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DIFFICULT CASES: CRACKING THE CODE:

CASE CLOSED! OPTIMIZING TREATMENT FOR


ENDOCRINOLOGIC DISORDERS
SATURDAY/10:15-11:15AM

ACPE UAN: 0107-9999-16-015-L01-P 0.1 CEU/1 hr


Activity Type: Application-Based

Learning Objectives for Pharmacists: Upon completion of this CPE activity participants should be able to:
1. Identify therapeutic targets for a given disease state for each patient presented
2. Recommend pharmacotherapeutic options that may improve the clinical course for each patient
presented
3. Review the literature for evidence-based findings that support the treatment recommendation for each
disease state discussed
4. Given a patient case, discuss pros and cons of available pharmacotherapy used to treat a clinical
problem

Speaker: Emily Knezevich, PharmD, BCPS, CDE


Emily Knezevich is an Associate Professor of Pharmacy Practice at Creighton Universitys School of
Pharmacy and Health Professions. She is a Board Certified Pharmacotherapy Specialist and Certified
Diabetes Educator who, along with her teaching and scholarly requirements, maintains a clinical
practice site at the CHI Alegent Creighton Dundee clinic in Omaha, Nebraska. Here, Dr. Knezevich is
part of the Diabetes Education team, serves as a drug information resource and provides medication
therapy management services for patients within the clinical practice. Her research interests include
pharmacotherapeutic management of endocrine disorders and the scholarship of teaching and learning.

Speaker Disclosure: Emily Knezevich reports no actual or potential conflicts of interest in relation to this
CPE activity. Off-label use of medications will be discussed during this presentation.

FEBRUARY 13, 2016 | IOWA EVENTS CENTER | DES MOINES, IOWA


2/16/2016

Disclosure
Emily Knezevich reports no actual or potential conflicts of
interest associated with this presentation

Case Closed! Optimizing Treatments for


Endocrinologic Disorders
Emily Knezevich, Pharm.D., BCPS, CDE

Learning Objectives
Upon successful completion of this activity, pharmacists
should be able to:
Identify therapeutic targets for a given disease state for
each patient presented CASE 1
Recommend pharmacotherapeutic options that may
improve the clinical course for each patient presented.
Review the literature for evidence-based findings that
TYPE 2 DIABETES
support the treatment recommendation for each disease
state discussed
Given a patient case, discuss pros and cons of available
pharmacotherapy used to treat a clinical problem

KS [12]1

Setting the Scene Many Options


MW is a 64yo female with Type 2 diabetes and
osteoporosis presenting to clinic today with a Hemoglobin
A1c of 8.4%.
Medications: Metformin XR 2g daily and Glargine U100 You Are
52 units nightly at bedtime. Here
MW reports appropriate adherence to prescribed regimen and
denies current symptoms of hyper- or hypoglycemia.
Weight: 212lb, height 54
VS: BP: 128/76mm Hg, RR 16 rpm, HR 72 bpm
Diabetic complications negative

Diabetes Care. 2016;37(suppl 1):S1480.

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KS [13]1

The case FOR basal-bolus therapy The case AGAINST basal-bolus therapy
Increased complexity of regimen = worse adherence
Efficacy demonstrated with significant FBG and A1c
reduction Hypoglycemia risk
Demonstrated to be significantly higher in all comparative trials
Dosing can be individualized
Weight gain likely with increased daily insulin dose
New delivery options make dosing mealtime insulin more
convenient The stigma of more insulin = Failure
V-Go
Afrezza

www.go-vgo.com
www.afrezza.com http://www.clinicme.com/2014/03/insulin-injecting-tips.html

GLP-1 Agonist + Basal Insulin Rationale for GLP-1 use


Postprandial glucose lowering
Slow gastic emptying, stimulate glucose-dependent insulin
secretion, inhibit glucagon
Positive hypoglycemia profile
Less likely to induce hypo vs. bolus insulin
Weight reduction likely
Mean weight reduction amongst GLP-1 RAs ~ 2 kg
Reduced insulin requirement?
Simplifies dosing regimen when compared to mealtime insulin
Could then lead to decreased weight and less hypoglycemia

Eng et al. The Lancet 2014; 384:2228-34

Diabetes Care. 2016;37(suppl 1):S1480.

Basal + GLP-1 vs. Alternatives Meta-analysis Results


Systematic review and Meta-analysis GLP-1 + basal > Decrease in A1c vs. any other treatment
Type 2 DM in adults, 8 weeks duration, reported effect on Hg A1c -0.44% A1c change overall (95% CI -0.60 to -0.29)
Sensitivity analysis comparing to basal/bolus was consistent with this
Excluded observational/retrospective studies
finding
Outcomes: -0.10 (95% CI -0.17 to -0.02)
Change in A1c between baseline and end of intervention Larger portion of patients reaching A1c < 7%
Proportion of participants achieving A1c of 7% RR 1.92 (95% CI 1.43-2.56)

Hypoglycemia rate Comparison to basal-bolus: RR 1.07 (95% CI 0.91-1.26)

Weight change Less hypoglycemia when compared to basal-bolus


RR 0.67 (95% CI 0.56-0.80)
15 studies included
No greater risk when compared overall (RR 0.99 95% CI 0.76-1.29)
Mean duration 24.8 weeks, baseline A1c 8.13%, baseline BMI
Significant weight reduction for all comparisons
32.9kg/m2, mean duration of DM 12.2 years
Overall Mean difference -3.22kg (95% CI -4.90 to -1.54)
Compared to basal/bolus: -5.66 (95% CI -9.8 to -1.51)
Eng et al. The Lancet 2014;384:2228-34 Eng et al. The Lancet 2014;384:2228-34

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KEL9

GLP-1 Agonist vs. Bolus Insulin SGLT-2 Inhibitors


Background Comparator Arms Change in A1c Change in weight Approved for addition to any oral or injectable antidiabetic
therapy (%) (kg)
medication
Glargine + MTF1 Exenatide BID -1.13 -2.5
Insulin secretion independent
Lispro w/ meals +2.1
-1.10 Can increase risk of hypoglycemia if added to secretagogue or
Glargine +/- MTF, Albiglutide QW -0.82 -0.73 rapid acting insulin analog
pio or both2 Canagliflozin, Dapagliflozin, or Empagliflozin
Lispro w/ meals -0.66 +0.81
Empagliflozin has demonstrated improvement in CV outcomes
Degludec + MTF3 Liraglutide -0.74 -2.8
EMPA-REG: 1st post-marketing study to demonstrate improvement in
Aspart w/ largest -0.39 +0.9 time to 1st CV death, non-fatal MI or stroke1
meal
Considerations: tolerability, cost, once daily dosing, positive effect
on weight and blood pressure
Degludec and exenatide ER have not been studied with basal insulin
GU infections, fracture risk ?, euglycemic DKA?

1. Diamant. Diabetes Care 2014; 37:2763-73; 2. Rosenstock. Diabetes Care 2014; 37:2317-25; 3.Mathieu C. Diabetes 1. Zinman et al. NEJM 2015; 373: 2117-28.
Obes Metab 2014; 16:636-44.

Basal + SGLT-2 Inhibitors Case 1 Summary


Study Intervention Hgb A1c change Weight Change Difference in When basal insulin and metformin have been maximized
author from PBO(%) (kg) daily insulin
dose vs. and patient needing add-on:
PBO(units)
GLP-1 RAs have demonstrated improved A1c reduction
Wilding Dapagliflozin -0.4 (p=0.00002) -3.33 -19.2
10mg + 30 (p<0.0001) (p<0.0001) and weight loss with less hypoglycemia when compared
units of insulin to increasing insulin dosing or adding on Rapid Acting
+/- OADs
Empagliflozin
Insulin (RAI) to regimen
Rosenstock -0.7 (p<0.001) -2.7 (p<0.001) -6.7 (p=0.002)
10mg + basal SGLT-2 Inhibitors are effective in reducting A1c while
Neal Canagliflozin -0.81 (p<0.001) -3.5 (p < 0.001) -8.7 reducing weight without significantly increasing risk of
300mg + 30
units insulin hypoglycemia when added on to insulin
+/- OADs
Addition of RAI to basal + MTF therapy is effective in
reaching A1c goals, but may increase risk of
Wilding JPH. Diabetes, Obesity & Metobolism 16: 124-136 2014. hypoglycemia and weight gain.
Rosenstock J, Diabettes, Obesity & Metabolism 17: 36-948 2015.
Neal B. Diabetes Care. 38: 403-11 2015.

Setting the Scene


59 year old female with osteoporosis, originally from
Southeast Asia referred for evaluation of osteoporosis and
probable atypical femoral fractures (AFF).
CASE 2 Taking Alendronate 70mg once weekly since 2005
She has been having pains in her thighs bilaterally for
OSTEOPOROSIS several months over the past year.
PMH: Hyperlipidemia
Other Meds: calcium carbonate 1200mg daily, fenofibrate
145mg daily, Multivitamin, Vit D 3 1000 units daily

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Case 2: Osteoporosis Case 2: Osteoporosis


VS: normal
Physical exam: limited ROM secondary to probably
fracture
Labs: normal thyroid, renal and liver functions, Normal
Phos, Mg, screening for celiac was negative
Corrected Calcium was normal 9.0 mg/dl (8.5-10.5).
25 OH Vit D was normal 60 (30-80)

ASBMR Task Force 2013 Revised Case


Bisphosphonates Definition of AFFs
Clear benefit in reduction of fractures and bone loss in Major Features
patients with Osteoporosis Minimal or no trauma, as in a fall from
a standing height or less
In the past decade, atypical femoral fractures (AFFs) have Fracture line originates at the lateral
emerged as potential complication of bisphosphonate cortex and is substantially transverse in
its orientation, although it may become
use. oblique as it progresses medially
First described in 13 women with low trauma sub trochanteric across the femur
fractures, 9 were on alendronate. Complete fractures extend through
both cortices and may be associated
Increased anxiety among patients and their prescribers. with a medial spike. incomplete
FDA Advisory Committee has not agreed on extent to fractures involve only the lateral cortex
The fracture is noncomminuted or
which cumulative doses of bisphosphonates increase risk minimally comminuted
of AFF Localized periosteal or endosteal
thickening of the lateral cortex is
Goh et al. J Bone Join Surg. 2007;89:349
present at the fracture site (beaking
Shane et al. JBMR 2014; 29.1-23 or flaring)
Shane et al. JBMR 2014;29:1-23

Fractures
that would be
prevented by
bisphosphonate
treatment

Fractures
associated with
bisphosphonate
treatment
Secondary analyses using the results of three large, randomized bisphosphonate trials (14,195 women) : the (under
Fracture Intervention Trial (FIT), the FIT Long-TermExtension (FLEX) trial, and the Health Outcomes and hypothetical
12,777 women 55 years of age or older sustained a fracture of the femur in 2008. they Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT). relative risk).
reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft
fracture and identified 59 patients with atypical fractures
Black et al. NEJM 2010;362:1761-71
Schilcher et al. NEJM 2011;364:1728-37

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Summary of AFF with Bisphosphonate Use Therapeutic options


The absolute risk of AFFs in patients on BPs is low, Bisphosphonate (or denosumab) should be discontinued
ranging from 3.2 to 50 cases per 100,000 personyears. Consider treatment with teriparatide
Rule out all other possible bone pathology
However, longterm use may be associated with higher Osteomalacia, vitamin D deficiency
risk (100 per 100,000 person-years). Patient will require Rest, immobilization and rehabilitation
Important Clinical Symptoms: Prodromal thingh pain presents in up
Calcium and vitamin D supplementation should be
to 75% of patients and 25-50% present bilaterally
ongoing
Calcium 1200mg daily, Vitamin D 1000-2000 units daily
Benefits of fracture prevention with bisphosphonate use
>> Risk of atypical femoral.

Shane et al. JBMR 2014; 29(1):123


Shane et al. JBMR 2014; 29:1-23
Schilcher et al. NEJM 2011;364:1728-37

Teriparatide use for Incomplete AFFs Case 2 Summary


No RCTs demonstrating efficacy for this indication Bisphosphonates (BP) are highly effective for prevention
Numerous case reports described in literature of worsened BMD and fracture in patients with
63yo woman with thigh pain and b/l AFF on BPs for 13 years osteoporosis.
After 6 months of teriparatide, reduced pain and edema at fracture site Though AFFs with BP use has been described, the
After 16 months complete healing and relief of pain benefit of use in preventing fractures outweighs the risk of
Other reports describe rapid closure, pain reduction and eventual one occurring
healing
Patients on BPs should be counseled to notify their
Teriparatide may not be effective in all patients with AFF
prescribers upon experiencing any type of chronic bone
Study of German women with AFF demonstrated only 1 of 3 repond
pain in the thigh or hip area.
with fracture healing
If an incomplete AFF is detected, teriparatide may be
ASBMR suggest teriparatide as an option for those with
effective in treating to prevent complete fracture and need
AFF who do not respond to conservative therapy
for surgery.
Shane et al. JBMR 2014;29:1-23

Setting the Scene


LJ is a 32yo female weighing 186lb, recently diagnosed with Hashimotos
thyroiditis. Four months ago, she was initiated on levothyroxine 125 mcg, but
after several titrations, she is now taking 275mcg daily. She complains of
ongoing fatigue, weight gain, and cold intolerance. Since starting treatment,

CASE 3 she complains of frequent diarrhea, usually shortly after taking levothyroxine.

Not currently taking any other prescription medication

HYPOTHYROIDISM OTC: loperamide as needed for diarrhea, usually 3-4 times weekly
Labs:
TSH 16mIu/L after dose increase 6 weeks ago
CBC significant for low Hgb of 10.6g/dL and Hct of 31%

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Levothyroxine Celiac disease and Hypothyroidism


Narrow therapeutic window for treatment Celiac disease affects 2-5% of patient with autoimmune
Administration can significantly affect absorption taken with or hypothyroidism
without food?
Those who should be screened:
Increased absorption with higher gastric acidity
Patients with iron deficiency anemia with or without symptoms
Medications that block gastric acidity may decrease absorption of Those with dose escalations not resulting in euthyroid state
levothyroxine Mechanism: May induce malabsorptive state, inflammatory cascade may
Malabsorptive conditions may decrease absorption as well. increase requirement, or genetic variability increasing disease severity
Treatment generally includes avoidance of oral intake of gluten
GI toxicity commonly reported
Dietary changes
Is it the active or inactive ingredient causing the problem?
Screening for medication excipients
Common ingredients: Lactose, Gluten, Food dyes, Alcohol, Sulfa,
Sugar, Povidone, Talc, magnesium stearate
Intolerance can lead to non-adherence with daily
administration of levothyroxine
Zubarik R. Euro J of Int Med 2015; 26:825-9
Pharmacotherapy, A Pathophysiologic Approach, 9th Ed. Chapter 58: Thyroid Disorders
Collins D. Am J of Med. 2012; 125(3): 278-282.

Celiac disease and Hypothyroidism Difference in Levothyroxine


Zubarik et al.
requirement with Celiac disease
Prospective study which enrolled 500 patients with levothyroxine
doses 125mcg/day Celiac disease No celiac P-Value
Group previously determined dose from retrospective evaluation disease
Primary objective was to determine if those patients with Levothyroxine 156.9 99.7 <0.001
autoimmune hypothyroidism taking dose > 125mcg/day are more dose (mcg)
likely to have celiac disease Weight based 1.8 1.3 0.001
Performed diagnostic testing for Celiac disease on all patients
Levothyroxine
dose (mcg/kg)
Serum tissue transglutaminase (tTG)
Those with elevated tTG then underwent endoscopy with duodenal
biopsies

Zubarik R. Euro J of Int Med. 2015; 26:825-9 Zubarik R. Euro J of Int Med. 2015; 26:825-9

Prevalence of CD with high dose Levothyroxine dose following disease for


Levothyroxine treatment of Celiac disease
Study found that prevalence was 5.6% in those Study author Levothyroxine Levothyroxine P-value
dose before dose after
requiring doses 125mcg/day (1.5mcg/kg/day) treatment treatment
Surpassed that reported with asyptomatic iron Collins, et al 2.6mcg/kg/d 1.9mcg/kg/day 0.04
deficiency anemia Zubaric, et al Only 2 patients (25%) had dose NS
reduction
Prevalence 12.5% in patients taking 200mcg/day
Virili, et al Gluten free diet adherence (11 ---
months) prevented need for increasing
dose to reach TSH of ~1mIU/L
maintained 1.32mcg/kg/d

Some question need for gluten free diet in asymptomatic individuals

Collins D. Am J of Med. 2012;125(3): 278-282.


Zubarik R. Euro J of Int Med. 2015; 26:825-9 Virili C. J Clin Endocinol Metab, 2012;97(3): E419-22.
Zubarik R. Euro J of Int Med. 2015;26:825-9

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Gluten Free Levothyroxine Products Case 3 Summary


Levothyroxine Generic Manufacturers The incidence of Celiac Disease existing concomitantly
Lannet and Mova ONLY with autoimmune hypothyroidism is increased in those
Levoxyl taking doses higher than 125mcg/day
Tirosint Levothyroxine doses may need to be reduced if patients
Has only 4 ingredients: levothyroxine, gelatin, glycerin, and water begin gluten free diet after diagnosis of celiac disease.
Armour Thyroid This interaction may be due to malabsorption, but may
Nature-Throid
also be a result of genetic variability requiring higher
doses to achieve euthyroid levels
WP Thyroid (formerly Westhroid Pure)
If patients begin gluten free diet or are having GI
sensitivity to levothyroxine product, there are options
http://www.glutenfreedrugs.com
available that do not contain gluten
http://thyroidpharmacist.com/articles/is-your-medication-gluten-free

Overall Case Summary


For patients with Type 2 diabetes, consider addition of
SGLT-2 Inhibitors or GLP-1 RAs prior to prandial insulin if
needing additional glycemic control beyond that basal
insulin is providing.
For patients using bisphosphonates, it is important to
counsel on the risk of atypical fracture, keeping in mind
the risk/benefit ratio, ensuring patients understand the
need to report prodromal symptoms.
Celiac disease may exist alongside autoimmune
hypothyroidism and may result in the need for higher
doses of levothyroxine or a change to a gluten free
preparation.