• 12 Jan 2018 2:40 PM | Deleted user

    Initial Combination versus Monotherapy for the Treatment of Type 2 Diabetes
    Authors: Kacie Kuehn, PharmD: PGY-2 Ambulatory Care Resident
    St. Louis College of Pharmacy/St. Louis County Department of Public Health – St. Louis, MO

    Justinne Guyton, PharmD, BCACP: Assistant Professor, Pharmacy Practice
    St. Louis College of Pharmacy

    Program Number: 2017-12-11
    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: mshp@qabs.com

    1) Describe the safety and efficacy outcomes of recent literature pertaining to initial combination therapy treatment of type 2 diabetes.
    2) Create a patient-specific treatment plan for the management of type 2 diabetes.

    The primary goals in the management of patients with type 2 diabetes are to reduce mortality and prevent microvascular and macrovascular complications. Although glycemic targets may be individualized, a targeted glycated hemoglobin (A1c) less than 7% set by the American Diabetes Association (ADA) is a glycemic goal of therapy to reduce the incidence of diabetes-related complications.1 However, only half of patients with diabetes are meeting this treatment goal, illustrating a need for improving diabetes management.2

    In most patients, treatment begins with lifestyle modifications and the addition of one antihyperglycemic agent. If glycemic control is not met after titration, patients are managed with sequential add-on agents at subsequent visits. However, there are instances in which dual therapy is recommended initially. The ADA recommends considering initial combination therapy in patients with an A1c at or above 9%.1 In contrast, the American Association of Clinical Endocrinologists (AACE) indicates that combination therapy be initiated when patients present with an initial A1c above 7.5%.3 This contrast leaves practitioners with an important clinical question: why might initial combination therapy be beneficial and when should it be utilized? To help answer this question, this article will focus on four characteristics that may influence the decision: efficacy, hypoglycemia, side effects, and cost.

    The concept of metabolic memory in type 2 diabetes has been discussed since the publication of the UKPDS 10-year follow-up in 2008. This trial established that a sustained period of early A1c control can have a long-term impact on subsequent risk of microvascular and macrovascular complications. In the UKPDS trial, a cohort of 3,867 patients newly diagnosed with type 2 diabetes was followed for 10 years. Patients were randomized to a standard A1c goal or an intensive A1c goal and then treated with a sulfonylurea alone or in combination with insulin. At 10 years, those in the standard A1c arm achieved a median A1c of 7.9% while the intensive A1c arm achieved a median A1c of 7.0% (P<0.001). Those treated with a sulfonylurea had a hypoglycemia rate of 17.7%, compared to 36.5% for those treated with insulin. Patients with diabetes managed with diet changes alone had a 1.2% rate of hypoglycemia. The patients in the intensive arm had a 25% risk reduction in microvascular complications (P<0.05), with no significant impact on cardiovascular outcomes.4 Interestingly, during post-trial monitoring, the A1c converged between arms within 1 year. At the end of the 10-year post-trial follow-up, both groups had a similar A1c at approximately 7.8% (P=0.71). Despite having a similar A1c upon completion of the follow-up period, those initially randomized to intensive A1c control still experienced long-term benefits. This intensive A1c arm had a 24% relative risk reduction in microvascular complications (P<0.05), a 15% relative risk reduction in myocardial infarctions (P<0.05), and a 13% relative risk reduction in all-cause mortality (P<0.01), compared to those with standard control at 10 years.5 These data support the concept of metabolic memory and begin to establish that a more aggressive early approach to glycemic control is essential to the treatment of type 2 diabetes.

    Literature and guidelines have established metformin as first-line therapy for the treatment of type 2 diabetes, in the absence of contraindications, due to evidence of safety, efficacy, and a reduction in cardiovascular events.2,6 As new literature is published establishing the pleotropic benefits of other anti-hyperglycemic medications, thought must be given to when it is appropriate to initiate a second anti-hyperglycemic medication. In particular, focused research has been done to establish microvascular and macrovascular outcomes related to glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is).7

    The LEADER trial randomized patients with type 2 diabetes to receive liraglutide or placebo. At the end of the almost 4-year trial period, the 3-point major adverse cardiac events (MACE) primary outcome occurred in 13% of patients in the liraglutide group, compared to 14.9% in placebo (P=0.01).8 Another randomized controlled trial of patients with type 2 diabetes and risk of cardiovascular disease found that treatment with liraglutide compared to placebo reduced new-onset, persistent A3 albuminuria; at 15% and 19%, respectively (P=0.003)9. Similarly, empagliflozin was compared to placebo in the EMPA-REG OUTCOME trial, which included patients with type 2 diabetes. Treatment with empagliflozin significantly reduced the incidence of the 3-point MACE; 10.5% vs. 12.1% (P<0.01).10 The EMPA-REG ESRD trial found that empagliflozin reduced progression to A3 albuminuria when compared to placebo; 11.2% vs. 16.2%, respectively (P<0.001).11 This evidence supports the use of these medication classes, or certain medications within these classes, to prevent complications, particularly renal and cardiovascular complications. Delaying add-on treatment with one of these medications because a patient’s A1c is not above 9% at initial presentation (as the ADA guidelines recommend) may not be best practice because of the additional benefits of complication prevention.

    Clinical inertia, the resistance to treatment initiation or intensification, despite a patient not reaching glycemic goals, also factors into the delay of add-on treatment.12 One study identified the prevalence of clinical inertia, with less than 50% of patients with type 2 diabetes and an A1c greater than 8% receiving treatment intensification.13 In 2014, Rajpathak and colleagues retrospectively analyzed the impact of timing of treatment intensification with oral add-on therapy on glycemic goal attainment among patients with type 2 diabetes failing metformin monotherapy. Almost 6,000 patients were evaluated and analyzed based on time to treatment intensification: no treatment intensification, early intensification at 3 months, intermediate intensification at 4 to 9 months, or late intensification within 10-15 months of first A1c above 7.5%. The majority of patients, 51%, stayed on metformin monotherapy during the study: 23% in the early group, 15% in the intermediate, and 11% in the late group. The baseline A1c was on average 8.01-8.5%. However, most patients never received therapy escalation, but if they did it was within 3 months. Patients with a baseline A1c of more than 8% and received early add-on of second agent, were more than 1.5 times more likely to reach their A1c goal of less than or equal to 7% at 2 years than those in the late add-on group.14 Use of dual initial therapy in patients with an A1c above 8% may help prevent clinical inertia and increase the chance of reaching an A1c goal of less than 7%, based on these results.

    In addition to reaching an A1c goal, maintaining A1c at goal is another long-term target. The EDICT trial, published in 2015, aimed to determine the efficacy and durability of initiating a combination of agents to treat new-onset diabetes, compared to the sequential addition of agents. This randomized controlled trial included only drug-naïve patients with type 2 diabetes diagnosed within two years. Patients were randomized to receive conventional, sequential addition of therapy or initial combination therapy. Conventional therapy consisted of metformin combined with glipizide and then insulin glargine at one, two and three months. Initial combination therapy consisted of metformin, pioglitazone, and exenatide titrated at one and three months, if glycemic goals were not being met. On average, patients included in the trial were within six months of diagnosis and had a baseline A1c of 8.6%. At 24 months, patients who received conventional therapy reached an A1c of 6.5% and those with initial combination therapy reached an A1c of 5.95% (P<0.05). These results, although statistically significant, have less clinical significance because both groups reached the A1c goal. However, less than 75% of patients in the conventional group maintained an A1c less than 7%, compared to those in the initial combination group, in which over 90% maintained A1c at goal. In the conventional group, 46% of patient experienced mild hypoglycemic events compared to 14% in the initial combination group.15 This is an expected result considering the variability of insulin use between arms. Data from this study provides evidence that an effective and durable A1c reduction can be achieved using agents with a lower hypoglycemia risk. The EDICT trial utilized triple therapy in the combination group, which may not be practical for most clinical situations where the close monitoring of a randomized controlled trial cannot be duplicated. However, translating combination therapy to clinical practice may be achieved through dual therapy.

    Limiting the risk of hypoglycemia is a major clinical consideration when choosing antihyperglycemic therapy. The EDICT trial illustrated that it is possible to achieve glycemic control without increasing the risk of hypoglycemia.15 The crux of this outcome is the choice of antihyperglycemic agents. Many agents confer a risk of hypoglycemia that increases with additional agents (Table 1). Excluding insulin, the highest rates of hypoglycemia occur with sulfonylureas, both as monotherapy and combination therapy. Therefore, if initiating dual initial combination therapy and hypoglycemia is a concern due to patient characteristics, it would be prudent to avoid sulfonylureas when possible. In addition, sulfonylureas have not demonstrated the same pleotropic benefits seen with SGLT2-Is or GLP1-RAs, further limiting their use in combination therapy.7

    Hypoglycemia is often cited as a reason for not initiating more aggressive initial therapy. A 2016 systematic review found that physicians cited fear of hypoglycemia and other side effects as an influence on diabetes treatment.16 Conversely, in a 2014 systematic review, patients indicated they would prefer glucose control over avoiding minor hypoglycemic events.17 While hypoglycemia should remain at the forefront of clinical decision-making, this research may highlight the value of having patient-centered conversations of the risk versus benefits. Thus, the potential roadblock of hypoglycemia may be less of a concern in the decision to use monotherapy or combination therapy for initial treatment.

    Side Effects
    Besides hypoglycemia, other side effects influence clinical decisions for use in combination therapy as well. Interestingly, more research has begun to identify possible combinations of medication classes that would strategically reduce risk of side effects through their mechanisms of action. For example, when SGLT2-Is were added to pioglitazone, there was a reduction in hypervolemia typically seen secondary to thiazolidinediones18. Dipeptidyl peptidase 4 inhibitors (DPP4-Is), when added to SGLT2-Is, reduced the incidence of genital infections, although the mechanism of action of this benefit has not been established19.

    This potential benefit of combination therapy comes with the caveat that any medication combination does: with each additional medication the side effect profile grows. If two medications started at the same time share a side effect, it may be difficult to discern which medication is the true cause. For example, GLP1-RAs and metformin can both cause gastrointestinal upset.20,21 If both medications were start concomitantly and the patient experienced nausea, it would be difficult to determine which medication to decrease to a lower dose or discontinue. This must be considered with dual initial therapy and patient education on side effects would be especially vital.

    Depending on a given patient’s insurance status, cost may play a critical role in the choice of antihyperglycemic agents. As has been established, dual initial therapy provides efficacy and durability benefits in the treatment of type 2 diabetes. These benefits could make a higher initial cost of multiple medications worthwhile. In addition, combination pills are available for a variety of drug classes (Table 2), which may eliminate the increased cost incurred with multiple medications. This depends heavily on the route of administration for a given drug class, as GLP1-RAs clearly cannot be included in a combination with an oral medication and typically have higher co-pays associated with them.20,21 Monotherapy will usually be less expensive and therefore may be the only option for certain patients. Every avenue for assisting patients in this situation should be explored, including combination pills, discounted generic medications at certain pharmacies, and patient-assistance programs through medication manufacturers.

    The ADA guidelines and AACE guidelines have established two different thresholds for when initial combination therapy should be considered; at or above 9% and above 7.5%, respectively.2,3 This establishes a “grey area” between an A1c of 7.5% and 9% -- should initial dual therapy be utilized in this range?

    The early treatment of type 2 diabetes is integral to long-term prevention of complications. Metabolic memory resulting from early glycemic control establishes pleotropic benefits that are sustained, even if glycemic control is lost.22 ,Certain medication classes or medications within these classes have microvascular and macrovascular beyond the benefit established with glycemic control. This makes early initiation with classes, such as GLP1-RAs and SGLT2-Is, an integral component of patient-centered care. Clinical inertia may be a barrier to attaining these benefits. Therefore, it may not be prudent to rely on escalation of therapy over time to achieve glycemic control or to prevent complications. However, initial combination therapy may help prevent clinical inertia. If hypoglycemia is concern, care should be taken to appropriately titrate medications and the choice of medications is vital. Avoiding combinations with sulfonylureas will help reduce the risk of hypoglycemia. However, as evidenced in the EDICT trial, combination therapy can be utilized effectively to reach glycemic control, increase durability of control, and decrease risk of hypoglycemia.

    In the evidence presented in this review, the majority of patients had a baseline A1c between 8-8.5%. Clearly, benefit is seen with initiating combination therapy in this population. Therefore, in treatment-naïve patients with an A1c greater than 8%, an initial dual oral antihyperglycemic regimen is favored.

    1. Glycemic Targets. Diabetes Care. 2017;40(Suppl 1):S48-S56.
    2. Dodd AH, Colby MS, Boye KS, Fahlman C, Kim S, Briefel RR, Treatment approach and HbA1c control among US adults with type 2 diabetes: NHANES 1999-2004. Curr Med Res Opin. 2009; 25:1605-1613.
    3. T2D Algorithm, Executive Summary, Endocr Pract. 2017;23(2).
    4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-53.
    5. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-89.
    6. Lamanna C, Monami M, Marchionni N, et al. Diabetes Obes Metab. 2011;13(3):221-8.
    7. Schnell O, Standl E, Catrinoiu D, et al. Report from the 2nd cardiovascular outcome trial (CVOT) summit of the diabetes and cardiovascular disease (D&CVD) EASD study group. Cardiovasc Diabetol. 2017;16(1):35.
    8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-22.
    9. Mann JF, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839-48.
    10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.
    11. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016:375(4):323-34.
    12. Bailey CJ. Under-treatment of type 2 diabetes: Causes and outcomes of clinical inertia. Int J Clin Pract. 2016;70(12):988-995.
    13. Shah BR, Hux JE, Laupacis A, Zinman B, Van walraven C. Clinical inertia in response to inadequate glycemic control: do specialists differ from primary care physicians?. Diabetes Care. 2005;28(3):600-6.
    14. Rajpathak SN, Rajgopalan S, Engel SS. Impact of time to treatment intensification on glycemic goal attainment among patients with type 2 diabetes failing metformin monotherapy. J Diabetes Complicat. 2014;28(6):831-5.
    15. Abdul-ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17(3):268-75.
    16. Rushforth B, Mccrorie C, Glidewell L, Midgley E, Foy R. Barriers to effective management of type 2 diabetes in primary care: qualitative systematic review. Br J Gen Pract. 2016;66(643):e114-27.
    17. Von arx LB, Kjeer T. The patient perspective of diabetes care: a systematic review of stated preference research. Patient. 2014;7(3):283-300.
    18. Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16(2):147-58.
    19. Scheen AJ. DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Expert Opin Drug Metab Toxicol. 2016;12(12):1407-1417.
    20. Trulicity® [package insert]. Eli Lilly & Co. Indianapolis, IN; 2017.
    21. Victoza® [package insert]. Novo Nordisk Inc. Princeton, NJ; 2017.
    22. Ceriello A. The emerging challenge in diabetes: the "metabolic memory". Vascul Pharmacol. 2012;57(5-6):133-8
    23. Januvia® [package insert]. Merck & Co. Kenilworth, NJ; 2017.
    24. Onglyza® [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE; 2016.
    25. Jardiance® [package insert]. Eli Lilly & Co. Indianapolis, IN; 2016.
    26. Invokana® [package insert]. Janssen Pharmaceuticals. Beerse, Belgium; 2017.
    27. Lexicomp Online® , Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc., 2017.
    28. Missouri Department of Social Services. Pharmacy clinical edits and preferred drug lists. MO.gov. Accessed October 2, 2017.


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  • 12 Jan 2018 1:47 PM | Deleted user
    Authors: Christiana Graham, PharmD, Candidate 2018
    St. Louis College of Pharmacy

    Laura Challen, PharmD, MBA, BCPS, BCACP: St. Louis College of Pharmacy

    Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality in patients with diabetes.1,2 In fact, patients with type 2 diabetes are at least two times more likely to die from cardiovascular causes than the general population.3 This disparity underscores the importance of considering therapy impact on cardiovascular morbidity and mortality in patients with type 2 diabetes. In 2008 the Food and Drug Administration (FDA) published a guidance document proposing that all sponsors of antihyperglycemic drugs should conduct cardiovascular outcome trials (CVOTs) to demonstrate that the new drug does not result in an unacceptable increase in cardiovascular risk.4 More recently, the American Diabetes Association (ADA) addressed emerging evidence concerning cardiovascular outcomes by adding a recommendation in their 2018 guideline publication. This recommendation suggests that in patients with established ASCVD, an agent with proven reductions in major adverse cardiovascular events and/or cardiovascular mortality should be incorporated after metformin and lifestyle modifications have failed.5 Of the medications that have come to market since the 2008 FDA guidance document, a class of antidiabetic medications called sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated promising cardiovascular effects.

    SGLT2 inhibitors are a class of oral antihyperglycemic medications that include empagliflozin, canagliflozin, and dapagliflozin. When used as add-on therapy to metformin, they provide an intermediate A1c lowering of around 0.5-1.0%.6 Apart from favorable effects on A1c and glucose control, SGLT2 inhibitors produce desirable metabolic effects, such as improved blood pressure and body weight (average reduction of 2 kg).7,8 Additionally, these agents have a low risk of hypoglycemia and may confer renal-protective properties.7,9

    The EMPA-REG OUTCOME study was the first CVOT published for the SGLT2 inhibitor class.10 Published in September 2015, this large randomized controlled trial studied the cardiovascular safety of empagliflozin. Nearly two years later in June 2017, the CANVAS Program was published which analyzed cardiovascular safety data pooled from two sister trials comparing canagliflozin to placebo.11 Overall, EMPA-REG and CANVAS were similar in study design. Both trials were multicenter, international, double-blind, non-inferiority to superiority, placebo-controlled, randomized trials. However, only patients with established cardiovascular disease were included in EMPA-REG, while approximately a third of the study subjects in CANVAS did not have a history of cardiovascular disease. The primary outcome studied was the same for both trials and was a composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. [See Table 1 for comparison of trials]

    The results of EMPA-REG and CANVAS were also comparable, with both trials demonstrating a 14% decrease in the primary composite endpoint [empagliflozin: (HR 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority), canagliflozin: (HR 0.86; 95% confidence interval, 0.75 to 0.97; P=0.02 for superiority)]. However, the individual components of the composite outcome were not necessarily lower. Empagliflozin was found to cause a statistically significant decrease in death from cardiovascular causes (HR 0.62; 95% CI, 0.49 to 0.77), but not in nonfatal myocardial infarction or nonfatal stroke event rates. On the other hand, canagliflozin did not achieve statistical significance for any individual component of the primary composite outcome. Interestingly, subgroup analyses of each of the trials revealed ethnic variations in cardiovascular benefits. These analyses revealed that Asian subjects had more desirable outcomes in the EMPA-REG study, while black patients had more desirable outcomes in the CANVAS Program.12 Although differences in study design prevent the direct comparison of results between these two trials, overall lower rates of adverse cardiovascular events were shown with empagliflozin and canagliflozin compared to placebo. Adding to CVOT data for this class of medications, another trial by the acronym of DECLARE-TIMI 58 evaluating the effects of dapagliflozin on cardiovascular events is anticipated for publication in 2019.13

    In addition to the cardiovascular outcomes data garnered from SGLT2 inhibitor CVOT trials, both expected and unexpected adverse events were observed. In line with previously reported adverse events, patients receiving an SGLT2 inhibitor were more likely to experience a genital infection, most often mycotic in nature. Volume depletion was observed at a somewhat increased incidence also in line with previous findings. Euglycemic diabetic ketoacidosis, an extremely rare adverse event for which there is a class warning, was observed at a slightly increased incidence, but at an expected rate of less than 1% of patients taking the interventional drug.14 Furthermore, two unexpected adverse effects were observed in the CANVAS Program that were not observed with SGLT2 inhibitors previously or in the EMPA-REG trial. The first of these was a 23% increased risk of low-trauma fracture (HR 1.23; 95% CI, 0.99 to 1.52). The second unexpected adverse effect was a nearly two-fold increase in lower extremity amputations (6.3 v. 3.4 amputations per 1,000 patient-years; HR 1.97; 95% CI, 1.41 to 2.75) with the majority of the amputations occurring at the toe or metatarsal. Although increased fracture and amputation risk was not observed in the EMPA-REG trial, rates of these complications were not systematically collected.12 Additionally, neither EMPA-REG nor CANVAS were adequately powered to detect a significant difference in fracture and amputation risks. The negative safety data of these agents, combined with the current average monthly cost of about $430, can make SGLT2 inhibitors less ideal for some patients.15

    All things considered, the results of the EMPA-REG OUTCOME study and CANVAS Program have changed the overall clinical picture of how SGLT2 inhibitors fit into therapy. As previously mentioned, advantages of SGLT2 inhibitors include weight loss, blood pressure reduction, renal-protective properties and a low hypoglycemia risk profile. Although the increase in low-trauma fracture and lower-extremity amputations observed in the CANVAS Program cannot be confirmed without further research, many practitioners are hesitant to utilize SGLT2 inhibitors because of these risks. Given current knowledge, whether or not the benefits of SGLT2 inhibitors outweigh the risks is not entirely clear. However, the positive cardiovascular outcomes data observed in the EMPA-REG OUTCOME study and CANVAS Program provide a larger picture of how SGLT2 inhibitors may be beneficial in patients with high cardiovascular risk.

    1. Gregg EW, Li, Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med. 2014; 370:1514-1523.
    2. American Diabetes Association. 9. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2018. Diabetes Care 2018;41(Suppl. 1):S86–S104.
    3. Sarwar N, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-22.
    4. FDA. Guidance for industry: diabetes mellitus--evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Washington, DC: US Department of Health and Human Resources; 2008.
    5. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes--2018. Diabetes Care 2018;41(Suppl. 1): S73-S85.
    6. Triplitt CL, Repas T, Alvarez C. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146065891. Accessed December 18, 2017.
    7. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose co-transporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262-74.
    8. Cai X, Ji L, Chen Y, et al. Comparisons of weight changes between sodium-glucose cotransporter 2 inhibitors treatment and glucagon-like peptide-1 analogs treatment in type 2 diabetes patients: A meta-analysis. J Diabetes Investig. 2017; 8: 510–517.
    9. Cherney DZ, Perkins BA, Soleymanlow N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587-97.
    10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.
    11. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657.
    12. Rastogi A, Bhansali A. SGLT2 inhibitors through the windows of EMPA-REG and CANVAS trials: a review. Diabetes Ther. 2017;8:1245-51.
    13. AstraZeneca. Bristol-Myers Squibb. The TIMI Study Group. Hadassah Medical Organization. ClinicalTrials.gov [Internet] Bethesda, MD: National Library of Medicine (US); 2000. [Accessed December 15, 2017]. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). Available from: https://clinicaltrials.gov/ct2/show/NCT01730534
    14. U.S Food and Drug Administration. SGLT2 inhibitors: drug safety communication – labels to include warnings about too much acid in the blood and serious urinary tract infections [Internet], 2015. Available from http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm475553.htm. Accessed 19 December 2017.
    15. Micromedex Healthcare Series. RED BOOK® Online. Greenwood Village, CO: Truven Health Analytics. http://truvenhealth.com/. Accessed 14 December 2017.

  • 12 Jan 2018 1:29 PM | Deleted user

    Teamwork Makes the Dream Work: Developing Collaborative Experiential Rotation Activities

    Authors: Lisa Cillessen, PharmD, BCACP; Elizabeth F. Englin, PharmD, BCPS; April Porter, PharmD, BCACP;
    Heather Taylor, PharmD, BCPS
    UMKC School of Pharmacy at MSU


    Collaborative learning activities involving multiple preceptors and students, within and between institutions, provide benefits to all involved. Due to increased precepting and clinical service demands, preceptors have difficulty incorporating learning activities into introductory/advanced pharmacy practice experiences (IPPE/APPEs). A unique way to overcome these demands, while enhancing student learning, is to develop collaborative learning activities with fellow pharmacy preceptors. The number of student pharmacists completing IPPE/APPEs has grown, due to development of new pharmacy degree programs and the addition of branch sites to established programs. This increase poses challenges for preceptors to meet the experiential education needs while balancing their clinical service and other work responsibilities. Developing collaborative learning activities within and between healthcare institutions can help mitigate precepting burdens. Multiple preceptors practicing within an institution facilitates one mode of collaboration. However, preceptors may practice within settings where they are the sole pharmacy preceptor. In these instances, they can collaborate with colleagues at other institutions. In addition to the preceptor benefits, collaborative learning activities enhance the students’ learning opportunities by increasing exposure to clinical insights and receiving additional feedback through involvement of multiple preceptors and peer learning.

    Within Institutions

    Institutions regularly have multiple students completing IPPE and/or APPE rotations at one time, often from different colleges of pharmacy. While balancing multiple students can be challenging, it also serves as an opportunity to develop collaborative learning activities to meet both student and preceptor needs. One such collaborative activity is site and computer orientation which can provide facility tours, badge access, introduction to electronic medical record, and location of resources. Group orientation can be led by a resident or preceptor, with the responsibility shifting based upon scheduling. Collaborative orientation ensures students are given a standardized overview, allowing preceptors to focus on rotation specific needs. Another collaborative learning activity within institutions is the coordination of topic discussions, journal clubs, and informal and formal presentations. Scheduling these activities to maximize student and preceptor participation allows students exposure to a variety of disease states and experiences. Another collaborative learning activity within institutions is student shadowing of other clinical pharmacists or healthcare professionals. This broadens the students’ exposure to areas of clinical pharmacy and may enhance inter-professional education. Students also get a comprehensive view of patient care services which allows for a greater understanding for cohesive care.

    Between Institutions

    At some institutions, there may be one or a few pharmacy preceptors, making it challenging to provide collaborative learning experiences within the institution. Preceptors can create opportunities to provide collaborative learning activities by identifying nearby pharmacists in similar practice settings to partner with. Collaborative activities can include, but are not limited to, orientation to the type of pharmacy, topic discussions, journal clubs, and informal and formal presentations. Collaborating between institutions allows students to gain different perspectives from other preceptors and students and compare procedures from different institutions to enhance learning.

    Benefits and Challenges of Collaborative Learning Activities 



    Collaborative learning activities can truly be endless when time for patient care is increased and learning experiences are enhanced. By providing you examples of current collaborations and activities, we hope to have sparked your creativity and inspiration for precepting students and working as a team within and outside of your current institution. The need for pharmacy preceptors will continue to increase as our demand for pharmacy-led services continues to expand. Will you help us make a meaningful impact on the training of student pharmacists?

  • 12 Jan 2018 1:25 PM | Deleted user

    Authors: Anna Parker, PharmD Candidate 2010: UMKC School of Pharmacy
    SSHP President – Elect for Kansas City
    Jordyn Williams, PharmD Candidate 2010: UMKC School of Pharmacy
    SSHP President – Elect for Columbia

    At the beginning of the fall semester, SSHP held a membership drive from August to October 2nd. We recruited members through a poster at orientation for the first-year pharmacy students and at an event called "lunch on the lawn" for all pharmacy students. Also, on August 28th we had our first meeting where our guest speaker, Dr. Jeremy Hampton, discussed reasons to join SSHP, MSHP, and ASHP. The Columbia campus also held a joint membership drive for MMSHP and SSHP through a Trivia Night on September 7th. MMSHP and SSHP leadership provided information about joining the organizations. At the end of our membership drive we had a total of 96 members join from Kansas City, Columbia, and Springfield campuses.

    Throughout the fall semester, we had monthly general meetings where guest speakers talked about their current employment and their journey to where they are now. Students were able to listen to these three speakers over the lunch hour to learn more about clinical pharmacy career options. We had the pleasure to have Dr. Austin Campbell, a clinical pharmacist specialist at University of Missouri Hospital's psychology department, Dr. Chuck Trebilcock, the Director of Pharmacy at Burrell Behavioral Health, and Dr. Amber Lucas, a chair in the ASHP House of Delegates.

    Across all three campuses, we hosted three events this semester. On October 2nd, we held the Clinical Skills Competition where students competed in a team-based analysis of a clinical scenario. This gave students the chance to practice skills in collaboration with other team members. The first round was a case work-up and the second round had the top teams present their cases to the judges. The winning team was then given the chance to compete nationally during the ASHP Mid-Year Clinical Meeting. On October 7th, we held a Residency Roundtable with Dr. Tony Huke as our keynote speaker. Forty-five students and 14 residency programs participated. Participants had the opportunity to network and students learned how to become a strong residency candidate. On November 4th, we held a new event called Residency Prep Day. The goal of the members-only event was to help boost students' confidence when applying for programs. Faculty members gave presentations regarding Midyear, PhORCAS, and interview tips and tricks. As this was a new event this year, we think it will gain popularity in the years to come. This event was very helpful to those that were able to attend.

    Our chapter is unique in that it is spread across three campuses, which enables our chapter to reach out to multiple local communities very easily. This past semester, our Columbia campus was able to serve their community through the Vial-of-Life Project at the Harry S. Truman Memorial Veterans’ Hospital. Students helped patients in completing an up-to-date home medication list and provided a sticker to put in their window. If emergency personnel or others see this sticker, they know that the patient has a complete medical history in the house. This project allows our organization to help others and improve patient safety, especially in emergencies. The Columbia campus handed out 76 Vial-of-Life kits and reached patients residing in over 25 different Missouri counties.

    For the spring semester, we are looking forward to our monthly general meetings and our next service project. Our Columbia members are teaming up with MMSHP and the Ronald McDonald House in February. Volunteers will prepare meals for patients and families receiving care at the Women and Children's Hospital in Columbia. We are excited to serve our community through this event and hope to make it a tradition.

  • 12 Jan 2018 12:25 PM | Deleted user

    Greater Kansas City Society of Health-System Pharmacists (GKCSHP)

    Upcoming Events:

    February 15th, 2018: Topic: Clinical Considerations in Neuromuscular Blockade Management, Location: Plaza III Steakhouse
    Social Hour: 6:00-6:30 pm
    Presentation: 6:30 pm
    RSVP: at Capacity

    March 22nd, 2018: Topic TBD, Location TBD
    Social Hour: 6:00-6:30 pm
    Presentation: 6:30 pm
    Location: TBD

    April 19th, 2018: Topic TBD, McCormick and Schmick’s
    Social Hour: 6:00-6:30 pm
    Presentation: 6:30 pm

    Incoming 2018 Board Members:
    President – Katie Korte
    Past President – Bryan Schuessler
    President Elect – Lauren Mishler
    Secretary – Annie Ungerman
    Treasurer – Sayo Weihs
    Membership Chair – Kat Burnett
    Programs Coordinator – Brianna Zinser
    Programs Coordinator Elect – Mel Smith
    Newsletter Editor – Suzy Burros
    Technician Liaison – Josh Brooks
    Resident Liaison – Lainie Linafelter
    Student Liaison (2017-2018)
    UMKC – Kyle Klindworth
    KU – Shiloh Wedermyer

    Outgoing 2017 Board Members:
    President – Bryan Schuessler
    Past President – Erin Pender
    President Elect – Katie Korte
    Secretary – Annie Ungerman
    Treasurer – Sayo Weihs
    Membership Chair – Ashley Duty
    Programs Coordinator – Lauren Mishler
    Programs Coordinator Elect – Brianna Zinser
    Newsletter Editor – Mel Smith
    Technician Liaison – Travis Myer
    Resident Liaison – Patricia Hoover
    Student Liaison (2016-2017)
    UMKC – Sundus Awan
    KU – Shiloh Wedermyer

    Statement from 2017 President Bryan Schuessler:
    We had a great year, and our members were able to enjoy a variety of programming and social activities throughout the year. We look forward to 2018 and all the exciting events planned by our new leadership!”

    GKCSHP is on Instagram! Follow us @gkcshp!

    President: Katie Korte, PharmD, BCPS, BCCCP 

  • 12 Jan 2018 11:24 AM | Deleted user

    Get Fit with ENFit®

    Author: Sarah Bledsoe, PharmD, CPHIMS
    Assistant Director of Pharmacy, 
    Children’s Mercy Kansas City

    Make it your New Year’s resolution to pump up your pharmacy muscles by learning about the new enteral connections standards, ENFit®. A new novel enteral tubing system called ENFit® was designed to make enteral tubing and supplies incompatible with other traditional luer lock systems. The Joint Commission previously reported over 100 errors and 21 deaths have been attributed to the administration of enteral nutrition through intravenous lines.1 To prevent these errors from occurring, the Global Enteral Device Supplier Association (GEDSA), a nonprofit trade association, was formed to establish a voice for addressing issues that face manufacturers, suppliers and distributors and to facilitate communication to healthcare facilities across the globe on enteral tubing changes through the Stay Connected 2014 initiative.2

    The initiative will result in practice changes for healthcare organizations and providers that care for patients with enteral tubing. Examples of enteral tubing include nasogastic (NG), nasojejunal (NJ) and g-tube sites. While many patients use enteral systems for nutrition, some may also use it to administer medication. With the ENFit system design, patients will need their medications prepared in special ENFit compatible syringes in order to administer medications. It will be especially important that health-systems pharmacists engage their organization in planning for, educating and supporting these patients. GEDSA has shared that based on feedback from manufacturers, they estimate 28% of hospitals in the United States have already made the transition to ENFit® products. 3 To help you get started on your ENFit® journey, we have recommended some essential steps every healthcare organization should take to prepare for ENFit®.

    Step 1 – Identify your needs and key stakeholders

    • Each healthcare organization should do an assessment of their current enteral tubing practices. This includes creating a line item inventory of all current enteral supplies.
    • Because enteral tubing is typically utilized in multiple healthcare settings including inpatient and ambulatory practices, key stakeholders should be contacted to represent all areas. Based on our experiences with hospitals that have successfully implemented ENFit®, a project team should consistent of the following key members: medical staff champion, pharmacy, nursing, supply chain, home care, discharge planning, quality, safety, patients and families.
    • Transition checklists are available on the GEDSA Stay Connected website www.stayconnected.org to help guide key stakeholders on steps to take in their focus area.

    Step 2 – Plan for your practice change

    • Multiple vendors are available for ENFit® products. Health care providers and supply chain will need to perform a value based assessment of available products and select vendors for individual ENFit® products to replace their current enteral supplies.
    • Throughout the process of learning and evaluating the new ENFit® products, health care organizations may find that they need to revise their standard operating procedures for tube cleaning, medication preparation and discharge planning.
    • Transition adapters between the old and new enteral tubing systems are available. While these adapters are necessary during the transition, ISMP alerted in their September 2017 Acute Care Newsletter that transition adapters will be eventually eliminated and defeat the purpose of ENFit itself. 4 Healthcare organizations should carefully evaluate the role of transition adapters in their short term and long term conversion plans to ENFit®.

    Step 3 – Get ready to go ENFit

    • Education is key for a successful ENFit® transition and each health care organization will need to develop a strong education plan that encompasses all health care providers which may interact with enteral tubing supplies.
    • GEDSA has ENFit® interactive demonstration stations available for order by sending an email request to info@gedsa.org. The GEDSA Stay Connected website also offers a variety of videos and handouts from hospitals that have successfully implemented.
    • Implementation should be carefully coordinated across the healthcare organization. Adequate resources for switching supply rooms, changing patient tubes, preparing medications, assisting front line staff and educating patients should be available.

    To learn more about GEDSA, ENFit® and the Stay Connected initiative, please visit www.stayconnected.org


    1. Sentinel Event Alert. Issue 53. The Joint Commission. 8/20/2014 http://www.jointcommission.org/assets/1/6/SEA_53_Connectors_8_19_14_final.pdf
    2. GEDSA Stay Connected 2014. http://stayconnected.org/about/. 9/30/2015
    3. GEDSA. September 2017.
    4. ISMP.http://www.ismp.org/newsletters/acutecare/issues/20170921.pdf. Vol 22. Issue 19. September 2017.

  • 12 Jan 2018 10:56 AM | Deleted user

    MSHP R&E Call for Award Nominations
    Author: Carla Zeilmann, PharmD, BCPS
    Executive Director, MSHP Research and Education Foundation

    MSHP R&E Foundation is currently accepting submissions and nominees for several awards. The deadline has been extended for all submissions and nominations will be April 5, 2018.

    Submit your Nomination

    MSHP R&E Best Practice Award

    The Best Practice Award program recognizes innovation and outstanding performance in a pharmacy directed initiative. The theme for the 2018 award focuses on Medication Safety. A poster of the program will be highlighted during the Spring Meeting Poster Session. The award recipient will be honored at a fundraising event during the Spring Meeting and have the opportunity to provide a brief podium presentation detailing the implementation and impact of the project to the attendees.

    Applicants will be judged on their descriptions of programs and practices currently employed in their health system based on the following criteria:

    • Inventiveness of the program
    • Significance of the program to the health system
    • Demonstration of benefit to patient care as supported by program evaluation data
    • Significance of the program to pharmacy practice
    • Quality of submitted program report
    • Relevance to other institutions

    Applicants must be active MSHP members practicing in a health-system setting such as a large or small hospital, home health, ambulatory clinic or other health care system. More than one successful program from a health system may be submitted for consideration.

    Award recipient will receive half off their meeting registration, a plaque and a $250 honorarium.

    Submission Instructions: A program summary not to exceed 400 words must be submitted with the application and include the following information:

    • Background – description of need for program
    • Goals and specific aims of the program
    • Program description/methods – description of development process, role(s) of the pharmacist, timeline
    • Results - when results are not yet available, include a description of how impact of the program will be measured
    • Conclusion – established and/or expected clinical impact of the program
    • Submissions may also include any pictures, graphs, figures or data tables that support the summary. Each of these must be clearly labeled and described. Such information will not count against the 400 word limit.
    • Email your submission to mshp@qabs.com with Best Practice Award Submission in the subject line.

    MSHP R&E Best Residency Project Award

    The Best Residency Project Award recognizes innovation and outstanding performance in a pharmacy residency project. A poster of the program will be highlighted during the Spring Meeting Poster Session.

    Applicants will be judged based on the following criteria:

    • Inventiveness of the project
    • Significance of the project to the health system
    • Demonstration of benefit to patient care as supported by project evaluation data
    • Significance of the project to pharmacy practice
    • Quality of submitted project report
    • Relevance to other institutions

    Applicants must be active MSHP members completing a residency in a health-system setting such as a large or small hospital, home health, ambulatory clinic or other health care system.

    Award recipient will receive half off their meeting registration, a plaque and a $250 honorarium.

    Submission Instructions: A program summary not to exceed 400 words must be submitted with the application and include the following information.

    • Background – description of need for project
    • Goals and specific aims of the project
    • Results - when results are not yet available, include a description of how impact of the project will be measured
    • Conclusion – established and/or expected clinical impact of the project
    • Email your submission to mshp@qabs.com with Best Residency Project Award Submission in the subject line.

    Garrison Award

    The Garrison award was established in 1985, named after Thomas Garrison for his long standing support of MSHP (past-president 1974-1976), ASHP (past-president 1984) and numerous professional and academic contributions to Pharmacy. The Garrison Award is presented each year in which a deserving candidate has been nominated in recognition of sustained contributions in multiple areas:

    • Outstanding accomplishment in practice in health-system pharmacy;
    • Outstanding poster or spoken presentation at a state or national meeting;
    • Publication in a nationally recognized pharmacy or medical journal;
    • Demonstrated activity with pharmacy students from St. Louis or the UMKC Schools of Pharmacy;
    • Development of an innovative service in a health-system pharmacy in either education, administration, clinical service, or distribution;
    • Contributions to the profession through service to ASHP, MSHP and/or local affiliates.

    Each letter of nomination must include:

    • Name, work address, and telephone number of nominee;
    • Name, work address, and telephone number of nominator;
    • Sufficient explanation and documentation of the nominee’s accomplishment(s) to allow a proper decision by the selection committee; and Curriculum Vitae of the Nominee.
    • To be considered for the Garrison Award, the nominee must be a current active member of the Missouri Society of Health-System Pharmacists. The winner will be selected by the Board of Directors of the MSHP Research and Education Foundation. Email your nomination to mshp@qabs.com with Garrison Award Submission in the subject line.

    Preceptor of the Year Award

    MSHP R&E Foundation is pleased to honor a health system pharmacist for outstanding service to the profession as a preceptor to pharmacy students and/or residents. Below are the Criteria and Procedures to nominate a preceptor for the award.


    • Must be a member of MSHP;
    • Must have been a clinical preceptor for minimum of 3 years;
    • Must have not received the award within the last five years; attention will be given to previous nominations.


    The award will be presented to a health system pharmacist that exemplifies the core values (Professionalism, Desire to educate and share knowledge with students, Willingness to mentor, Willingness to commit the time necessary for precepting, Respect for others, Willingness to work with a diverse student population) and the following characteristics:

    • Partner in education: Is actively involved in instructing and educating in pharmacy practice
    • Role model: Demonstrates willingness to mentor and serve as an example
    • Experience: Has depth of experience and knowledge in area of expertise
    • Coaching: Provides timely and meaningful feedback to the learner
    • Enthusiasm: Demonstrates passion towards the profession and advancement of practice
    • Professionalism: Conducts himself/herself with highest level of dignity and professionalism
    • Teamwork: Facilitates team work and approach to patient care
    • Opportunity: Creates innovative learning experiences and opportunities to for growth
    • Research: Makes regular contributions to the profession through papers or presentations
    • Education
    • Evaluation
    • Investment
    • Negotiation
    • Guidance
    Submit your Nomination

    Questions:  Please contact Jim Andrews at MSHP 

    Alternative Submission: Please briefly explain (in no more than 500 words) the ways in which the nominee models these core values. Email your submission to mshp@qabs.com with Preceptor of the Year Award Submission in the subject line.
  • 12 Jan 2018 10:47 AM | Deleted user

    Author: Elaine Ogden, PharmD, BCPS, BC-ADM
    MSHP Secretary/Kansas City VA Medical Center


    The MSHP board is in the process of reviewing and updating all of our policies and plan to have all polices updated this year.
    • The MSHP board has been reviewing and collaborating with MHA regarding the role of technician certification...move to come so stay posted!!
    • Our membership committee is working on establishing a new practitioner committee - let us know if you are interested in being on the committee.
    • The programming committee is working closely with KCHP to standard the format for the Spring meeting!
    • The board is studying the strategic plan closely and working on each element for the new year!
    December: The board took a little holiday break, but are excited to get back to work in January!
  • 12 Jan 2018 9:45 AM | Deleted user

    MSHP Public Policy Committee
    Author: Amy Benson, PharmD, MHA
    MSHP Public Policy Chair/Director of Pharmacy at Liberty Hospital

    The MSHP Public Policy Committee has been receiving monthly reports from the Hospital Advisory Committee (HAC). The following information was submitted by Greg Teale, on behalf of the HAC:

    • In the past three months, the HAC has worked with the Board of Pharmacy, Department of Health and Senior Services and Missouri Hospital Association (MHA) to review the DHSS pharmacy regulations. Senate bill 501 required the removal of duplicative language from the DHSS regulations. The committee reviewed the current language and compared it with the CMS conditions of participation. The committee reviewed the current language and made recommendations to remove several sections that are already covered by CMS language.
    • The HAC was also provided language on expanded pharmacy technician roles developed in collaboration with MHA. This language would allow for hospitals to implement pharmacy technicians and/or pharmacy interns to check the work of another pharmacy technician or intern. There are requirements around quality assurance and patient safety. In addition, there was recommended language added to allow for electronic supervision of pharmacy technicians utilizing camera or video technology.
    • All of these changes were submitted in December to meet the deadline required by DHSS.
    • All of these recommendations will be open for comment in early 2018, with an expected implementation of July 2018.

    Practice Advancement Initiative
    Author: Daniel H. Good, MS, FASHP
    Regional Executive Director of Pharmacy-Mercy

    Do you remember the Medication Therapy Services (MTS) statute from 2007?

    Landmark Legislation for Missouri to grant pharmacists more opportunity to affect positive patient outcome in medication therapy?

    For the past 10 years, pharmacists across the state have been training and practicing MTS to the benefit of Missouri citizens. This past year, a coalition of pharmacists from MSHP, MPA, BoP, MHA and the Colleges of Pharmacy have been working together to take the MTS practice to the next level with a legislative proposal. The coalition has identified some best practice settings that maximize the MTS opportunities as well as identify additional professional services pharmacists could provide to patients if the regulations allowed. The coalition has asked the legislative pundits at MHA and MPA to work together to identify a Bill Sponsor in the Legislature and prepare a bill for consideration. The coalition is currently working on writing some short narratives and case studies to describe the benefits and potential benefits of pharmacy services in the current model and in the proposed future state. These narratives can be shared with key stakeholders and elected officials to gain support for this proposal. We are asking pharmacists to attend the Pharmacy Legislative Day on March 28th in Jefferson City and support this effort in your local communities.

    2018 Missouri Legislative Session
    Author: David Wolfrath, PharmD, MS
    Inpatient Pharmacy Manager: University of Missouri Hospital

    We are a little over a week into the 2018 Missouri Legislative session and there are many pharmacy-related bills that have been introduced. Representative Holly Rehder is again sponsoring her prescription drug monitoring program bill (House Bill 1619) which would establish the Narcotics Control Act. Another bill of interest is House Bill 1870. HB 1870 bill is sponsored by Representative Jay Barnes. HB 1870 would allow certain medications in multi-dose containers used by a patient during a hospital stay to be sent with the patient at discharge. As it remains very early in the legislative session, a hearing for this bill has not been filed yet. The language was derived from suggestions from several years ago from the DHSS Hospital Pharmacy Working Group draft rule that was not acted on. During recent Board of Pharmacy Hospital Advisory Committee review of the DHSS rules, the language was modified. This amended language is not included in the current version of the bill. HB 1870 can be found at: http://www.house.mo.gov/billtracking/bills181/hlrbillspdf/5479H.01I.pdf.

  • 06 Dec 2017 2:54 PM | Anonymous

    Monoclonal Antibodies Use in Clostridium Difficile Infections

    Authors: Karli Kurwicki, STLCOP Pharm.D. Candidate 2018
    Kendall Shultes, Pharm.D.

    Clostridium difficile infections (CDIs) affected approximately half a million patients in 2011 and its incidence continues to grow.1 CDIs are a major health concern as they can be associated with a mortality rate as high as 38%.2 CDIs add nearly $1 billion to the overall health-care related costs in the United States. A recurrence of CDI occurs in up to 35% of patients who have completed appropriate initial therapy.3 Patients who are associated with a higher risk of recurrent CDIs are age 65 years and older, severe initial CDI, use of proton-pump inhibitors or H2 receptor antagonists, prolonged hospitalization, and current use of antibiotics for other infections.4 With the high incidence of recurrence and growing costs, studies have sought additional therapies for treating and preventing CDIs. Studies have shown the benefit of monoclonal antibodies in both the initial treatment and prevention of CDI recurrence and may fill that niche.

    The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) clinical practice guidelines recommend either vancomycin 125 mg by mouth four times daily or metronidazole 500 mg by mouth three times daily for 10-14 days for mild, moderate, and severe uncomplicated infections. Severe, complicated infections are treated more aggressively with a combination of vancomycin 500 mg by mouth and metronidazole 500 mg intravenously. SHEA and IDSA guidelines recommend this same treatment strategy for the first recurrence of CDI.5

    In current practice, metronidazole is generally considered first line treatment for the initial CDI and recurrence of CDI. A recently published retrospective study comparing vancomycin and metronidazole treatment demonstrated that patients with severe CDI who received vancomycin had a statistically significant lower rate of mortality compared to patients who were given metronidazole (p = 0.01) however, there was no statistical or clinical difference between vancomycin and metronidazole in the prevention of CDI recurrence. As these medications are the mainstay of therapy but do not prevent the recurrence of CDIs, there is a need for a preventative agent to help lower the risk of recurrence.6

    CDIs are caused by two exotoxins, TcdA and TcdB. Toxins TcdA and TcdB are found in healthy individuals’ gastrointestinal tract. When a patient is exposed to antibiotics, the activity against the natural bacteria in the gastrointestinal tract compromises the body’s natural defense against CDIs. This allows the toxins to bind to cell receptors in the gastrointestinal tract and upon entry into the cell, inactivate enzymes that lead to the release of interleukin 8 (IL-8) and an increase in cell permeability. The release of IL-8 and increased permeability of the cells leads to severe diarrhea that can occur several times per day.7

    Monoclonal antibodies, such as actoxumab and bezlotoxumab, which bind to toxins A and B respectively, have shown great promise for preventing recurrence in patients who have had CDIs through neutralizing toxins and preventing binding to cells in the gastrointestinal tract.8 Two clinical trials, MODIFY I and MODIFY II, recently studied the use of monoclonal antibodies in the prevention of recurrent CDIs. Subjects in these trials were randomized to receive either bezlotoxumab 10 mg/kilogram (kg) alone, bezlotoxumab and actoxumab 10 mg/kg each, actoxumab 10 mg/kg alone in MODIFY I, or placebo in addition to their standard of care antibiotics which included vancomycin, metronidazole, or fidaxomicin. MODIFY I showed that actoxumab alone did not demonstrate efficacy and had more deaths and adverse effects associated with its therapy so it was not analyzed in MODIFY II. If randomized to the treatment group, patients received one 60-minute infusion along with their standard of care antibiotics as indicated above. Both studies demonstrated that bezlotoxumab statistically significantly decreased the recurrence of CDIs compared to placebo, MODIFY I 28% vs 17%, and MODIFY II 26% vs 16%, each p< 0.001. These trials also demonstrated that subjects receiving bezlotoxumab alone compared to placebo had improved sustained clinical cure rates (MODIFY I 60% vs. 55%; MODIFY II 67% vs. 52%). The results were statistically significant in MODIFY II (p< 0.001). Common adverse effects reported in the treatment groups from MODIFY I and II were headache, nausea, and diarrhea.3

    Based on trials, bezlotoxumab is FDA approved for use in patients greater or equal to 18 years old who are receiving antibiotic treatment for a CDI and who have a high risk of recurrent CDI.9 Bezlotoxumab is given as a one-time infusion at 10 mg/kg given over 60 minutes. Bezlotoxumab needs to be given with a low protein binding filter (0.2-5 microns) and should be diluted prior to use with 0.9% sodium chloride or 5% dextrose. Once it has been diluted, bezlotoxumab can be stored at room temperature for 16 hours or in the refrigerator for 24 hours. Common adverse effects associated with bezlotoxumab are nausea, pyrexia, and headache. In clinical trials, patients with a history of heart failure who received bezlotoxumab experienced a worsening of their heart failure and it should be used cautiously in this patient population.9

    Another agent with a similar mechanism of action as monoclonal antibodies is intravenous immune globulin (IVIG). It works by neutralizing toxins A and B to provide passive immunity against Clostridium difficile toxins. IVIG, although does not have FDA approval for use in recurrent CDI prevention, is currently used last line for CDIs as a salvage treatment and is reserved for use in severe, complicated CDIs when patients do not respond to other available therapies.5 Treatment of CDIs with IVIG in combination with metronidazole and vancomycin has been shown to decrease the rate of recurrence of CDIs by up to 14%.10 Unfortunately, a dose and duration for IVIG has not been standardized for the treatment of CDIs. A dose that has been studied for treatment of severe CDI is a single 400 mg/kg dose either three times weekly or as two single doses.11 Common adverse effects of IVIG are headache, pyrexia, edema, fatigue, nausea, and hypotension.12

    CDI is a major healthcare problem affecting the United States and as the mortality rates for CDIs continue to grow, it is important to find a treatment that helps the initial cure rates and decreases the recurrence of CDIs. Monoclonal antibodies have shown great benefit in reducing the recurrence of CDIs when used with standard of care antibiotics. Although expensive, they offer promise in decreasing mortality associated with CDIs. As research continues, monoclonal antibodies, such as bezlotoxumab, should be added into clinical practice guidelines to increase initial clinical cure rates, decrease recurrence, and decrease mortality caused by Clostridium difficile infections.


    1. Centers for Disease Control and Prevention. Healthcare-associated infections: Clostridium difficile infections. https://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html. Feb 25, 2015. Updated March 1, 2016. Cited July 9, 2017.
    2. Mitchell BG, Gardner A. Morality and Clostridium difficile infection: a review. Antimicrob Resist Infect Control. 2012;1(20):1-6.
    3. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305-317.
    4. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect. 2012;6:21-27.
    5. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infections in adults: 2010 updated by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
    6. Stevens VW, Nelson RE, Schwab EM, et al. Comparative effectiveness of vancomycin and metronidazole for the prevention of recurrence and death in patients with Clostridium difficile infection. JAMA Intern Med. 2017:E1-E8. 
    7. Castagliuolo I, LaMont JT. Pathophysiology, diagnosis and treatment of Clostridium difficile infection. Keio J Med. 1999;48(4):169-174.
    8. Yang Z, Ramsey J, Hamza T, et al. Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab. J Infect. 2015;83(2):822-831. 
    9. Zinplava (bezlotoxumab) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc., 2016.
    10. Zhao S, Chose-Paul G, Zhang K, et al. Immune-based treatment and prevention of Clostridium difficile infection. Hum Vaccin Immunother. 2014;10(12):3522-3530.
    11. Abourgeri MS, Kwon JH. Intravenous immunoglobulin for the treatment of Clostridium difficile infection: a review. Dig Dis Sci. 2011;56:19-26.
    12. Gammaplex (intravenous immune globulin) [package insert]. Esltree, Hertforshire: Bio Products Laboratory Limited, 2015. 

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