mg subcutaneously. The recommended dose and route for pediatric patients who weigh 45 kg and over or who are 12 years of age and older is 1 mg subcutaneously. Areas recommended for injection are the outer, upper arm, outer thigh, or lower abdomen. Similar to Baqsimi®, following a dose, emergency medical services should be called. If a patient is unresponsive after one dose, a second dose can be administered 15 minutes later.4 Gvoke® is to be stored at room temperatures ranging from 68oF to 77oF.7 Per Micromedex® Red Book, the WAC package price for the Gvoke® HypoPen and Gvoke® PFS 1 packs are both $280.80, the same price as Baqsimi®.8,9
Drug Interactions, Adverse Drug Events, Contraindications, Use in Pregnancy and Lactation
Gvoke® and Baqsimi® may interact with indomethacin, interfering with their ability to increase blood glucose. They also have potential drug interactions with beta-blockers, which can lead to increases in blood pressure and pulse. Gvoke® and Baqsimi® can increase warfarin’s anticoagulation effects.3,7
For Baqsimi®, the most common potential side effects include headache; vomiting and nausea; nasal discomfort and congestion; watery, itchy, or red eyes, and itchy throat.5 Gvoke®’s most common side effects for adults include headache, nausea, vomiting, and injection site edema. Gvoke®’s most common side effects for pediatric patients include headache, nausea, vomiting, pain in the abdomen, injection site reaction and discomfort, urticaria, and hypo- and hyperglycemia.10 Both are contraindicated in patients with a medical history of pheochromocytoma, insulinoma, and glucagon hypersensitivity.5,10
From case reports and observational studies, there has not been a reported link between administration of glucagon in pregnant women and risk of miscarriage, defects, or other negative outcomes for the fetus and mother.5,10 There is currently no data on glucagon being present in breast milk, but glucagon is hypothesized to be of no danger to infants since it can be broken down in their gastrointestinal tracts.3,7
Baqsimi® Clinical Trials Review
Intranasal glucagon has been studied in three clinical trials. In an open-label, randomized, crossover, and two-period trial, Suico et al. showed that all of the 66 type I diabetes mellitus (T1DM) patients who were administered intramuscular and nasal glucagon experienced a rise in the plasma glucose to at least 70 mg/dL or a rise of at least 20 mg/dL from baseline in 30 minutes of administration. The results showed that 3 mg nasal glucagon was non-inferior to 1 mg intramuscularly administered glucagon with a 0.0% treatment difference (-1.52%, 1.52%).11
Rickels et al. conducted a randomized, crossover, non-inferiority trial with 75 adult T1DM patients. The study showed that 98.7% of the 3 mg intranasal and 100% of the 1 mg intramuscular glucagon visits had a rise in plasma glucose to 70 mg/dL or greater or an increase by 20 mg/dL or greater from baseline within 30 minutes of administration (98.7% vs. 100%; CI 4.0%).12
Sherr et al. conducted a randomized, crossover trial studying the rise in blood glucose of T1DM patients (4 to less than 8 years of age and 8 to less than 12 years of age) who received either 2 or 3 mg intranasal glucagon at two different times vs. one weight-based dose of intramuscular glucagon. Children under 25 kg received a 0.5 mg dose. Children weighing at least 25 kg received a 1 mg dose. Sherr et al. also studied patients 12 to less than 17 years of age. They were administered a 1 mg intramuscular dose of glucagon during one time and a 3 mg intranasal glucagon at another time. The results showed that 58 out of 59 intranasal and all 24 intramuscular glucagon administrations resulted in a glucose rise greater than or equal to 25 mg/dL from baseline within 20 minutes of administration. The study supported use of 3 mg intranasal glucagon for pediatric patients ranging from 4 to less than 17 years. Intramuscular and intranasal glucagon administrations reported nausea at 67% and 42%, respectively (p=0.05).13
Gvoke® Clinical Trials Review
Gvoke® has been studied in 2 multicenter crossover studies of adult T1DM populations (18 to 74 years). One study was double-blinded with 80 participants. The other study was single blinded with 81 participants. A single-arm trial of 31 T1DM pediatric patients from 2 to under 18 years of age was also conducted. Nearly all (98.7%) of the adult patients that were administered Gvoke® and all (100% ) of the adult patients that were administered a Glucagon Emergency Kit® had a rise in blood glucose to more than 70 mg/dL or an increase of 20 mg/dL or more from baseline 30 minutes post administration. Gvoke®’s mean time to the aforementioned outcomes was 13.8 minutes while the Glucagon Emergency Kit® was 10 minutes. In the pediatric arm, 30 out of 30 (100%) of the evaluated patients experienced a rise of greater than or equal to 25 mg/dL in blood glucose.10
From the total of 154 adult patients who were administered Gvoke®, the most common adverse reactions were nausea, vomiting, edema at injection area, and headache. For the pediatric population (n=31), most common adverse reactions experienced by all age groups were nausea, hypoglycemia, and vomiting.10
Comparison with Previous Glucagon Products
Unlike previous glucagon injections, both Gvoke® and Baqsimi® do not require reconstitution prior to administration.3,4 This can result in saving precious minutes during the event of a severe hypoglycemic attack. This may also be easier for a caretaker to administer compared to GlucaGen® and Eli Lilly and Company’s glucagon due to lack of reconstitution. Preparation and administration of Gvoke® was also shorter by 60-70 seconds versus the Glucagon Emergency Kit®.4 Novo Nordisk’s GlucaGen® HypoKit®’s WAC package price is $293.05 each, slightly costlier than Baqsimi® and Gvoke®.14 Fresenius’s Glucagon Emergency Kit®’s WAC package price is $279.80 while Eli Lilly and Company’s Glucagon Emergency Kit®’s WAC package price is $280.80, comparable to Gvoke® and Baqsimi®.15
Gvoke® and Baqsimi® are new glucagon devices with shorter preparation time and comparable pricing to those currently available on the market.3-10,14,15 However, as with all new products, time will gauge their popularity and preference amongst patients with diabetes.
By: Miriam Bisada, PharmD Candidate 2021 and Yostena Khalil, PharmD Candidate 2022; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis.
Mentor: Erica F. Crannage, Pharm.D., FCCP, BCPS, BCACP; Associate Professor, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Clinical Pharmacist Mercy Clinic-Family Medicine
Diabetes mellitus is a disease of abnormal carbohydrate metabolism related to relative or absolute impairment in insulin secretion. Pharmacogenomics, the study of drug responses impacted by genes, is a drastically growing field especially after the Human Genome Project (HGP) mapped DNA for the entire human genome in 2000. However, the clinical utilization of pharmacogenomics has been limited to severe idiosyncratic adverse drug reactions, variations in drug metabolism, and chemotherapy interventions.1 The International Diabetes Foundation estimated 463 million in the world were diagnosed with diabetes in 2019 and predicted 578 million by 2030.2 Through the efforts of the Genome-Wide Association Study (GWAS), 50 genetic loci were found associated with various glycemic traits and at least 90 loci with type 2 diabetes.3 Over the past 20 years, many monogenic forms of diabetes have been identified which have great response to targeted treatments. However, diabetes remains a complex polygenic disease with many variants contributing to the risk and prevalence.
Type 1 diabetes mellitus (T1DM) is likely to be triggered at an early age by the development of autoantibodies against islet cells, insulin, and/or glutamic acid decarboxylase.4 The greater the number of types of beta cell autoantibodies, the higher the risk of progression of diabetes.5 There are several genetic mutations that have been identified which increase a patient’s likelihood of developing type 1 diabetes mellitus. A patient is more likely to develop type 1 diabetes mellitus if they have variants of the HLA-DQA1, HLA-DQB1, and HLA-DRB1 genes.6 These genes belong to the human leukocyte antigen (HLA) complex which is a group of proteins encoded by the MHC gene complex, a large locus of vertebrate DNA, in humans. These proteins are responsible for the regulation of the immune system, which aids our immune system to recognize foreign substances and differentiate them from our own. Along with genetics, environmental factors, such as a virus, can also trigger the progression of type 1 DM.7
Unlike T1DM, diet and exercise can significantly decrease the development of diabetes type 2 (T2DM), but these measures alone have not been effective at curtailing the increase in prevalence of T2DM, especially with the growing obesity pandemic.8 T2DM is an insulin resistant disease and patients with a first-degree diagnosed relative are three times likely at risk for T2DM. Genes that are candidates for disease susceptibility involve pancreatic β cell function, insulin action/glucose metabolism, or other metabolic conditions that increase T2DM risk. There are more than 50 candidate genes affecting T2DM, but only few are promising for future use in clinical practice; PPARγ, ABCC8, KCNJ11, and CALPN10 mutations are associated with T2DM. CALPN10, encodes intracellular calcium dependent cysteine protease, has been linked with T2DM diagnosis.
Metformin is the first-line treatment of T2DM but causes gastrointestinal (GI) effects in about 10% of patients. Patients had better response to metformin with reduced GLUT2 transport (up to 0.5% HbA1c); however, side effects were more pronounced in patients with reduced function of SLC22A1 genes had 2.4 times higher odds (95% confidence interval (CI) =1.48–3.93, P=0.001) of developing GI side effects.9 There was also a 0.33% greater reduction in HbA1c for patients taking metformin that carried an C allele for SLC2A2 single-nucleotide polymorphism rs8192675 (reduces the expression of GLUT2 that alters metformin action) than patients that didn’t.8 SLC22A1 (encodes OCT1 transporter), SLC29A4 (encodes PMAT transporter), and SLC6A4 (encodes serotonin transporter) genes are expressed in human gut responsible for transporting of metformin. The GWAS found that patients with three or more alleles of these genes affect their tolerance of metformin with odds of 2.15 (95% CI, 1.2–4.12).8 However, current metformin pharmacogenomics data has a 3 evidence level which means it is not clinically practical yet as the results have not been replicated or have a clear evidence based association.12 Patients with loss-of-function variants in CYP2C9 have higher exposure to sulfonylureas and thus experience a greater glycemic response.10 ATP binding cassette, subfamily C, member 8 (ABCC8), has a high affinity for sulfonylurea receptors along with KCNJ11 as both regulate hormones released like insulin and glucagon in beta cells. Peroxisome proliferator-activated receptor-γ (PPARγ) is widely studied because of its adipocyte and lipid metabolism effects as one form can decrease insulin sensitivity and increase T2DM risk. PPARγ is the therapeutic target of thiazolidinediones (TZD) class of medications. Variants in PPARγ where patients carry alleles experienced an increased glycemic response to TZDs with odds of 2.32 ([95% CI = 1.10–4.87] P = 0.03).9 Patients with altered CYP2C8 and SLCO1B1 activity have a different response to pioglitazone and rosiglitazone in glycemic response and side effects that might be driven from genotype-based differential drug responsiveness.13 Overall, TZD have a grade C level of evidence on the CPIC guidelines and a 3 PharmGKB level of evidence so there are no prescribing actions because dosing based on PGX data has weak evidence or unclear.12 Unlike T1DM, T2DM has defined genes linked to drug mechanisms like ABCC8, which encodes the high-affinity sulfonylurea receptor, and KCNJ11, both of which are known to be ATP-sensitive potassium channels to regulate insulin and glucagon release.
An uncommon subtype of T2DM known as Maturity Onset Diabetes of the Young (MODY) occurs before the age of 25 and accounts for <5% of all the T2DM cases.7 Currently, there are six forms of MODY which are caused by mutations in GCK, HNF, and NEURODI genes involved in metabolism of glucose, regulation of insulin, glucose transport, and development of fetal pancreas.8 It was thought that MODY3 severe diabetes, to be T1DM, but changed to T2DM diagnosis once realized that the mutations in MODY3 are sensitive to sulfonylureas. Given the autosomal dominant inheritance of MODY, early genetic diagnosis may reduce long-term complications. Revealing genetic mutations could help us better diagnose and personalize treatments.
With a growing focus on genetic studies and pharmacogenomics, our understanding is expanding to where we could match treatments based on a patient's genomic makeup in the near future. A world of personalized medicine practice through global research and data-based medicine could reduce healthcare cost with more rapid identification of needed preventative strategies and/or ideal treatments. The Type 1 Diabetes TrialNet has a strategy to gene test high risk patients and use preventive measures to avoid onset of disease since T1DM is not curable.8 Early findings remain promising; however, we are not at a point where the benefits of using genetic information for diabetes is robust enough to be generalizable to all patients and is outweighed by the cost.8 Although genetic links to diseases, drug mechanisms and effects have been reported in literature, more comprehensive robust studies are needed before pharmacogenomics for diabetes can be utilized in routine clinical disease management. Pharmacists, as interprofessional team members with a goal to optimize medications, should continue to contribute to and monitor future pharmacogenomic research efforts to fulfill the promise of the Human Genome Project and find consistent results across populations for genetic conclusion to better our patient outcomes.