Tera Raymond, PharmD; PGY-1 Pharmacy Resident: Kansas City VA Medical Center
Keith Anderson, PharmD, BCPP: Kansas City VA Medical Center
Rachel Walker, PharmD, BCPP: Kansas City VA Medical Center
Parkinson’s disease, a chronic and progressive neurologic disorder, afflicts nearly 10 million people worldwide.1 The characteristic motor symptoms of Parkinson’s disease, including bradykinesia, muscular rigidity, resting tremor, and postural instability, are thought to be caused by a loss of dopamine producing cells, along with decreased dopamine concentrations within the brain.2 Many of the common therapies available for Parkinson’s disease work to alleviate these motor symptoms through either dopamine agonism or blockade of dopamine metabolism in the brain. Despite medication strategies being available to manage bothersome motor symptoms, no therapies exist for the prevention or cure of Parkinson’s disease. While medication therapies are available for managing the burden that may arise with progressive motor symptoms, even fewer treatment options are available for non-motor symptoms, which are often reported by patients and caregivers as more troublesome and distressing.2
Non-motor symptoms, such as depression, dementia, and sleep disturbances are associated with a decreased quality of life and increased lifestyle strain to patients and their caregivers than the more well-known motor symptoms.3 Psychosis is the most frequently reported non-motor symptom, and is often the most debilitating, affecting more than 50% of patients with Parkinson’s disease.4,5 The clinical presentation may vary, but is generally characterized by features such as visual and presence hallucinations and less commonly delusions and illusions.6 Previously, there had been no standard diagnostic criteria for Parkinson’s disease psychosis. However, in 2007 a new set of criteria was proposed by the National Institutes of Neurological Disorders and Stroke-National Institute of Mental Health (NINDS-NIMH).7 This new criteria defines Parkinson’s disease psychosis as the presence of illusions, hallucinations, delusions, or a false sense of presence that is recurrent or continuous for one month after the onset of Parkinson’s disease, and cannot be attributed to another cause.7
The underlying pathophysiology of Parkinson’s disease psychosis is associated with three main neurotransmitter systems: dopaminergic, cholinergic, and serotonergic.3 The primary hypothesis for psychosis previously revolved around the overstimulation of dopamine receptors in the brain, and subsequently involved dose reduction of dopaminergic medications as initial therapy for psychosis.3 However, several observations have shown no difference in resolution of psychotic symptoms with dopaminergic medication adjustments.3 Additional neurotransmitter pathways have become entwined in the mechanism, specifically an imbalance of anticholinergic and dopaminergic systems in the striatum and a loss of serotonergic neurons and dysregulation in the brain.3 In addition, other factors of Parkinson’s disease outside of neurotransmitters may also play a part in the development of psychosis, including advanced Parkinson’s disease, patient age, and cognitive decline.3 Despite a proposed mechanism for the development of psychosis and the neurotransmitters thought to play a part in developing symptoms, the therapies available for treatment are sparse.
Historically, antipsychotic medications have been the primary treatment modality studied in regards to managing Parkinson’s disease psychosis. Prior to initiating or adjusting medication therapy for symptom management, any potential underlying causes for acute psychosis should be addressed, such as including acute infections or ingestion of stimulants.8 Medication adjustments and tailoring of therapies to remove any non-essential medications that may exacerbate or worsen psychosis symptoms, such as anticholinergic medications or benzodiazepines, is a key first step.9 This may also require a step-wise approach to remove dopaminergic medications, while still maintaining motor function.7 At this step in therapy, patients and caregivers may have to consider initiation of additional medications if psychosis symptoms are not effectively managed with adjustments of dopaminergic medications.7
Currently, the medications commonly utilized in Parkinson’s disease psychosis include quetiapine and clozapine. However, more recently, pimavanserin has been studied as a novel therapy for this unique niche of patients.3 While these antipsychotics are the mainstay of therapy, it is important to note that the second generation antipsychotics still carry a black box warning in patients with dementia in regards to concern for causing sudden death.9 First generation antipsychotics are often not utilized in this population due to lack of data supporting improvement of psychosis symptoms, and the tendency to cause worsening of motor symptoms.10 Second generation antipsychotics, including olanzapine, aripiprazole, and risperidone have also been studied. The data is limited supporting the use of these medications to improve psychosis symptoms and have not shown statistical significance for symptom relief but instead have shown a worsening of motor symptoms.3 In patients with both psychosis and dementia, cholinesterase inhibitors have also been studied. Although data from these trials show improvement in cognitive function, there was no significant changes in psychotic symptoms.3
Clozapine is the most heavily-studied therapy for Parkinson’s disease psychosis, with evidence to support its use in minimizing psychosis symptoms, including hallucinations, due to its unique mechanism of action involving all three neurotransmitters affected in psychosis.3,7 Although recommended in guidelines and showing promise in clinical trials, clozapine requires extensive monitoring and frequent laboratory draws due to the risk of agranulocytosis.3,11 At the lower doses utilized in Parkinson’s disease, clozapine has not been shown to cause long-term metabolic problems as seen with higher doses. However, other side effects, such as hypotension and sedation, are still commonly encountered.9 While effective for symptom control and with little to no worsening of motor symptoms, the intense monitoring makes it a less favorable choice for initial management.9 Despite the data that supports clozapine’s use in therapy, quetiapine is often utilized as first-line therapy. Quetiapine is similar to clozapine in structure and mechanism, but with less frequent required monitoring.9 Although quetiapine has been studied in the treatment of Parkinson’s disease psychosis, evidence is lacking regarding its efficacy in managing psychosis symptoms, specifically hallucinations.3 Regardless of the data, use of quetiapine is still recommended by the American Academy of Neurology guidelines and has not been shown to worsen motor symptoms.11
Pimavanserin, a novel therapy, has recently received FDA approval for hallucinations and delusions associated with Parkinson’s disease psychosis.12 Pimavanserin acts via a combination of selective serotonin antagonism and inverse agonism, and demonstrated beneficial results in clinical trials by reducing non-motor symptoms associated with psychosis, including minimization of hallucinations and delusions.12 When compared to placebo, pimavanserin did not show an effect on worsening motor function, and was the first medication to show a beneficial effect in reducing caregiver burden.12,4 The most common adverse reactions noted in clinical trials were nausea, constipation, peripheral edema, and confusion. Post-marketing monitoring has also noted adverse effects including somnolence, rash, and reactions similar to angioedema.12 Pimavanserin is classified as an atypical antipsychotic and still carries a warning for increased mortality in elderly patients with dementia and risk for increased QT prolongation, similar to warnings and precautions with other antipsychotics.12
Pimavanserin shows potential as a novel agent for management of non-motor symptoms associated with Parkinson’s disease psychosis. However, more data and clinical trials are needed comparing pimavanserin versus current treatments to determine its appropriate place in therapy. In addition, the guidelines for non-motor symptoms in Parkinson’s disease by the American Academy of Neurology have not been updated since 2006. Consequently, quetiapine and clozapine are still recommended as first-line agents.11 Despite the lack of support within guidelines at this time, pimavanserin shows promise for use in patients suffering from hallucinations and delusions caused from Parkinson’s disease. With less rigorous monitoring and clinical data supporting its effect on psychosis, pimavanserin may soon find a place in the guidelines as recommended therapy for Parkinson’s disease patients.
1. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014 Apr 23-30;311(16):1670-83. doi: 10.1001/jama.2014.3654.
2. Combs BL, Cox AG. Update on the treatment of Parkinson's disease psychosis: role of pimavanserin. Neuropsychiatr Dis Treat. 2017 Mar 8;13:737-744. doi: 10.2147/NDT.S108948. eCollection 2017.
3. Goldman JG1, Vaughan CL, Goetz CG. An update expert opinion on management and research strategies in Parkinson's disease psychosis. Expert Opin Pharmacother. 2011 Sep;12(13):2009-24. doi: 10.1517/14656566.2011.587122. Epub 2011 Jun 2.
4. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014 Feb 8;383(9916):533-40. doi: 10.1016/S0140-6736(13)62106-6. Epub 2013 Nov 1.
5. Taddei RN, Cankaya S, Dhaliwal S, et al. Management of Psychosis in Parkinson's Disease: Emphasizing Clinical Subtypes and Pathophysiological Mechanisms of the Condition. Parkinsons Dis. 2017;2017:3256542. doi: 10.1155/2017/3256542. Epub 2017 Sep 12.
6. Friedman JH. Parkinson disease psychosis: Update. Behav Neurol. 2013 Jan 1;27(4):469-77. doi: 10.3233/BEN-129016.
7. Wilby KJ, Johnson EG, Johnson HE, Ensom MHH. Evidence-Based Review of Pharmacotherapy Used for Parkinson's Disease Psychosis. Ann Pharmacother. 2017 Aug;51(8):682-695. doi: 10.1177/1060028017703992. Epub 2017 Apr 6.
8. Frei K, Truong DD. Hallucinations and the spectrum of psychosis in Parkinson's disease. J Neurol Sci. 2017 Mar 15;374:56-62. doi: 10.1016/j.jns.2017.01.014. Epub 2017 Jan 5.
9. Chang A, Fox SH. Psychosis in parkinson’s disease: epidemiology, pathophysiology, and management. Drugs. 2016 Jul;76(11):1093-118. doi: 10.1007/s40265-016-0600-5.
10. Weintraub D, Chen P, Ignacio RV, et al. Patterns and trends in antipsychotic prescribing for Parkinson disease psychosis. Arch Neurol. 2011 Jul;68(7):899-904. doi:10.1001/archneurol.2011.139.
11. Miyasaki JM, Shannon K, Voon V, et al. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006 Apr 11;66(7):996-1002.
12. Neuplazid [package insert]. San Diego, CA: ACADIA Pharmaceuticals Inc.; 2017.
Lara Kerwin, PharmD and Roxane Took, PharmD
Millennial Assistant Professors of Pharmacy Practice at the St. Louis College of Pharmacy
The “411” on Millennials
...as People:Students of the “Millennial Generation” are born between the years of 1980-2000. This group also goes by the name of “Gen Y,” “Nexters,” and the “Me, Me, Me Generation.”1-3 Historic events that have occurred during and impacted the way they view the world include September 11th, 2001; legalization of gay marriage, and the election of the first African American president of the United States of America. Millennials have grown up in the age of technology. They have a reputation for being lazy, entitled narcissists who “live with their parents but will save us all!”1
Millennial students are goal-oriented multi-taskers. They want context and to understand purpose behind the task at hand.3,4,14 They care more about collaborative, active learning in groups than studying. These learners may be needy for feedback and anticipate immediate responses from their instructors. Millennials appreciate scheduling flexibility as well as customization of learning experiences to their goals and interests.3-5 Having a strong predisposition toward praise for any work and that they do contributes to the generalization that Millennials have poor work ethic, lack critical thinking skills, and have a superficial awareness of self.6
Precepting Millennials with Intention Several effective approaches to training Millennial learners in the experiential setting have been described:
Table 1. Anticipated Challenges and Proposed Solutions for Precepting Millennials10-12,14
1. Stein J. Millennials: the me, me, me generation. Time. May 2013. http://time.com/247/millennials-the-me-me-me-generation/.
2. Gardner SF. Preparing for the nexters. Am J Pharm Educ. 2006;70(4):Article 87.
3. Boysen PG, Daste L, Northern T. Multigenerational challenges and the future of graduate medical education. Ochsner J. 2016;16(1):101-107.
4. Dilullo C, Mcgee P, Kriebel RM. Demystifying the millennial student: a reassessment in measures of character and engagement in professional education. Anat Sci Educ. 2011;4(July/August):214-226. doi:10.1002/ase.240.
5. Preceptor Newsletter. http://news.pharmacy.vcu.edu/wp-content/uploads/sites/3395/2014/01/Newsletter_Vol_10_Issue_1_Winter_Spr_2014.pdf. Published 2014.
6. Fjortoft N. The selfie generation and pharmacy education. Am J Pharm Educ. 2017;81(4):Article 61.
7. Weitzel KW, Walters EA, Taylor J. Teaching clinical problem solving: a preceptor’s guide. Am J Heal Pharm. 2012;69(18):1588-1599. doi:10.2146/ajhp110521.
8. Sylvia L, Barr J. What matters in a student-centered approach? In: Pharmacy Education: What Matters in Learning and Teaching. Sundbury: Jones & Bartlett Learning; 2011:25-56.
9. Case Di Leonardi B, Gulanick M. Precepting and diversity: focus on cultural and generational differences. In: Precepting Graduate Students in the Clinical Setting. Chicago; 2008:83-99.
10. Nevin CR, Westfall AO, Rodriguez JM, et al. Gamification as a tool for enhancing graduate medical education. Postgrad Med J. 2014;90:685-693. doi:10.1136/postgradmedj-2013-132486.
11. Desy JR, Mph DAR, Wolanskyj AP. Milestones and millennials: a perfect pairing--competency-based medical education and the learning preferences of generation Y. Mayo Clin Proc. 2017;92(2):243-250. doi:10.1016/j.mayocp.2016.10.026.
12. Meister J, Willyerd K. Mentoring Millennials. Harv Bus Rev. 2010;(May).
13. Cuellar L, Ginsburg D. Preceptor’s Handbook for Pharmacists. 3rd ed. Bethesda: American Society of Health-System Pharmacists; 2016.
14. Roberts DH, Newman LR, Schwartzstein RM. Twelve tips for facilitating millennials’ learning. Med Teach. 2012;34:274-278. doi:10.3109/0142159X.2011.613498.
Authors: Dip Patel, SSHP President and Hubert Kusdono, SSHP President-Elect
St. Louis College of Pharmacy’s SSHP has started off the spring semester with multiple career development and community outreach events.
First, we had a fundraiser called “Pants with a Purpose.” This was a fundraising event in which for every pair of pants purchased, a pair was donated to St. Patrick’s Center for the Homeless. This event was a way for students to give back to their community, and SSHP was fortunately able to donate about $1800 to the charity.
Next, we had a Ronald McDonald House Outreach Event. During this volunteer and community outreach event, students from our chapter cooked and prepared meals for patients’ families at the Ronald McDonald House. Our students were able to give back to the community by interacting with and providing food for families of patients from Cardinal Glennon Children’s Hospital.
In February of this year, our SSHP chapter expanded our Practice Advancement Initiative (PAI) Week greatly. PAI is one of ASHP’s best-known initiatives to promote and advance the profession of pharmacy. The five pillars of PAI week include: integrating pharmacists into health-care systems, leveraging pharmacy technicians, promoting pharmacist credentialing and training, technology, and ensuring pharmacists are leaders in medication use. Many students on campus are unaware of PAI week, so SSHP’s goal was to educate students on PAI and discuss ways students can maximize our profession’s potential. We created a national advocacy video for PAI in which we advocated for pharmacists’ role in the healthcare team. To create awareness, we also had an event for every day of the week in which we had a volunteering opportunity through Blankets for Cancer Patients and had advocacy booth to promote provider status for pharmacists. Our SSHP chapter also held a blood pressure clinic at Walgreens. During this event, students were able to talk to patients regarding their medication adherence, diabetes, asthma, and hypertension management. We were also able to reach out to the community by advocating the importance of medication adherence. This event was a great opportunity for students, who are learning about how to take blood pressure in some of their classes, to enhance their skills by obtaining blood pressure from real patients in the community. Overall, PAI Week was a great success.
Our biggest career development event was the Residency Directors Roundtable. This is an event we held for the first time. Students were able to network and connect with residency directors from throughout the St. Louis area. This provided students with an opportunity to learn about what residency programs seek and expect from their candidates.
SSHP plans to hold more service and career development events throughout March and April. A volunteer event at the St. Mary’s NICU is planned for later this spring. This will provide students with a unique opportunity to volunteer their time and services towards a specialized area of healthcare, and in the meantime, learn more about what a pharmacist’s role may be in a neonatal intensive care unit. All profits from a fundraiser held for this event will be used to make “baby care packages” for newborn babies through the “Sweet Babies” program.
We have also planned Mock Interview Practice Sessions where students will be able to partake in a residency, fellowship, or job interview simulation conducted by various pharmacy practice faculty. This will give students the opportunity to sharpen their interviewing skills and know to what kind of questions to expect in a potential residency interview.
Other upcoming events in March and April include Aseptic Technique Lab, CV Review, Clinical Journal Club, and Cancer Care Packages.
Author: Gwen Ratermann, Associate Director of Outreach, Show-Me ECHO, Missouri Telehealth Network, University of Missouri
The nationwide opioid crisis is focusing attention on why pharmacists must be involved in interdisciplinary care, especially for patients suffering from chronic pain or addiction. Treatment for these patients is improving in Missouri because pharmacists, physicians and other health professionals are sharing their expertise and experiences through Show-Me ECHO.
ECHO (Extension for Community Healthcare Outcomes) uses videoconferencing to connect an interdisciplinary team of experts with primary care providers. They collaborate in case-based learning sessions to help primary care providers develop advanced skills and best practices, which in turn increases the availability and quality of patient care.
Pharmacists help lead the Chronic Pain Management and Opioid Use Disorder teams at the University of Missouri’s Show-Me ECHO program. More than 170 health professionals from across the state have already participated in these two ECHO teams. Both teams follow the latest federal recommendations, and they continuously examine the growing body of research on why and how to limit opioid use.
The University of Missouri launched one of the first ECHO programs in the country to focus on opioid use disorder. Supported by a Substance Abuse and Mental Health Services Administration grant awarded to the Missouri Department of Mental Health, Show-Me ECHO’s opioid program recommends a medication-first treatment strategy for addiction. On the other hand, the Chronic Pain Management ECHO emphasizes how to avoid addiction in the first place by examining alternatives to opioids and methods for limiting their use.
In addition to pharmacists, these complimentary ECHO teams include experts in psychiatry, psychology, addictionology, pain management, physical therapy and social work. The University of Missouri is the only university to also put health literacy experts on all of its ECHO teams. The teams meet every other week via videoconferencing to discuss real but de-identified patient cases that are particularly complex or problematic for primary care providers.
Participating pharmacists realize benefits to themselves, their health care colleagues, and ultimately patients. Like all participants, pharmacists are exposed to the rewards and challenges of working with a variety of experts who must collaborate to provide the best possible care. Pharmacists also become comfortable using telehealth technology that can help them collaborate on improving medication reconciliation, transitional care or follow-up interactions with patients.
Learning more about how pain intersects with mental, behavioral and psychosocial conditions is of particular interest to participating pharmacists. They’re very familiar with widely used psychiatric medications, but medicine is always learning more about the prevalence of depression in patients with chronic pain, or how pain can originate from trauma that occurred decades earlier in childhood. Show-Me ECHO experts recognize the value of behavioral health screenings for patients to help identify the true origins of pain and potentially avoid for unnecessary medication.
Every ECHO team is richer when it includes pharmacists because their knowledge base is both broad and unique. Pharmacists might be the only team members to figure out that a patient’s excruciating leg pain is caused by powerful statins. They might also be the first to suggest that peripheral neuropathy is related to untreated prediabetes. Whatever kind of case is discussed, pharmacists always have special insight into a wide variety of illnesses and conditions.
Registration for all Show-Me ECHOs – including dermatology, Hepatitis C, child psychology, asthma, autism, healthcare ethics and community health workers – is available at showmeecho.org. The state-funded programs are provided at no cost to participants, including no cost continuing education credits for health care professionals. A new Show-Me ECHO program addressing behavioral health for veterans will launch in 2018.
University of Missouri Show-Me ECHO is designated as an international SuperHub, meaning the founding ECHO program at the University of New Mexico has certified MU to train other organizations wanting to adopt the ECHO model. Show-Me ECHO immersion trainings and orientations have been provided to health professionals from California, Indiana, Kansas, Kentucky, Iowa, Nebraska, Tennessee and West Virginia, as well as Kenya, Thailand and Vietnam.
Author: Elaine Ogden, PharmD, BCPS, BC-ADM
MSHP Secretary/Kansas City VA Medical Center
Going GLP-1Authors: James Rhodes, PharmD Candidate 2019,
UMKC School of Pharmacy
Amanda Stahnke, PharmD, BCACP:
UMKC School of Pharmacy/Kansas City
VA Medical Center
Since the first-in-class approval in 2005, there have been more glucagon-like peptide-1 (GLP-1) receptor agonists approved for type 2 diabetes mellitus (T2DM) than any other noninsulin monotherapy agent.1 These agents provide clinicians more options in the diabetes armamentarium to individualize their patients’ regimens to meet individualized short-term and long-term goals. According the American Diabetes Association, a GLP-1 may be added if noninsulin monotherapy failed to help patients reach their A1c target.2 Alternatively, practitioners may also need an additional agent for glycemic control after basal insulin has been maximized. Should a clinician decide to use a GLP-1, it is important to know how either short-acting (SA-GLP-1) or long-acting (LA-GLP-1) agonist subgroups can help a patient reach their goals, with an understanding of each agent’s pharmacokinetic profiles and clinical trial data.
An Incretin Introduction3GLP-1 is a physiologic regulator of appetite and caloric intake. These gut-derived agents also manage glucose control by influencing hyperglycemic insulin secretion, euglycemic glucagon inhibition, anoretic effects, and slowing gastric emptying. Mechanistic discovery of GLP-1s began after gastrointestinal secretion was identified to induce pancreatic insulin release after eating carbohydrates and fats. Also known as the incretin effect, dietary caloric intake has been identified to secrete GLP-1 from intestinal cells, thus contributing to glucose-dependent pancreatic insulin release. This process becomes impaired in individuals with T2DM,4 further disrupting glucose homeostasis which leads to uncontrolled hyperglycemia. Endogenous GLP-1 plays a significant role in augmenting these insulin secretions, which has led to the development of exogenous GLP-1 agents resistant to degradation by dipeptidyl peptidase 4 (DPP4).
Short-Acting GLP-1sUse of SA-GLP1s have been shown to reduce hyperglycemia and glucose excursions in the postprandial state.3 There are two SA-GLP-1s currently approved for glycemic control in adults with T2DM: exenatide (Byetta™) and lixisenatide (Adlyxin™). These exogenous GLP-1 agents have N-terminal modifications to provide half-lives between 2-6 hours.5,6 These agents slow intestinal absorption of nutrients and reduce postprandial hyperglycemia by reducing the rate of gastric emptying into the duodenum; providing a suitable alternative to bolus insulin in combination with basal insulin to reduce postprandial glycemic excursions and incidences of hypoglycemia. However, this notable short-acting therapeutic property requires special considerations for additional medications for patients. For oral medications which the efficacy is concentration-dependent (i.e. antibiotics or oral contraceptives), it is recommended to take these at least 1 hour prior to SA-GLP-1 administration. If such medications are advised to be taken with food, these medications should be administered at a different meal than the SA-GLP-1.5,6
Long-Acting GLP-1sSubgroup LA-GLP-1s notably reduce basal hyperglycemia for greater than 24 hours due to the prolonged pharmacokinetics. There are five LA-GLP-1’s currently authorized for clinical use as an adjunct to diet and exercise in adults with T2DM: exenatide XR (Bydureon™), liraglutide (Victoza™ & Saxenda™), dulaglutide (Trulicity™), and newly approved semaglutide (Ozempic™). Each active agent possesses unique chemical modifications to sustain half-lives longer than 12 hours,7-11 which would allow for once daily or weekly administrations. These modifications include albumin-binding (liraglutide3, semaglutide11), immunoglobulin-binding (dulaglutide3), or encapsulation of slow-release polymicrosperes (exenatide XR3). Consistent therapeutic drug levels induce hyperglycemic insulin release from the pancreas. However, such concentrations also lead to prolonged activation and tachyphylaxis of the GI tract receptors,3 consequently having a less pronounced effect on gastric motility compared to SA-GLP-1s. Nevertheless, the clinical outcomes of LA-GLP-1s have been superior regarding the control of basal hyperglycemia3 over SA-GLP-1 counterparts.
Cardiovascular Outcomes of LA-GLP-1sThere have been two LA-GLP-1 agents identified to reduce long-term cardiovascular (CV) risk as evidenced by the LEADER12 (liraglutide) and SUSTAIN-613 (semaglutide) trials (Appendix A). These trials were designed as time-to-event analyses of a primary composite endpoint of CV death, nonfatal myocardial infarction, or nonfatal stroke in participants with T2DM and established CV disease. Liraglutide and semaglutide both significantly decreased the incidence of the primary composite endpoint versus placebo. A subgroup analysis of the LEADER trial revealed significant interactions favoring patients with reduced renal function (CrCl < 60 mL/min/1.73 m2; p = 0.01) and established CVD (≥ 50 years of age and established CVD; p = 0.04), but no significant interactions were identified for the SUSTAIN-6 trial. Neither agent showed benefit regarding secondary heart failure outcomes.12,13
An Added Benefit by Subtracting WeightWeight reduction is also a common outcome attributed to delayed gastric emptying and suppressing appetite centers in the brain. Although weight loss has been observed as a significant secondary measure for most GLP-1 clinical studies, the SCALE14trial was statistically powered to determine liraglutide’s effect on weight loss (Appendix A). Obese T2DM participants received either liraglutide 3mg, 1.8mg, or placebo comparator over 56 weeks to measure three coprimary endpoints: relative change in body weight, reduction in 5% or more from baseline body weight, and reduction in more than 10% of body weight from baseline. Weight loss was significantly greater with liraglutide (3.0mg) and liraglutide (1.8mg) than the matching placebos for all three co-primary endpoints.14
Considering a Place in TherapyIn the absence of precautions5-11 (e.g. gallbladder disease, acute pancreatitis) and contraindications7-11 (e.g. personal or familial history of thyroid cancer), injectable GLP-1s are useful agents in glucose-lowering strategies as second line option after metformin, if weight gain is a concern or as a third line agent, particularly in combination with metformin and basal insulin. GLP-1s are also offered in fixed-combinations with basal insulin to reduce daily injections. The adverse effects7-11 are primarily gastrointestinal such as nausea, vomiting, and diarrhea but hypoglycemia is still possible when used in combination with other agents. When deciding between GLP-1s, either SA or LA-GLP-1 are acceptable; dosing convenience may give preference for the latter subclass. An additional consideration may also be room temperature stability of GLP-1s as times vary significantly (Appendix A) and proper refrigeration may not always be widely accessible. While these antidiabetic agents may be considered effective for individuals with T2DM, they do so at the expense of higher rates of gastrointestinal side effects and cost. Therefore, it is important to discuss these potential barriers with patients prior to starting GLP-1 treatment.
1. U.S. Department of Health and Human Services. Food & Drug Administration (FDA). (2017). FDA-Approved Diabetes Medicines. Retrieved from https://www.fda.gov/forpatients/illness/diabetes/ucm408682.htm2. American Diabetes Association (ADA). 8. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care. 2018; 41(Suppl. 1): S73-S85.
3. Meier JJ. GLP-1 receptor agonists for individualized treatment for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2012; 8: 728-742.
4. Madsbad S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes, Obesity, and Metabolism. 2014; 16: 9-21.
5. Byetta (exenatide) injection [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE; 2015.
6. Adlyxin (lixisenatide) injection [package insert]. Sanofi-Aventis US LLC. Bridgewater, NJ; 2016.
7. Bydureon (exenatide extended-release) injectable suspension [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE; 2017.
8. Victoza (liraglutide) injection [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
9. Saxenda (liraglutide [rDNA origin] injection) [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
10. Trulicity (dulaglutide) injection [package insert]. Eli Lilly and Company. Indianapolis, IN; 2017.
11. Ozempic (semaglutide) injection [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
12. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2016, 375(4): 311-322.
13. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2016; 375: 1834-1844.
14. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes. Journals of American Medical Association. 2015; 314(7): 687-699.
Latent Autoimmune Diabetes of Adults
Authors: Dorothy Holzum, PharmD Candidate 2018,
St. Louis College of Pharmacy
Weston Thompson, PharmD, LCDR, BCPS, NCPS
Latent autoimmune diabetes of adults (LADA) is an intricate subset of diabetes that is complex and difficult to diagnosis. The American Diabetes Association (ADA) does not specify LADA as a separate diagnostic entity with confirmed treatments. As a result, the exact prevalence of LADA is unknown. However, 10% of patients in the United Kingdom Prospective Diabetes Study (UKPDS) trial most likely met criteria for LADA, totaling around 500 patients.1
Patients with LADA present with symptoms of type 2 diabetes, including BMI > 30 kg/m2, adult onset, and comorbidities including hypertension and hyperlipidemia. However, they also test positive for a glutamic acid decarboxylase (GAD) antibody, which resembles type 1 diabetes.1-5
While it can be difficult to clinically diagnose LADA based on patient symptoms and history on presentation, there are three set diagnostic criteria that a patient must have in order to be diagnosed with LADA. Patients first must have a GAD antibody. The GAD acts as an autoantigen, which provokes the generation of antibodies. The patient’s T cells mistakenly identify beta cells in the pancreas as foreign and thus produce antibodies to destroy the beta cells. This is consistent with type 1 diabetes. In addition, patients present with diabetes at an older age, specifically over the age of 18 years. Finally, patients must have retention of their beta cell function, meaning they will not require insulin for at least six months. The last two characteristics are consistent with type 2 diabetes.1,2
There are two subsets of LADA, based on bimodal distribution of GAD titers. Patients that have high GAD titers will resemble type 1 diabetics, as they are younger and leaner.6 These patients generally have higher A1c levels and lower C-peptide levels. On the other hand, patients with low GAD titers will resemble type 2 diabetics, as they are older and have a high BMI.6,7
The pathophysiology of LADA is a combination of the autoimmune destruction of pancreatic beta cells, which leads to insulin deficiency, as well as insulin resistance. Insulin resistance is the result of several risk factors including age > 45 years, BMI > 25 kg/m2, and habitual physical inactivity. Due to these risk factors, the body’s normal response to a given amount of insulin is reduced. As a result, higher levels of insulin are needed in order for insulin to have its proper effects.6,8
Patients can present with polydipsia, or increased thirst, polyuria, or increased urination, polyphagia or increased hunger, or they can be asymptomatic. Laboratory tests will show a positive GAD antibody and elevated blood glucose levels. Patients can progress into diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome and develop microvascular complications including retinopathy, peripheral neuropathy, and nephropathy, as well as macrovascular complications including peripheral artery disease and cerebrovascular disease.1
Currently there is not an established therapeutic regimen for the treatment of LADA. Ultimately, treatment is tailored to preserve beta cell function as long as possible. Clinical trials are difficult to design because there is not a gold standard method to measure beta cell mass.1 A few studies have shown sulfonylureas are harmful in LADA patients, causing them to require insulin at an accelerated rate.9 Sulfonylureas stimulate the pancreas to secrete insulin. This stimulation causes an increased autoantigen expression, which further augments the autoimmune process in LADA patients.1 Thus, sulfonylureas should not be used in LADA patients. If the patient is still secreting some insulin, metformin is the first line medication, as it is the only medication shown by the UKPDS trial to decrease the development of macrovascular complications.9 Metformin should be titrated to a maximum of 2,000 mg per day and then all other oral antidiabetic therapies should be maximized.6 Once all oral therapies are at the maximum dose and the patient is still not at their A1c goal, insulin must be initiated.5
The goals of therapy for LADA include reducing the risk of any acute complications and preventing micro and macrovascular complications. Blood sugars should be treated to an A1c of < 7%, FPG 80-130 mg/dl and PPG < 180 mg/dl per the ADA guidelines. There are some circumstances where a patient’s goal A1c is only < 8%, particularly in elderly patients with a decreased life expectancy or if the patient has several episodes of hypoglycemia when trying to treat their A1c to < 7%. On the other hand, there are some patients whose A1c goal will be < 6.5%, specifically if the patient is young and the goal can be obtained without significant hypoglycemia. Furthermore, for non-pharmacological treatment, patients should be educated about the disease state, the importance of keeping their blood sugars controlled, and signs of hypo and hyperglycemia. Medical nutrition therapy, a nutrition assessment to evaluate a patient’s nutrition intake and metabolic status should also be recommended. Furthermore, patients should get 150 minutes of exercise per week and check their blood sugars regularly, which is different for every patient.10
In conclusion, LADA is a subset of diabetes where patients present with symptoms of type 2 diabetes, however they also have a positive GAD antibody. These patients will require insulin sooner than traditional type 2 diabetes patients.1 Pharmacists must address barriers to insulin therapy early in LADA patients. In addition, robust clinical trials are needed to determine the appropriate treatment that will lengthen the beta cell function in these patients.
References: 1. Cernea S, Buzzetti R, Pozzilli P. Beta-cell protection and therapy for latent autoimmune diabetes in adults. Diabetes Care. 2009;32(2):246-252.
2. Laugesen E, Ostergaard JA, Leslie RD. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. DIABETICMedicine. 2015;32(7):843-852.
3. Hernadez M, Lopez C, Real J, et al. Preclinical carotid atherosclerosis in patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes and classical type 1 diabetes. Cardiovasc Diabetol. 2017;16:94:1-9.
4. Grant SA, Hakonarson H, Schwartz S. Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? Endocrine Reviews. 2010;31(2):183-193.
5. Stenstrum G, Gottsatter A, Bakhtaedze E, et al. Latent autoimmune diabetes in adults: definition, prevalence, beta-cell function, and treatment. Diabetes. 2005;54(2):68-72.
6. Yang Z, Zhou Z, Li X, et al. Rosiglitazone preserves islet beta-cell function of adult-onset latent autoimmune diabetes in 3 years follow-up study. 2009;83:54-60.
7. Lu J, Hou X, Pang C, et al. Pancreatic volume is reduced in patients with latent autoimmune diabetes in adults. Diabetes Metab Res Rev. 2016;32:858-866.
8. Grant SA, Hakonarson H, Schwartz S. Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? Endocrine Reviews. 2010;31(2):183-193.
9. Brophy S, Brunt H, Davies H, et al. Interventions for latent autoimmune diabetes (LADA) in adults (review). Cochrane Database of systematic Reviews. 2007;3:1-3.
10. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2017;41(Supplement 1). doi:10.2337/dc18-s002.
Management of Diabetic Ketoacidosis in Critically Ill Patients
Authors: Anahit R. Simonyan, PharmD Candidate 2018, St. Louis College of Pharmacy
Gabrielle A. Gibson, PharmD, BCPS, BCCCP: Barnes-Jewish Hospital
Introduction/Epidemiology:It is estimated that patients with diabetes are more likely to be hospitalized and experience longer hospital stays than those without diabetes.1 Additionally, severe hyperglycemia can lead to either diabetic ketoacidosis (DKA) and/or hyperosmolar hyperglycemic state (HHS), which are two of the most serious acute complications of diabetes associated with significant morbidity and mortality. Diabetic ketoacidosis is an acute complication of diabetes, responsible for over 500,000 hospital stays per year.2 The remainder of this paper will be focused on the management of DKA.
Pathophysiology:The pathophysiology of DKA can be explained by an absolute insulin deficiency leading to ketosis. The decrease in effective insulin concentration causes an increase in production of counterregulatory hormones. These hormones cause a decrease in glucose utilization, increase in gluconeogenesis, and increase in glycogenolysis. The characteristic finding of ketoacidosis is due to upregulation of lipolysis and availability of free fatty acids. The liver converts the free fatty acids to ketone bodies, resulting in ketonemia and acidosis. Diabetic ketoacidosis can be precipitated by several factors, including infection, non-adherence to therapy, concomitant illnesses, and medications such as corticosteroids and sympathomimetic agents. Although DKA may present with symptoms ranging from abdominal pain to severe polyuria, polydipsia, or polyphagia, diagnosis of DKA is based on abnormal pH and serum bicarbonate values, an elevated anion gap with additional fluid and electrolyte abnormalities, and positive urine and serum ketones.1,2
Goals of DKA treatment include improvement of organ perfusion through increasing circulatory volume, gradual reduction of osmolality and serum glucose, clearance of both serum and urine ketones, and normalization of electrolytes. The three main treatments for DKA are fluid therapy, reversal of hyperglycemia, and correction of electrolyte abnormalities while concomitantly identifying and treating the underlying cause.
Management: Intravenous (IV) fluids1,2Administration of IV fluids is utilized in the treatment of DKA in order to correct hypovolemia. In the absence of cardiac compromise, all patients should receive normal saline (0.9% NaCl) for intravascular volume repletion. The initial isotonic saline should be infused at a rate of 15-20 mL/kg/hr or 1-1.5 L during the first hour. Subsequent choices of fluid are determined by the patient’s volume and hemodynamic status, corrected sodium, and the patient’s urine output in addition to cardiac and renal function. Fluids may then be changed to include dextrose once the patient’s serum glucose reaches an acceptable level of 200 mg/dL. As patients become volume resuscitated, monitoring for improved renal function, blood pressure, lab values, and clinical exam should occur within the first 24 hours.
Insulin1-4The cornerstone of DKA treatment lies with administration of insulin. The optimal initial treatment regimen for DKA patients is IV regular insulin. A randomized, prospective study performed by Fisher and colleagues evaluated 45 patients with DKA to determine the most efficacious route of insulin administration. The group receiving IV regular insulin had a statistically significant faster decrease in plasma glucose (two hours vs four hours, P<0.01) and ketone bodies (4 hours versus 6 hours, P<0.05) compared to subcutaneous or intramuscular insulin. About 90% of participants receiving IV insulin had a decrease in plasma glucose by at least 10% in the first hour, compared to only 30-40% of the participants in the subcutaneous and intramuscular insulin groups. Thus, the administration of continuous IV regular insulin infusions are preferred because of the short half-life and ability to easily titrate.
Guideline recommendations suggest a bolus of 0.1 units/kg of regular insulin with subsequent continuous infusion of regular insulin at 0.1 units/kg/hour. The patient can be transitioned to subcutaneous short-acting insulin once the hyperglycemic crisis has resolved and certain criteria have been met. A patient must have a blood glucose <200 mg/dL in addition to two of the following: serum bicarbonate >15 mEq/L, pH >7.3, or calculated anion gap <12 mEq/L. In order to prevent hyperglycemia, the short-acting subcutaneous injection should be overlapped with the infusion by 1-2 hours. In the case that patients are to remain NPO, a regular insulin infusion should be continued with appropriate IV fluids. Hypoglycemia is one of the most common complications from treatment of DKA, thus it is imperative that these patients have frequent blood glucose monitoring at least every 1-2 hours to prevent and manage hypoglycemia.
Patients with DKA may experience elevations in potassium as a result of insulin deficiency and metabolic acidosis. Potassium is stored in the intracellular compartment, and in the presence of acidosis the potassium shifts from the intracellular to the extracellular space. This causes an increase in serum potassium, despite the fact that most patients have a total body deficit of potassium. With insulin and fluid therapy, and subsequent correction of acidosis and volume status, a decrease in serum potassium may occur. Supplementation may be initiated once the serum potassium < 5.2 mEq/L. It is rare to have a patient present with hypokalemia, but if this does occur, insulin therapy should be held until the serum potassium is restored to >3.3 mEq/L, to avoid arrhythmias and respiratory muscle weakness.
Phosphate2At presentation of DKA, levels of phosphate may be elevated. However, patients receiving insulin therapy for treatment of DKA will have decreased phosphate levels. In order to avoid cardiac dysfunction, muscle weakness, and respiratory distress secondary to hypophosphatemia, vigilant monitoring and replacement of phosphate must be employed. In those with a serum phosphate <1.0 mg/dL, supplementation with 20-30 mEq of potassium phosphate should be administered in addition to IV fluids. Correction of phosphate should not exceed 4.5 mmol/hour in order to prevent severe hypocalcemia and further complications.
Bicarbonate5The American Diabetes Association (ADA) does not recommend the routine use of bicarbonate therapy unless the patient has extreme acidosis (pH <6.9) with severe systemic complications, such as impaired myocardial contractility. Duhon and colleagues performed a retrospective analysis to determine whether the use of IV bicarbonate therapy led to improved outcomes in DKA patients. The primary outcome was the time it took to resolve acidosis, with secondary outcomes of hospital length of stay, and additional therapy requirements within the first 24 hours of admission. The study showed no statistically significant difference in the time it took to resolve acidosis between the two groups. The only statistically significant difference found was an increase in insulin and fluid requirements in those receiving bicarbonate therapy than those not receiving it. However, this study is limited by its retrospective nature and its small sample size with 40 patients included in each group.
ConclusionIt is imperative to treat the manifestations of DKA in order to prevent complications and reduce mortality in critically ill patients. Appropriate IV fluid, insulin, and correction of electrolyte abnormalities is necessary for the safe and effective treatment of DKA. Patients should be educated on how to prevent DKA, including the medications and conditions that may precipitate its occurrence. Pharmacists can play a vital role in the education and prevention process, and should promote awareness to diabetic patients regarding this condition.
References:1. Moghissi ES, Korytkowski MT, DiNardo M, et al.; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009;32:1119–1131.
2. Kitabchi AE, Guillermo UE, Miles JM, Fisher JN. Hyperglycemia Crises in Adult Patients with Diabetes. Diabetes Care. 2009;32:1335-1343.
3. Fisher JN, Shahshahani MN, Kitabchi AE, et al. Diabetic ketoacidosis: low-dose insulin therapy by various routes. N Engl J Med. 1977;297(5):238-241.
4. Finfer S, Blair D, Bellomo R, et al. Intensive versus Conventional Glucose Control in Critically Ill Patients (NICE-SUGAR). N Engl J Med. 2009;360(13):1283-1297.
5. Duhon B, Attride RL, Franco-Martinez AC, Maxwell PR, Hughes DW. Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother. 2013;47(8):970-975.
Subcutaneous Administration of Testosterone as an Alternative to Intramuscular Injection
Authors: Jackson Warner, PharmD Candidate 2018, UMKC School of Pharmacy
Andrew Bzowyckyj, PharmD, BCPS, CDE: UMKC School of Pharmacy/Truman Medical Center
IntroductionSubcutaneous (SC) testosterone is a novel delivery method that may alleviate concerns associated with intramuscular injections, improving adherence and patient attitude towards therapy. Intramuscular (IM) testosterone injections are often reported to cause pain, bruising, and a need to schedule injections with a healthcare provider if unable to self-administer.1 IM injections often result in supraphysiologic levels of testosterone, followed by subtherapeutic troughs. This fluctuation in hormone levels can lead to an undesirable variability in mood, energy, and libido. Topical formulations can have adverse events such as local reactions, risk of skin-to-skin transmission, unpleasant odors, and unreliable absorption.2 These formulations are not often covered by insurance and may be cost-prohibitive. A form of SC testosterone is currently available as implantable pellets. However, this formulation requires placement by a physician and carries the risk of infection and fibrosis, or extrusion of the pellets.2 Ease of administration, less pain compared to IM injections, and decreased fluctuation of hormone levels are all attractive qualities that may sway patients and providers alike to prefer SC injections of current testosterone formulations.
Pharmacokinetic Profile of SC TestosteroneSeveral studies have observed the effects of SC administration of testosterone cypionate (TC) and enanthate (TE) on serum levels, alleviation of the hypogonadal symptoms, and masculinization of transgender patients to determine its viability as an alternative to IM injections. Spratt et al.1 measured the testosterone levels in 96 female-to-male (FTM) transgender patients using weekly SC injections. The initial dose was 50mg (TC or TE, based on availability) SC once weekly. Doses were increased sequentially until normal serum total testosterone levels were attained (348-1197ng/dL). All patients (n=63) achieved normal serum total testosterone levels, regardless of BMI, suggesting that obesity is not a limitation of SC testosterone. Average levels were significantly different between the normal weight and obese patients (754 vs. 606 ng/dL, p-0.04), but not overweight patients (765ng/dL). Though not clinically significant, all subjects who received at least six months of optimized therapy experienced satisfactory masculinization. Kaminetsky et al.2 compared TE 50mg SC (n=15) and 100mg SC (n=14) once weekly to TE 200mg IM every two weeks in males with hypogonadism. The 50mg dose provided an increase in total testosterone levels, which fell back to baseline between doses. However, the 100mg dose demonstrated a rise in total testosterone levels for the first three weeks. At week four and beyond, this group demonstrated steady-state exposure. The apparent half-life was 239.63 hours (100 mg SC) and 172.57 hours (200 mg IM). The kinetic profile of SC testosterone appears to be dose-proportional, with AUC and Cmax values for the 100mg SC dose being approximately twice those of the 50mg SC dose. 100mg SC testosterone demonstrated a similar overall AUC compared to 200mg IM testosterone at week five and six, suggesting that bioavailability is similar. McFarland et al.3 observed the total testosterone levels of 11 FTM transgender patients who were already on weekly doses of TC SC with documented therapeutic levels. Levels were taken prior to injection and at serial intervals post-injection (mean dose: 75mg weekly). Serum concentrations significantly increased between pre-injection and six hours post-injection (497 vs. 656 ng/dL; p=0.02), but did not significantly decrease between the sample drawn prior to injection and the sample seven days afterwards (497 vs. 477 ng/dL, p=0.58). The regression analysis of the relationship between SC testosterone dose and serum total testosterone concentration yielded a significant positive correlation (r2=0.59, p=0.006), further demonstrating dose-dependent kinetics. A separate regression model included BMI as a covariate (mean BMI 28.5 ± 7.4, range of 20.3–39.3 kg/m2). In this model, only the dose of testosterone was found to be a significant predictor of the total testosterone level, (standardized β coefficient, 0.77, p=0.005) showing that BMI is likely not a predictor of serum testosterone levels and should not be regarded as a limitation to using SC testosterone. Olson et al.4 measured the total testosterone levels in 35 FTM transgender patients naïve to hormone replacement therapy. TC doses were started at 25mg SC every two weeks and gradually increased to 50mg weekly as tolerated (mean dose: 46.4mg). Thirty-two of the 35 patients achieved testosterone levels within the normal male range at six months. The six-month total testosterone levels significantly increased from baseline levels (521.4 vs 35.2 ng/dL, p<0.001).
Lastly, a pilot study5 investigated the effect of subcutaneous TE in 22 hypogonadal men. The starting doses ranged from 25–50mg SC weekly. One week after initial injection, a trough and peak total testosterone level were taken with doses adjusted based on these levels and patient-reported symptoms (mean dose: 55 mg weekly). The mean trough was 418 ng/dL (normal range 288–1110) and the mean peak was 624 ng/dL. All 22 patients had both peaks and troughs within the normal range.
Safety and TolerabilitySC testosterone is well tolerated and generally safe with injection site reactions being the most commonly reported concern. One case of cellulitis was observed, but resolved without intervention.1 Insomnia (n=2), acne (n=1), and minor pain at the injection site have also been reported.2 Some patients have reported erythema, swelling, and pain at the injection site that subsided after switching from a sesame oil formulation to one with cottonseed oil. In one trial, the six-month mean systolic blood pressure increased (114.5 vs. 119.5mmHg, p=0.041) but this increase was not found to have clinical significance. Depression and suicidality have been reported with testosterone use, but it was not reported in any of the studies above. Surveys given to patients switching from IM to SC showed that the vast majority of subjects preferred SC.4
On the HorizonThe 2015 Subcutaneous Testosterone Enanthate Safety in Adult Men Diagnosed with Hypogonadism (STEADY™) trial was presented at the Endocrine Society Annual Meeting in April 2017 and American Urology Association Annual Meeting in May 2017. Antares Pharma claims the results of this trial (which are not yet published) demonstrated Xyosted®, formerly called QuickShot Testosterone, achieved steady state testosterone levels.7 However, the FDA has declined to approve Antares Pharma’s new drug application for Xyosted® based on two safety concerns: risk of increased blood pressure and occurrence of depression and suicidality.8 The FDA’s response letter did not cite any manufacturing, device, or efficacy issues. The company plans to meet with the FDA to discuss a path to the approval of Xyosted®.
ConclusionWhen injected at weekly intervals, SC testosterone appears to be a safe and effective alternative to IM injection. Overall, weekly SC testosterone offers stable total testosterone levels with infrequent supraphysiologic peaks or subtherapeutic troughs. In transgender men, SC testosterone results in appropriate masculinization. In cisgender men, it alleviates symptoms of hypogonadism. BMI does not appear to affect the ability of SC testosterone to achieve appropriate serum levels. Weekly SC testosterone appears to have dose-proportional kinetics with an increase in dose resulting in a proportional increase in serum testosterone levels. Mild, transient injection site reactions appear to be the most frequently reported adverse reaction to SC testosterone. With the evidence supporting the use of SC testosterone and at least one pharmaceutical company already seeking approval for it, a testosterone suspension product approved for subcutaneous administration is likely to become available soon.
References:1. Spratt DI, Stewart II, Savage C, et al. Subcutaneous injection of testosterone is an effective and preferred alternative to intramuscular injection: demonstration in female-to-male transgender patients. J Clin Endocrinol Metab. 2017;102(7):2349–55.
2. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single-use autoinjector: a phase II study”. Sex Med. 2015;3:269–279.
3. McFarland J, Craig W, Clarke NJ, Spratt DI. Serum testosterone concentrations remain stable between injections in patients receiving subcutaneous testosterone. J Endo Soc. 2017;1(8):1095-1103.
4. Olson J, Schrager SM, Clark LF, Dunlap SL, Belzer M. Subcutaneous testosterone: an effective delivery mechanism for masculinizing young transgender men. LGBT Health. 2014;1(3)165–7.
5. Al-Futaisi AM, Al-Zakwani IS, Almahrezi AM, Morris D. Subcutaneous administration of testosterone: a pilot study report. Saudi Med J. 2006;27(12):1843–6.
6. McMahon CG, Shusterman N, Cohen B. Pharmacokinetics, clinical efficacy, safety profile, and patient-reported outcomes in patients receiving subcutaneous testosterone pellets 900mg for treatment of symptoms associated with androgen deficiency. J Sex Med. 2017;14:883–90.
7. “Antares Pharma Announces Poster Presentation of Quickshot Testosterone Data at the Endocrine Society Annual Meeting”. https://globenewswire.com/news-release/2017/04/03/953464/0/en/Antares-Pharma-Announces-Poster-Presentation-of-Quickshot-Testosterone-Data-at-the-Endocrine-Society-Annual-Meeting.html. 03 Apr. 2017. Accessed November 8, 2017.
8. “Antares Pharma Receives Complete Response Letter from the FDA for XYOSTED™”. https://seekingalpha.com/article/4115409-update-antares-pharma-post-complete-response-letter. 20 Oct. 2017. Accessed November 8, 2017.
The Role of Non-Insulin Therapies in the Treatment of Type 1 Diabetes
Authors: Sara Lingow, PharmD, PGY2 Ambulatory Care Pharmacy Resident
St. Louis College of Pharmacy/Saint Louis County
Department of Public Health
Justinne Guyton, PharmD, BCACP,
Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy
Program Number: 2017-12-09
Approval Dates: 2/7/2018 to 5/6/2018
Approved Contact Hours: One (1) CE(s) per LIVE session.
Submit Answers to CE Questions to Jim Andrews at: firstname.lastname@example.org
I. Describe the proposed role of GLP-1 receptor agonists and SGLT inhibitors in type 1 diabetes.
II. Identify adverse effects that may limit the use of GLP-1 receptor agonists or SGLT inhibitors.
III. Evaluate primary literature to determine the risks and benefits of both GLP-1 receptor agonist and SGLT inhibitor therapy in patients with type 1 diabetes.
IV. Select the best non-insulin therapy for a patient with type 1 diabetes who is not achieving glycemic control with insulin therapy alone.
IntroductionType 1 Diabetes Mellitus (T1DM) is characterized by autoimmune pancreatic β-cell destruction, leading to an insulin deficiency. Pancreatic α-cell dysfunction is also present, resulting in excess glucagon in both the fasting and postprandial state. Onset is most common during adolescence, but adults have also been diagnosed with T1DM. Patients with T1DM will have autoimmune markers present, and little to no residual C-peptide (a marker of insulin production).1,2
The Center for Disease Control and Prevention (CDC) estimates that 5 to 10% of patients with diabetes have type 1.3 Insulin is the mainstay of therapy for T1DM, as the characteristic β-cell destruction in T1DM results in minimal to no endogenous insulin production. While exogenous insulin is necessary, it does not account for the excess glucagon production or the altered gastric emptying rate in T1DM. Additionally, the two most common adverse effects of insulin are hypoglycemia and weight gain, which is of concern in patients with T1DM.2 A study published in 2015 found that patients in the United States with T1DM have an average A1C of 8.2%, with only 30% of patients achieving an A1c goal of less than 7%. Furthermore, 68% of patients are overweight or obese, diabetic ketoacidosis (DKA) occurs at a rate of 10% per year in some age groups, and severe hypoglycemia occurs at a rate of 9 – 20%.4 These data alone illustrates the need for alternative therapies to treat T1DM without risking further weight gain and hypoglycemia with insulin monotherapy.
In 2016 Schwartz and colleagues introduced the β-cell-centric classification schema of diabetes in which abnormal β-cell function is the common denominator for all types of diabetes. This model also identified ten other pathways of hyperglycemia, highlighting the idea that different treatment pathways can reduce hyperglycemia through different mechanisms in order to achieve glycemic goals.5 The ideal treatment regimen for a patient with T1DM would not only target the β-cell dysfunction, but also decrease blood glucose by targeting hyperglycemic pathways independent of β-cell function.
Pramlintide was FDA-approved for the treatment of T1DM in 2005.6 Pramlintide is an amylin analogue that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety.7 Clinical trials showed that when pramlintide 30 or 60 mcg was administered subcutaneously three to four times daily, in addition to insulin therapy, the agent provided several positive benefits. The combination modestly lowered A1c, lowered the total daily dose (TDD) of insulin, and resulted in a decrease in body weight in patients with T1DM.8-10 Despite these benefits, pramlintide is rarely used in T1DM due to the multiple daily injections, significant nausea and vomiting, and overall cost of the medication. Metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, and thiazolidinediones (TZD) have also been studied in T1DM, but have not shown clinically significant beneficial outcomes and therefore are not FDA-approved for treatment.2 The role of two other non-insulin classes of medications, sodium-glucose co-transporter (SGLT) inhibitors and glucagon-like-peptide 1 receptor agonists (GLP-1 RA), have been recently studied in T1DM. The remainder of this article will focus on a literature review of these agents with regard to lowering A1c, reducing insulin dose, and reducing body weight in patients with T1DM.
Sodium-Glucose Co-Transporter-InhibitorsThe SGLT-2 receptor is located in the proximal tubule of the kidney and is responsible for 90% of renal glucose reabsorption. Inhibition of this transporter reduces reabsorption of filtered glucose, thereby increasing glucosuria and reducing plasma glucose concentrations.7 The SGLT-1 receptor is located both in the proximal renal tubule and in the proximal small intestine. In the proximal renal tubule, it is responsible for the remaining 10% of renal glucose reabsorption. In the small intestine, it is the primary transporter in glucose and galactose absorption. Inhibition of this receptor therefore prevents glucose absorption in the small intestine, and a small amount of reabsorption in the kidneys. 11,12 Because the mechanism of SLGT inhibitors are independent of beta-cell function, this drug class may offer A1c lowering benefit to patients with T1DM, both by increasing glucose excretion in the kidney through SGLT-1 and-2 inhibition, and preventing glucose absorption in the small intestine through SGLT-1 inhibition.2 Currently, only SGLT-2 inhibitors are available in the United States. Known adverse effects of SGLT inhibitors include lipid abnormalities, genital infections, hypotension, and euglycemic diabetic ketoacidosis.7 A list of all available agents and their respective average wholesale prices can be found in Appendix I, Table 1. The first studies of SGLT inhibitors in patients with T1DM were limited by small sample size and a short duration. However, a few key findings warrant the necessity of future trials. Reduction in A1c, varying from -0.24% to -0.7%, a significant decrease in body weight, and a decrease in TDD were all seen in preliminary literature. While these benefits were apparent, patients receiving SGLT inhibitors also experienced more episodes of ketoacidosis and genital infections. 11,13-16
Two new, larger scale, landmark clinical trials were recently published in September 2017 evaluating the role of SLGT inhibitors in T1DM. The DEPICT-1 trial evaluated the role of dapagliflozin, an SGLT-2 inhibitor added to insulin therapy in 833 patients with T1DM. The primary outcome, change in A1c at 24-weeks, favored treatment with both dapagliflozin 5 mg (-0.42%) and dapagliflozin 10 mg (-0.45%) compared to placebo (p<0.0001). Severe hypoglycemia occurred in 21 (8%), 19 (6%) and 19 (7%) of the patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%), five (2%), and three (1%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups respectively. This trial was still relatively short in duration, and excluded patients at a higher risk for hypoglycemia and DKA, however, it still offers promising benefit of an SGLT-2 inhibitor in addition to insulin for patients with T1DM who are not achieving glycemic goals.17
The inTandem 3 trial was also published in September 2017. This trial evaluated the role of sotagliflozin, an SLGT-1 and SLGT-2 inhibitor, in 1402 patients with T1DM. The primary outcome targeted both efficacy and safety endpoints, assessing the number of patients to achieve an A1c < 7.0% without hypoglycemia or DKA. Two hundred of the patients in the sotagliflozin group (28.6%) achieved this primary outcome, while only 107 (15.2%) patients in the placebo group achieved the outcome (p<0.001). This resulted in a number needed to treat of eight patients. Conversely, there were also more patients in the sotagliflozin group who did not meet the A1c goal and had at least one episode of DKA compared to placebo (16 patients (2.3%) vs. 13 patients (1.8%) respectively, p <0.003). This resulted in a number needed to harm of 50 patients. This trial was also relatively short in duration at only 24 weeks, excluded patients with a recent history of DKA or hypoglycemia, and demonstrated an increased risk of DKA in the treatment group.12
The data from these two recent landmark trials confirm the benefits of A1c reduction, weight loss, and reduction in total daily insulin doses with SGLT inhibitors seen in preliminary literature. Furthermore, the literature does not show an increased risk of hypoglycemia with these agents, though both trials excluded patients at baseline with a recent history of severe hypoglycemia. However, these benefits do not come without the risk of ketoacidosis, and should therefore not be used in patients with a history of, or at an increased risk for DKA. Additionally, the cost of these newer, brand-name agents may introduce an additional barrier (Appendix I, Table 1). Future trials that are longer in duration and specifically evaluate the safety of these medications in patients with T1DM are essential. Additionally, future studies should be designed so that the primary outcome is patient-related, evaluating the benefit of this class in prevention or delay of microvascular and/or macrovascular diabetic complications.
Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1 RA)Human GLP-1 is a peptide that, in conjunction with glucose-dependent insulinoptropic polypeptide (GIP), is responsible for over 90% of the increased insulin secretion seen from an oral glucose load. GLP-1 is secreted from L-cells, located in the intestine and colon, in response to meals. Human GLP-1 levels rise shortly after food ingestion, enhancing insulin secretion, suppressing glucagon secretion, slowing gastric emptying and reducing food intake by increasing satiety.18 GLP-1 receptor agonists are analogs of human GLP-1 which increase glucose-dependent insulin secretion, delay inappropriate glucagon secretion, increase β-cell growth and replication, delay gastric emptying, and decrease food intake. The proposed benefit of GLP-1 receptor agonists in T1DM is mostly related to the mechanistic avenues independent of β-cell function. However, the potential to improve residual β-cell function and increase glucose-dependent insulin secretion may be beneficial early on in the diagnosis of T1DM. The most common adverse effects of GLP-1 receptor agonists include gastrointestinal disturbances, such as nausea and vomiting, increased heart rate, and headache. This class should not be used in patients with a personal or family history of thyroid cancer or multiple endocrine neoplasia syndrome (MENS).7,19 A list of available GLP-1 receptor agonists and their respective costs are available in (Appendix I, Table 2).
Preliminary literature evaluating the role of GLP-1 RAs in T1DM are largely inconclusive. Most trials had a small sample size and duration ranged from four to 26 weeks, with the exception of one 56-week trial. The results of the trials were variable regarding A1c reduction (-0.3 to -2.3%), weight loss (-0.5 kg to 6 kg), and reduction in TDD of insulin up to 20%. While the results of these earlier studies suggest potential benefit of this class, many were retrospective, open-label, or observational, limiting their usefulness.20-26. The ADJUNCT-ONE trial, published in 2016, evaluated the role of liraglutide added to treat-to-target insulin with regard to effects on A1c, insulin requirement, and body weight in patients with T1DM. The trial was a double-blind, randomized controlled trial including 1,398 adults with a duration of 52 weeks. Subjects were randomized in a 3:1 fashion to receive either liraglutide 0.6 mg, 1.2 mg, 1.8 mg or placebo added to insulin. At 52 weeks, liraglutide at both the 1.8 mg and 1.2 mg doses significantly reduced A1c compared to placebo (-0.54% and -0.49% vs. -0.34% respectively). Reduction in total daily insulin dose also significantly favored liraglutide at the 1.8 mg and 1.2 mg doses when compared to placebo (-5% and -2% vs. +4% respectively). Reduction in weight was significant for all three treatment groups compared to placebo. While benefits were seen at the higher doses of liraglutide, they were accompanied by an increased rate of symptomatic hypoglycemic events. The rate of symptomatic hypoglycemia events observed was 16.5/patient-year of exposure (PYE) and 16.1/PYE in the liraglutide 1.8 mg and 1.2 mg groups, respectively compared with a rate of only 12.3/PYE in the placebo group (p<0.05). Additionally, liraglutide 1.8 mg was associated with a higher rate of hyperglycemic episodes with ketosis. Gastrointestinal adverse effects were notable in all liraglutide groups. In the subgroup analysis, ADJUNCT-ONE authors identified that patients with residual C-peptide levels (n=17%) at baseline had a greater decrease in A1c with liraglutide 1.8 mg and 1.2 mg compared to those without residual C-peptide at baseline at the same dose. Additionally, patients with residual C-peptide experienced fewer episodes of hypoglycemia or hyperglycemia with ketosis.27
The ADJUNCT-TWO trial, published shortly after ADJUNCT-ONE in 2016, evaluated the efficacy and safety of liraglutide added to a capped insulin dose in patients with T1DM. This was a 26-week randomized, double-blind trial enrolling 835 patients randomized in a 3:1 fashion to receive liraglutide 0.6 mg, 1.2 mg, 1.8 mg or placebo added to capped insulin. At 26-weeks, there was a statistically significant reduction in A1c with all three doses of liraglutide compared to placebo (-0.35%, -0.23%, -0.24% and +0.01% for liraglutide 1.8 mg, 1.2 mg, 0.6 mg and placebo respectively). Reduction in total daily dose of insulin and body weight also significantly favored all three liraglutide doses. The highest rate of symptomatic hypoglycemia was unexpectedly seen in the liraglutide 1.2 mg arm. Like the ADJUNCT-ONE trial, hyperglycemia with ketosis was seen most often in the liraglutide 1.8 mg arm. The subgroup analysis of ADJUNCT-TWO revealed that, similar to the ADJUNCT-ONE findings, patients with residual C-peptide (15%) at baseline also showed a greater reduction in A1c with liraglutide 1.8 mg compared to those without residual C-peptide.28
ADJUNCT-ONE and ADJUNCT-TWO are the largest trials available to date to evaluate liraglutide in T1DM. While the results of both trials are favorable with regard to A1c reduction, weight loss, and reduction in insulin doses, the treatment arms did show an increased risk of dose-dependent hypoglycemia and hyperglycemia with ketosis as well as gastrointestinal adverse events. Similar to the SGLT inhibitors, all available GLP-1 RAs are brand-name with a high price tag, often limiting their use (Appendix I, Table 2). Future studies focused on patient-oriented evidence that matters, such as prevention of microvascular or macrovascular outcomes, would be beneficial to truly determine their clinical utility.
When to Choose an SLGT Inhibitor or GLP-1 RA in T1DM?A patient with T1DM may be a good candidate for an SLGT inhibitor if overweight or obese and interested in an oral agent in addition to an insulin regimen. Duration of diabetes does not appear to be a factor affecting efficacy of SGLT inhibitors in T1DM. This class may be considered in patients who are at risk for hypoglycemia, as the recent clinical trials did not show an increase rate of hypoglycemia in the treatment groups. This class should be avoided in patients with a recent history of, or who are at high risk for, a DKA episode. On the other hand, a GLP-1 RA may be the best option to add on in a patient with newer-onset T1DM, residual β-cell function, or residual C-peptide levels, as the preliminary literature and subgroup analyses show the most benefit in this population. Obese and overweight patients with T1DM may benefit from the weight loss properties, and the class should be used with caution in patients at a higher risk of DKA or hypoglycemic events, as the recent evidence showed a higher incidence of these adverse effects. Overall, the benefits of both classes in addition to insulin therapy in T1DM appear to be promising. However, due to the potential for adverse effects, in addition to cost, lack of FDA-approval, and lack of insurance coverage, the practicality of using either class is relatively low at this time.
Paradigm ShiftOver the past few years there has been a shift in framework for managing diabetes. Landmark trials such as the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated that the longer amount of time patients with T1DM spend meeting glycemic goals, the lower risk of long-term microvascular and macrovascular complications.29,30 Newer trials, such as LEADER and EMPA-REG, have shown cardiovascular benefit (and even renal benefits) with specific drug classes in patients with type 2 diabetes within 3 to 5 years.21,32 Perhaps, there is more to prevention of complications in patients with diabetes than merely meeting glycemic goals. Future trials evaluating the prevention of microvascular and macrovascular complications with SLGT inhibitors and GLP-1 RAs in the treatment of T1DM have the potential to transform the current treatment algorithms.
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