June 2017 Newsletter
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Clinical Articles
Tresiba ® (insulin degludec) in Type 2 Diabetes
Eryn Thacker, Pharm.D. Candidate Class of 2017 and Maria Miller Thurston, Pharm.D., BCPS
Corresponding Author:
Maria Miller Thurston, Pharm.D., BCPS
Clinical Assistant Professor
Mercer University College of Pharmacy
3001 Mercer University Drive
Atlanta, GA 30341
T: (678) 547-6253
F: (678) 547-6384
According to the American Diabetes Association (ADA), the prevalence of diabetes mellitus has increased from 15.2 million Americans in 2004, to 22 million Americans in 2014, with the majority having Type 2 diabetes.1 This statistic alone is alarming enough to raise attention to the impact of diabetes on the United States population. Additionally, diabetes mellitus costs 245 billion dollars annually due to direct medical costs, as well as reduced productivity associated with the condition. Type 2 diabetes is the most common form of diabetes, accounting for 90-95% of all diabetes cases.2 Type 2 diabetes begins with insulin resistance which results in the pancreas attempting to produce more insulin to correct the problem. However, the pancreas cannot keep up with the demands of the body and hyperglycemia occurs.2 Diagnosis may be made using various methods: a fasting plasma glucose (FPG) level of ≥ 126 mg/dL, 2-hour plasma glucose of ≥ 200 mg/dL during an oral glucose tolerance test (OGTT), or an A1c >/= 6.5%.2 The patient can also be diagnosed with diabetes if they present with classic symptoms of hyperglycemia with a random plasma glucose ≥ 200 mg/dL.2 Some patients with Type 2 diabetes may be managed with diet and exercise alone; however, many patients will need pharmacologic intervention, such as oral antidiabetic medication(s) and/or insulin.1
Guideline Directed Therapy Recommendations
The ADA publishes treatment guidelines, "Standards of Medical Care in Diabetes," in January of each year. This publication drives treatment recommendations and practice in the United States. Once a patient is diagnosed with Type 2 diabetes based on blood glucose levels or the hemoglobin A1c (HbA1c), the recommended first-line treatment is generally monotherapy with metformin, an oral agent that decreases gluconeogenesis and increases insulin sensitivity.3 Before initiating metformin, the patient's renal function should be assessed as it is contraindicated in patients with an eGFR < 30 mL/min and initiation is not recommended if the eGFR is 30-45 mL/min, according to new prescribing information.3 If the patient is a candidate for metformin, therapy will be initiated, and the HbA1c will be reassessed after three months. If the HbA1c is not at goal of < 7% (for most patients) per the ADA guidelines, combination therapy with an additional agent is warranted.2 Combination therapy offers a variety of options from the following six drug classes: sulfonylureas, thiazolidinediones, dipeptidyl peptidase-3 (DPP-4) i nhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin.2 Insulin therapy can be added after oral medications or it can be initiated in newly diagnosed patients with Type 2 diabetes if they have severe symptoms or markedly elevated blood glucose or HbA1c levels.2 If after three months of combination therapy with two medications does not achieve the target A1c of < 7%, a third agent can be added from a different class.2
Insulin therapy is initiated in a progressive fashion. Initiation often occurs with basal insulin using 10 units per day or 0.1 to 0.2 units/kg/day and is adjusted to target a FPG goal between 80-130 mg/dL. If the target FPG is achieved, yet the patient is not controlled, then a rapid insulin injection may be added before the largest meal of the day or the patient may be changed to a twice-daily premixed insulin. If the patient is still not achieving all goals, a basal-bolus insulin regimen may be initiated. This regimen involves two or more rapid insulin injections before meals as well as the basal insulin.2
Optimizing Basal Insulin Therapy: Tresiba®
Insulin therapy for Type 2 diabetes is typically initiated with basal insulin therapy, and basal insulin remains a vital component of the patient's regimen thereafter. Thus, optimization of basal insulin therapy options is desired. Due to the importance of basal insulin, Tresiba® (Iinsulin degludec) has been introduced to the market by Novo Nordisk as of September 25, 2015. Considered an ultra-long acting insulin, Tresiba® is a once-daily injection with a half-life of over 24 hours. The molecular design of Tresiba® resembles a "string of pearls" which gradual breaks off piece by piece to allow for slow and sustained blood glucose control that has been shown to last for up to 42 hours.3 The goal of this ultra-long acting insulin is the prospect of more consistent blood glucose levels and less hypoglycemic episodes.4
Clinical Trials
The recent approval and introduction of Tresiba® was based on the key clinical trials that have been completed in the past few years. While Tresiba® has been studied in Type 1 and Type 2 diabetes, the SWITCH 2 trial, BEGIN®: Flex trial, and Begin®: Low Volume trial show specific data regarding the safety and efficacy of Tresiba® in patients with Type 2 diabetes.
A trial comparing the safety and efficacy of insulin degludec and insulin glargine, with or without OADs in subjects with type 2 diabetes (SWITCH 2)
Tresiba® was studied in the SWITCH 1 trial in patients with Type 1 diabetes, which compared Tresiba® to Lantus® (insulin glargine) using a crossover design.6 This trial set the format for the SWITCH 2 trial which evaluated Tresiba® in patients with Type 2 diabetes with or without oral medications, an HbA1c ≤ 9.5%, and a body mass index (BMI) ≤ 45 kg/m2.5 In this study, 721 patients were blinded and randomized to receive either Lantus® or Tresiba® for 16 weeks of initiation and 16 weeks of maintenance therapy. After the initial 32 weeks, the patient was switched to the opposite therapy. The primary outcome of this trial was the number of treatment emergent or symptomatic hypoglycemic episodes during the maintenance period. Tresiba® showed a statistically significant reduction in hypoglycemic episodes compared to insulin glargine. The rate for severe hypoglycemia during the full treatment period was 0.04 in the Tresiba® arm compared to 0.09 in the insulin glargine arm (p<0.0306). Additionally, there was a statistically significant difference in the rate of nocturnal hypoglycemia at a rate of 0.72 during the full treatment phase with the Tresiba® arm as compared to 0.88 in the insulin glargine arm (p=0.007).7 The SWITCH 2 trial demonstrated that Tresiba® is not only safe, but additionally showed that the ultra-long half-life contributes to its efficacy as a basal insulin.  
The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec, dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes
The BEGIN®-Flex study was a 26-week, open-label trial involving patients with Type 2 diabetes that were insulin naïve with a HbA1c between 7%-11% or were previously on basal insulin with a HbA1c between 7%-10%. The purpose of this study was to compare the efficacy and safety of the timing of insulin degludec. The Flex group received insulin degludec on a forced rotation morning-and-evening dosing regimen where each dose was between 8 and 40 hours after the previous dose. This Flex group was compared against traditional once-daily insulin degludec, as well as traditional once-daily insulin glargine. The primary outcome was the change from baseline in HbA1c after 26 weeks of treatment. The reduction HbA1c for the groups were 1.26% for insulin degludec Flex, 1.07% for insulin degludec once daily, and 1.26% for insulin glargine once daily. There was no significant difference between the groups with an estimated treatment different (ETD) of 0.04% (95% CI -0.12 to 0.20) compared to insulin glargine and an ETD of -0.13% (95% CI -0.29 to 0.03) compared with once-daily insulin degludec. While the Flex dosing schedule did not show any difference, the manufacturer does not recommend this schedule as a prescribed regimen. Nevertheless, it was used to show that varying dosing similar to "real-life" patient schedules may occur with no significant consequence on the blood glucose or HbA1c levels.8
Low-volume insulin degludec 200 units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN: Low Volume trial
An additional trial, known as the BEGIN®: Low Volume trial was designed as a 26-week, randomized, controlled, treat-to-target trial to evaluate the efficacy and safety of insulin degludec 200 units/mL once daily as compared with insulin glargine 100 units/mL once daily. The primary objective of the Begin®: Low Volume trial was change in HbA1c from baseline which was shown to be non-inferior to insulin glargine (CI -0.11 to 0.19) . The trial also demonstrated a statistically significant FPG reduction of -3.7 mmol/L with insulin degludec compared to -3.4 mmol/L with insulin glargine (p=0.02). This formulation of insulin degludec did not demonstrate statistically significant differences in hypoglycemic episodes compared to insulin glargine.9
Clinical Implications
Tresiba® has been proven safe and effective in multiple studies and is a valid option for patients with Type 2 diabetes who require basal insulin therapy. Variability of the timing of Tresiba® dosing has been tested and has indicated no significant impact on HbA1c reductions or hypoglycemic risk which would potentially allow for enhanced glycemic control and less consequences for patients with adherence issues. This is a major advantage for patients who struggle with the burden of complex insulin dosing schedules. Tresiba® also offers two different dosages of the Flexpen: U-100 and U-200. The U-200 pen is highly concentrated and allows for a dose of up to 160 units in one single injection which lessens the needle burden for patients. However, it is important to note that through the extensive studies, Tresiba® was never tested in a superiority trial and has only been proven to be non-inferior. Another limitation of the data with Tresiba® is that the trials only included patients with HbA1c levels less than 10% and had strict limits on the BMI of its participants which leaves out a large population of uncontrolled patients who have HbA1c levels much greater than 10% or are obese.
Unfortunately, along with its ultra-long half-life comes a hefty price tag. Each box of Tresiba® Flexpens contains 5 pens that are 3 mL each (15 mL total). One box of the Tresiba® U-100 pens has a cash price of $532.69, while one box of the Tresiba® U-200 pens has a cash price of $1065.29. Many insurance programs have incorporated Tresiba® into their formulary, though it may be a higher tier medication with a larger co-pay than other insulin therapies. Tresiba® has been added to the Georgia State Medicaid and Peachcare formularies as a non-preferred drug; however, it can be covered through the prior authorization program.10 Novo Nordisk does offer a Patient Savings Card that saves up to $500 per prescription for up to 2 years. This card must be used in combination with primary insurance, not including any government-funded insurance such as Medicare or Medicaid. Tresiba® is not included on Novo Nordisk's Patient Assistance Program at this time.
While Tresiba® is not an ideal option for all patients with Type 2 diabetes, it is a great solution for those patients who have a high risk or history of hypoglycemia. Additionally, patients who require high unit doses of insulin may also benefit from Tresiba® due to the U-200 Flexpen option. Finally, Tresiba® is ideal for patients with primary insurance that can use the Patient Savings Card to obtain Tresiba® at a reasonable price and is a sensible option for patients with varying schedules and adherence issues due to its long half-life and flexible dosing.  
  1. Statistics About Diabetes: Overall Numbers, Diabetes and Prediabetes. Available at: http://www.diabetes.org/diabetes-basics/statistics. Accessed December 5, 2016.
  2. American Diabetes Association. Standards of Care in Diabetes 2016. Diabetes Care. Volume 39, Supplement 1. January 2016.
  3. Metformin. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH: Lexi-Comp, Inc; 2016. Accessed December 5, 2016.
  4. Novo Nordisk. Tresiba®. Available at: http://www.tresiba.com. October 2016. Accessed November 30, 2016.
  5. Wysham C, Bhargava A, Chaykin L, et al. "A Trial Comparing the Safety and Efficacy of Insulin Degludec and Insulin Glargine, With or Without OADs in Subjects With Type 2 Diabetes (SWITCH 2)." ClinicalTrials.gov. Novo Nordisk A/S, Dec. 2015. Web. Accessed 28 Nov. 2016.
  6. Heller S, Buse J, Fisher M, at al. BEGIN Basal-Bolus Type 1 Trial Investigators. Insulin degludec, an ultra-long acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012 Apr 21;379(9825):1489-97
  7. Wysham, C et al. Poster 90-LB presented at: 76th American Diabetes Association Scientific Sessions; June 10-14, 2016; New Orleans, LA.
  8. Meneghini L, Atkin SL, Gough SC, et al. NN1250-3668 (BEGIN FLEX) Trial Investigators.. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec, dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care. 2013 Apr;36(4):858-64.
  9. Gough SC, Bhargava A, Jain R, Mersebach H, Rasmussen S, Bergenstal RM. Low-volume insulin degludec 200 units/mL once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN: Low Volume trial. Diabetes Care. 2013 Sep;36(9):2536-42.
  10. Georgia Department of Community Health. 2016 Preferred Drug List. Updated November 1, 2016. Accessed December 5, 2016.

Gabapentin Misuse
McKinley G. King, Pharm.D. Candidate 2017
Stephanie V. Phan, Pharm.D., BCPP
Clinical Assistant Faculty
University of Georgia College of Pharmacy
Since coming to market, gabapentin has been widely prescribed for many off-label indications (e.g. insomnia, various neuropathic pain conditions, substance use disorders, and psychiatric illnesses as well as other medical conditions) and particularly as an alternative to other scheduled medications.1 Approximately 83-95% of all gabapentin usage is for an off-label purpose.2,3 Gabapentin, initially approved by the Food and Drug Administration in 1993 for seizure disorder treatment, has increased in infamy among clinicians, though sole gabapentin dependence and overdose appears to be anecdotal. Its rise in use amongst patients, clinicians, and drug users alike begs the question of its potential addictiveness and dangerousness compared to medications with an established addictive nature. Gabapentin's unscheduled status may lead providers to believe that gabapentin is without risk of being misused.4 The prescribing information states that though gabapentin does not appear to innervate benzodiazepine, opioid, or cannabinoid receptors, a small number of post-marketing case reports showed evidence of misuse amongst patients taking higher-than-recommended doses for unapproved indications.5
In the general population, overall prevalence of gabapentin misuse has been reported at 1%.1 Rates increase and range between 40 and 65% in people with gabapentin prescriptions.1 When including both gabapentin and pregabalin, a prevalence of 1.6% was observed and ranged from 3 to 68% in opioid abusers .6 Based on the European Medicines Agency's EudraVigilance database, between 2004 and 2015, 4.8% of adverse drug reaction reports related to gabapentin included reference to misuse, abuse, or dependence .7 Rates of misuse, abuse, and dependence reporting were 6.6% with pregabalin .7 The number of reports increased per year .7 The National Estimates of Drug-Related Emergency Department Visits' (NEDREDV) data show that from 2004 to 2011 gabapentin-related emergency department admission rates (of a 100,000 sample) rose from 2.7 to 4.9.8 This increased trend is small compared to the jump observed with opioid related admissions (67.7 to 178.9).8 A separate study analyzing blood samples of patients arrested for "driving under the influence" revealed that 7% of gabapentin-positive blood samples detected gabapentin only; all others contained gabapentin with additional substances: benzodiazepines and opioids being the most common.9 Most studies evaluating toxicology found multiple substances, including alcohol, other central nervous system depressants, cannabinoids, cocaine, and stimulants, present alongside gabapentin.1 Thus, it appears the prevalence of gabapentin misuse is low, though increasing, compared to other illicit substances and that it generally occurs at higher rates alongside misuse of other substances.
A literature review by Smith et al. published in August 2015 revealed that more than half of the 33 publications identified described gabapentin misuse with a concurrent addiction or history of addiction.1 In one article, approximately 22% of a sample of 162 opioid dependent individuals reported having a prescription for gabapentin, and 40% of those with a prescription reported using more than originally prescribed.10 Though health services or providers appear to be the main sources for misused gabapentin, other sources include family or friends and the internet.1 Reeves' research found that gabapentin could be sold or traded for other drugs.11 Gabapentin's street value varies by strength, but is approximately $1-7 per pill in the United States.12 Individuals taking gabapentin with benzodiazepines may be actively seeking a "high," whereas others taking gabapentin alone or in other combinations may experience a sedative, "calming" sensation.1 Still, other users may seek euphoria or dissociative effects, similar to the effects of certain recreational or illicit substances.7 A combination of drugs was commonly used to obtained the desired effect.1 Individuals misusing gabapentin may also be self-treating mood and/or anxiety problems, potentiating effects of or avoiding withdrawals associated with other drugs, and intentionally harming themselves.1
The intended recreational, self-harm, and self-medicating effects of gabapentin are obtained within the therapeutic range or at supratherapeutic doses.1,13 This is especially interesting because of gabapentin's saturable kinetics and inconsistent permeation of the blood brain barrier. Because gabapentin is transported by the L-amino acid transport system in the intestinal lumen and the blood brain barrier, an acute overdose of gabapentin would result in nonlinear increase in serum levels.14 Yet, the first published postmortem case of gabapentin overdose reported a peripheral drug concentration of 88 mcg/mL, at the lower end of concentration ranges previously reported from both accidental and intentional overdoses where the patients survived. Though the autopsy did reveal the presence of clonazepam and its metabolite, the blood concentrations were below therapeutic ranges. It is unlikely that the use of benzodiazepines in this case was a contributor to the fatality.15
Clinicians may question gabapentin's addictiveness and kinetics compared to that of its scheduled counterpart, pregabalin. Pregabalin misuse occurs in individuals with a history of substance misuse and addiction.16 Most doses reported are well above the maximum therapeutic dose and with half of users habitually using more than one psychoactive substance.16 The difference in pregabalin versus gabapentin and the reason for its schedule V status may lie in its kinetic profile. Pregabalin is more rapidly absorbed (faster onset), possesses a higher absolute bioavailability, and its potency has been described to range from 2.5 to 6 times more potent than gabapentin.7,16 Absorption occurs throughout the intestinal tract and is not saturable, leading to increased side effects and a "high" feeling when taken in excess.16 Though generally taken orally, individuals misusing gabapentinoids may use other routes of administration as well, such as inhaling, smoking, injecting, and rectal plugging .6 Withdrawals (suggesting physical dependence) associated with pregabalin and gabapentin have been described to include agitation or anxiety, sweating, insomnia, fatigue, heart palpitations, tremors, or diarrhea.6,7 Craving has also been reported.7
Though gabapentin is an unscheduled drug, a number of case reports and recently published reviews have brought increasing recognition to gabapentin abuse, dependence, and withdrawal.6,7,17 Gabapentin has a favorable tolerability when used at therapeutic doses for appropriate indications .6 It has not yet been proven to display harm likening it to addictive illicit and prescription options. As always, the risks and benefits of a medication should be assessed prior to prescribing. Though history of or current substance misuse disorder is not a known risk factor for gabapentin misuse, it generally has been identified in the context of co-occurring substance use disorders, particularly opioid misuse.1,6 Awareness to signs and symptoms or risk factors for substance misuse disorders should be assessed by providers to aid in safe prescribing.6 Gabapentin, a useful and well-tolerated medication, should continue to be monitored for future trends in use and subsequently, possible harmful events.
  1. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016 Jul;111(7):1160-74.
  2. Hamer AM, Haxby DG, McFarland BH, Ketchum K. Gabapentin use in a managed Medicaid population. J Manag Care Pharm. 2002; 8: 266-71.
  3. Bradley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006; 166: 1021-6.
  4. Public Health England and NHS England. Advice for prescribers on the risk of the misuse of pregabalin and gabapentin. Public Health England. 2014.
  5. Pfizer Inc. Neurontin medication guide. Retrieved from http://www.accessdata. fda.gov/drugsatfda_docs/label/2011/020235s036,020882s022,021129s022lbl.pdf.
  6. Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs 2017. DOI: 10.1007/s40265-017-0700-x. [Epub ahead of print]
  7. Chiappini S, Schifano F. A decade of gabapentinoid misuse: an analysis of the European Medicines Agency's 'Suspected Adverse Drug Reactions' Database. CNS Drugs 2016;30:647-54.
  8. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network. Retrieved from http://www.samhsa. gov/data/DAWN.aspx.
  9. Peterson BL. Prevalence of gabapentin in impaired driving cases in Washington State in 2003-2007. J Anal Toxicol. 2009; 33: 545-9.
  10. Wilens T, Zulauf C, Ryland D, Carrellas N, Catalina- Wellington I. Prescription medication misuse among opioid dependent patients seeking inpatient detoxification. Am J Addict. 2015; 24: 173-7.
  11. Reeves RR, Burke RS. Abuse of combinations of gabapentin and quetiapine. Prim Care Companion CNS Disord. 2016; 16.
  12. Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among nonmusical prescription opioid users in Appalachian Kentucky. Am J Psychiatry. 2015; 172: 487-8.
  13. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010; 49: 661-9.
  14. Dickens D, Webb S, Antonym S, Giannoudi A, Owen A, Rädisch S, Pirmohamed M. Transport of gabapentin by LAT1 (SLC7A5). Biochemical Pharmacology. 2013: 85, 1672-1683.
  15. Middleton O. Suicide by Gabapentin Overdose. J Forensic Sci. 2011 Sep;56(5):1373-5.
  16. Papazisis G, Tzahanis D. Pregabalin's abuse potential: a mini review focusing on the pharmacological profile. Int J Clin Pharmacol Ther. 2014 Aug;52(8):709-16.
  17. Mersfelder TL, Nichols WH. Gabapentin: abuse, dependence, and withdrawal. Ann Pharmacother 2016;50(3):229-33.
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