NW Convention June 2016 HANDOUT Session 1 [Read-Only] · XX XXX Pharmacotherapy X XXX Bariatric...
Transcript of NW Convention June 2016 HANDOUT Session 1 [Read-Only] · XX XXX Pharmacotherapy X XXX Bariatric...
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Cacophony To Harmony: A Composition of Chronic Disease State Updates
Northwest Pharmacy ConventionCoeur d’Alene, Idaho
June 2016
Sonia Allen, PharmD, BCACPAndrea Corona, PharmD, BCACP, CDEDaniela Dandridge, PharmD, BCACP
Session Composition
Session 1
• Case Presentation
• Lipid Treatment
• Diabetes Update
• Venous Thromboembolism
• Case Review
Session 2
• Case Presentation
• Asthma and COPD
• Inhaler Round Table
• E-cigarettes and Vaporizers
• Heart Failure
• Case Review
Objectives – Session 1
1. Recommend appropriate statin therapy for a specific patient and identify patients who may benefit from PCSK9 inhibitors.
2. Identify place in therapy for new concentrated basal insulin products and SGLT2 inhibitors in diabetes treatment.
3. Summarize updated venous thromboembolism guidelines.
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Patient Case55 yo Caucasian female with type 2 DM who presents to clinic for evaluation of newly diagnosed PE secondary to proximal DVT. No provoking factors identified. The emergency room provider initiated LMWH anticoagulation therapy last evening and sends her to clinic for further anticoagulation therapy management.
Past medical history includes HTN, hyperlipidemia (TC 240, HDL 30, LDL 150, TG 175). She is a current smoker, 1 ppd. BP in clinic today is 130/78. Chem 7 reveals Scr 0.8 (estimated GFR > 60) and electrolytes WNL.
Current medications include Lisinopril, insulin glargine 80 units SQ nightly and metformin at target dose.
Recent A1c is 9.5% (Est Avg 220 mg/dL). She presents her BG log which reveals 3 episodes of nocturnal hypoglycemia in the last month however, the majority of her blood glucose readings are > 180 mg/dL.
Allergies include penicillin and a clearly documented intolerance to statins (she has tried multiple agents with equal intolerance)
Questions
1. How would you address therapy management of new VTE?
2. How would you address diabetes drug therapy management?
3. How would you address her CV risk? Would you consider additional therapy?
Lipid Treatment
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Similarities between ACC/AHA and NLA Guidelines
• Screen for primary prevention every 5 years
• Lifestyle therapy is first-line
• ASCVD risk reduction is goal of therapy
• Moderate- or high-intensity statin use
• Regular lipid follow-up to assess adherence to therapy
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013. Jacobson TA, et al. NLA Recommendations for Patient‐Centered Management of Dyslipidemia. Journal of Clinical Lipidology (2015) 9, 129‐169
Notable Differences
ACC/AHA
• Pooled cohort risk calculator
NLA
• Count number of risk factors
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013. Jacobson TA, et al. NLA Recommendations for Patient‐Centered Management of Dyslipidemia. Journal of Clinical Lipidology (2015) 9, 129‐169
NLA Major Risk Factors
Jacobson TA, et al. NLA Recommendations for Patient‐Centered Management of Dyslipidemia. Journal of Clinical Lipidology (2015) 9, 129‐169
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Notable Differences
ACC/AHA
• Pooled cohort risk calculator
• No recommendation for or against lipid goals
NLA
• Count number of risk factors
• Maintenance of lipid goals with emphasis on non-HDL
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013. Jacobson TA, et al. NLA Recommendations for Patient‐Centered Management of Dyslipidemia. Journal of Clinical Lipidology (2015) 9, 129‐169
NLA Lipid Goals
Jacobson TA, et al. NLA Recommendations for Patient‐Centered Management of Dyslipidemia. Journal of Clinical Lipidology (2015) 9, 129‐169
Notable Differences
ACC/AHA
• Pooled cohort risk calculator
• No recommendation for or against lipid goals
• Discourage non-statin therapy due to less favorable net benefit
NLA
• Count number of risk factors
• Maintenance of lipid goals with emphasis on non-HDL
• +/- non-statins if necessary to achieve lipid goals
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013. Jacobson TA, et al. NLA Recommendations for Patient‐Centered Management of Dyslipidemia. Journal of Clinical Lipidology (2015) 9, 129‐169
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UPDATE: FDA pulled non-statin indications
• If patient is on a statin, no indication to add niacin or fenofibric acid for CV risk reduction– Despite HDL raising or TG lowering there is not evidence to
support risk reduction
http://www.empr.com/news/fda‐withdraws‐indications‐for‐two‐cholesterol‐medications/article/490515/?DCMP=EMC‐MPR_DailyDose_cp&cpn=fp_md,pcp_md,harvoni64297,pcp_all,respiclick70052,Arnuity71530&hmSubId=aLsnDgbTgIQ1&hmEmail=y9‐jV8Tk8w7I_kBkCqKHCWSfvDHhcXvDDl
"based on the collective evidence from several large cardiovascular outcome trials… the totality of the scientific evidence no longer supports the conclusion that a drug‐induced reduction in triglyceride levels and/or increase in HDL‐cholesterol levels in statin‐treated patients results in a reduction in the risk of cardiovascular events.”
Why are there differences?
• ACC/AHA
– RCT with ASCVD outcomes and meta-analyses
• NLA
– RCT with ASCVD outcomes and meta-analyses
– Post-hoc analyses of RCT
– Genetic, metabolic and mechanistic studies
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013. Jacobson TA, et al. NLA Recommendations for Patient‐Centered Management of Dyslipidemia. Journal of Clinical Lipidology (2015) 9, 129‐169
AHA/ACC Algorithm
Progression of questions for eligibility for statin use. Algorithm‐ Adapted from Figure 2.
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Algorithm- Adapted from Figure 2.
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013.
Reminder of Definition of ASCVD*
• Acute coronary syndromes
• Myocardial Infarction
• Stable or unstable angina
• Revascularization
• TIA/CVA
• Peripheral artery diseaseStone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013.
Algorithm- Adapted from Figure 2.
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013.
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Algorithm- Adapted from Figure 2.
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013.
% LDL Reduction of Statin Dose^
Generic Brand 10 mg 20 mg 40 mg 80 mg
Rosuvastatin Crestor 51% 57% 63%
Atorvastatin Lipitor 35‐39% 43% 50% 55‐60%
Simvastatin Zocor 28% 35% 41% 46%
Pravastatin Pravachol 22% 32% 34% 37%
Lovastatin Mevacor 21% 24‐27% 30‐31% 40‐42%
Fluvastatin Lescol 20% 25% 35%
1 mg 2 mg 4 mg
Pitavastatin Livalo 31‐32% 36‐39% 41‐45%
Algorithm- Adapted from Figure 2.
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013.
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Calculate a life-time risk
• Motivational tool for lifestyle modification
• http://tools.acc.org/ASCVD-Risk-Estimator/
32yo, White, Male, TC 190, HDL 32, SBP 120, No treatment for hypertension, not diabetic but smokes
If he stops smoking life‐time risk reduces to 36%
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Algorithm- Adapted from Figure 2.
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013.
Algorithm- Adapted from Figure 2.
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013.
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45yo, White, female, TC 210, HDL 36, SBP 135, Treatment for hypertension, diabetic and does not smoke
Same patient as a smoker
Algorithm- Adapted from Figure 2.
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline. Circulation. Published online November 12, 2013.
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Same patient as a smoker but without diabetes
Algorithm- Adapted from Figure 2.
1. Secondary Prevention?2. LDL > 190 mg/dL?3. > 40 years old?4. Diabetes diagnosis?5. Primary prevention?
New Lipid Agents
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PCSK9 Inhibitor MOA
Evolucumab (Amgen): OSLER-1, OSLER-2 Trials
– 140 mg SQ Q2 weeks OR 420 mg SQ Q 4 weeks
Alirocumab (Sanofi): ODYSSEY FH I & II, Long-Term, and combo trials
– 150 mg SQ Q 2 weeks
PCSK9: Proprotein Convertase Subtilisin Kexin 9Hepatic enzyme that breaks down hepatocyte LDL receptors—inhibiting this enzyme will lead to higher concentrations of LDL receptors on the surface of the hepatocyte and lower serum
LDL levels as LDL is taken from blood into hepatocyte
Who is a candidate for PCSK9 Inhibitors?
1. Secondary Prevention (i.e. post-MI)
2. Patients with CV disease intolerant to statin therapy
3. Hypertriglyceridemia
4. All of the above
PCSK9 Inhibitor Place in Therapy
• High risk CV patients who are intolerant to statin therapy
• As add-on therapy to maximal statin therapy to get additional LDL lowering in patients with CV disease
• Familial Hypercholesterolemia
– Alirocumab—Heterozygous FH FDA indication only
– Evolucumab—Heterozygous FH + Homozygous FDA indications
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PCSK9 Inhibitor Trial Data
ALIROCUMAB (Praluent)
ODDYSEY LONG-TERM Trial
n = 2341; 78 weeks
Treatment Groups• Alirocumab + statin• Placebo + statin
PRIMARY: % change in LDL at week 24
SAFETY: safety & incidence of ADR;
POST-HOC SAFETY: CV events
EVOLUCUMAB (Repatha)
OSLER 1 & 2
n = 4465; 12 months
Treatment Groups• Evolucumab + statin • Statin alone
PRIMARY: safety & incidence of ADR
SECONDARY: % change in LDL @ week 12
PRESPECIFIED EXPLORATORY: CV events
PCSK9 Inhibitor % LDL Reduction
ALIROCUMAB (Praluent)
ODDYSEY LONG-TERM Trial
PRIMARY ENDPOINT:
% LDL reduction at week 24
62% reduction with alirocumab vs 0.8% with placebo (p<0.001)
EVOLUCUMAB (Repatha)
OSLER 1 & 2
SECONDARY ENDPOINT:
% change in LDL @ week 12
61% further LDL reduction in Evolucumabgroup (p<0.001)
PCSK9 Inhibitor Safety
ALIROCUMAB (Praluent)
ODDYSEY LONG-TERM Trial
SAFETY ENDPOINTS:
No significant difference in ADR between Treatment and Placebo groups except Myalgias (5.4% Treatment vs 2.9% Placebo, p <0.05)
37.1% pts in Treatment Group had LDL levels fall < 25 mg/dL
EVOLUCUMAB (Repatha)
OSLER 1 & 2
PRIMARY ENDPOINT:
No significant difference between Evolucumab and Standard-Therapy groups but neurocognitive ADR more frequent with Evolucumab Group
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PCSK9 Inhibitor CV Events and Limitations
ALIROCUMAB (Praluent)
ODDYSEY LONG-TERM Trial
POST-HOC SAFETY: CV event rates
Alirocumab group (1.7%) vs. placebo group (3.3%) (HR 0.52, 95% CI, 0.31-0.90; p=0.02)
Study Limitations• Lack of formal neurological testing as
part of study design• Low CV event rates
EVOLUCUMAB (Repatha)
OSLER 1 & 2
PRESPECIFIED EXPLORATORY: CV event rates
Evolucumab group (0.95%) vs. statin-only group (2.8%) (p=0.003)
Study Limitations• Open-label design• Low CV event rates
PCSK9 Inhibitor Cost
~ $14,000 to $15,000 per year
Results currently inconclusive- require outcomes trial data
• FOURIER
• ODYSSEY OUTCOME
PCSK9 Inhibitor Safety
ALIROCUMAB (Praluent)
ODYSSEY OUTCOMES Trial
18,000 patients enrolled
Evaluating Alirocumab in patients with ACS for the reduction of primary endpoint of CHD death, nonfatal MI, fatal & non-fatal ischemic stroke and USA requiring hospitalization
Results expected in 2018
EVOLUCUMAB (Repatha)
FOURIER Study
27,500 patients enrolled
Evaluating Evolucumab in patients with known CV disease for the reduction of primary composite endpoint of CV death, MI, USA requiring hospitalization, stroke or coronary revascularization.
Results expected in 2016
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PCSK9 Inhibitor Payor Coverage
Express Scripts:
October 2015 statement released
– Cover both PCSK9 Inhibitors
– Must have evidence of failed statin therapy or LDL lowering
still required while on max dose of statin
CVS:
November 2015,
– Included evolucumab (Repatha) as only PCSK9 inhibitor
on formulary
Diabetes Update
Standards of Medical Care in Diabetes--2016
General Changes– No longer use the word “diabetic” when referring to individuals with diabetes– “Diabetic” is used as an adjective for complications related to diabetes
(e.g. diabetic retinopathy)
Section 2: Classification and Diagnosis of Diabetes*– No one test is preferred over another test for diagnosis – ADA revised screening recommendations:
• Test all adults ≥ 45 regardless of weight• Test symptomatic adults of any age who are overweight/obese
AND ≥ 1 additional risk factors for diabetes
Section 4: Glycemic Targets– People who use continuous glucose monitoring and insulin pumps should
have continued access after they turn 65 years of age
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Section 6: Obesity Management for the Treatment of Type 2 Diabetes*
Adapted from: http://care.diabetesjournals.org/site/misc/2016‐Standards‐of‐Care.pdf
BMI category (kg/m2)
23* or
25‐26.927‐29.9 30‐34.9 35‐39.9 ≥ 40
Diet, physical activity
& behavioral therapyX X X X X
Pharmacotherapy X X X X
Bariatric Surgery X X
*cutoff point for Asian American individuals
X: treatment may be indicated for selected motivated patients
At what age would you recommend aspirin for primary prevention in a diabetic patient?
1. ≥ 40 years
2. ≥ 50 years
3. ≥ 60 years
4. ≥ 65 years
Section 8: Cardiovascular Disease and Risk Management*
Aspirin
– men and women aged ≥ 50 years with diabetes AND
• 10 year ASCVD risk > 10%
• one or more major risk factors: – smoking– hypertension– dyslipidemia– family history of premature ASCVD– albuminuria
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Section 8: Cardiovascular Disease and Risk Management*
Aspirin (continued)
– Not recommended if low risk of ASCVD:
• Men & women < 50 years old
• No other major ASCVD risk factor
• 10-year ASCVD risk < 5%
– Clinical judgment should be used if intermediate risk of ASCVD
• Younger patients with one or more risk factors
• Older patients with no risk factors
• Those with 10-year ASCVD risk of 5-10%
Section 8: Cardiovascular Disease and Risk Management*
Ezetimibe
– IMPROVE-IT Trial (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial)
– Adding ezetimibe to moderate-intensity statin provides additional cardiovascular benefits for select individuals with diabetes and should be considered
Section 11: Children and Adolescents
– Obtain a fasting lipid profile in children starting at age 10 years (changed from starting at 2 years)
Section 12: Management of Diabetes in Pregnancy*
– New recommendation to highlight the importance of discussing family planning and effective contraception with women with pre-existing diabetes
– A1C recommendations for pregnant women with diabetes changed:
• Target of 6-6.5% (from target < 6%)
• Glyburide in gestational diabetes was deemphasized
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New Concentrated Insulins
What are the characteristics of an ideal basal insulin?
1. Peak-less basal coverage
2. 24 hour duration of action
3. Low volume/concentrated
4. Low risk for hypoglycemia
5. All of the above
Comparison of Basal Insulins
NPHInsulin Detemir
Levemir®
Insulin Glargine
Lantus®
Regular Insulin
U‐500
Concentration 100units/ml 100units/ml 100units/ml 500units/ml
Onset (hrs) 1‐2 1‐2 1 0.5
Peak (hrs) 4‐12 ‐‐ ‐‐ 1‐3
Duration (hrs) 16‐24 7‐24 11‐24 6‐10
Cost ($/unit)0.11 (vial)
0.23 (pen)
0.25 (vial)
0.25 (pen)
0.25 (vial)
0.25 (pen)
0.05 (vial)
0.2 (pen)
Adapted from Pharmacist Letter. < http://pharmacistsletter.therapeuticresearch.com>.
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Comparison of Basal Insulins
NPH
Insulin
Detemir
Levemir®
Insulin
Glargine
Lantus®
Regular
Insulin
U‐500
Insulin
Glargine
Toujeo®
Insulin
Degludec
Tresiba®
Concentration100units/ml 100units/ml 100units/ml 500units/ml 300units/ml
100units/ml
200units/ml
Onset (hrs) 1‐2 1‐2 1 0.5 6 0.5‐1.5
Peak (hrs) 4‐12 ‐‐ ‐‐ 1‐3 ‐‐ ‐‐
Duration (hrs) 16‐24 7‐24 11‐24 6‐10 >24 42
Cost ($/unit) 0.11 (vial)
0.23 (pen)
0.25 (vial)
0.25 (pen)
0.25 (vial)
0.25 (pen)
0.05 (vial)
0.2 (pen)0.25 (pen) 0.30 (pen)
Adapted from Pharmacist Letter. < http://pharmacistsletter.therapeuticresearch.com>.
Insulin Glargine U-300 (Toujeo®)
• Same molecule as Lantus® only concentrated
• Decreased surface area:
– Slows absorption
– Prolongs duration
– Lowers peak effectLantus 20 units
Toujeo 20 units
Switching Insulin Products
Switching TO Toujeo Dose Adjustments Comments
From NPH Once daily: unit‐per‐unitTwice daily: ↓ dose 20%
•May take ≥ 5 days to see max effect•Do not increase more than every 3‐4 days•Give doses once daily
*for patients controlled on Lantus, expect that a 10‐18% higher daily dose will be needed to maintain control
From insulin glargine(Lantus)
Once daily: unit‐per‐unitTwice daily: unit‐per‐unit (or ↓ by 10% or less)*
From insulin detemir(Levemir)
Once daily: unit‐per‐unitTwice daily: ↓ dose 20%
Adapted from Pharmacist’s Letter 6/2014, www.PharmacistsLetter.com
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Switching Insulin ProductsSwitching FROM Toujeo Dose Adjustments Comments
To NPH No specific informationConsider↓ 20% to be conservative
Divide dose & give twice daily
To insulin glargine (Lantus) ↓ dose 20% to be conservative
To insulin detemir (Levemir) No specific information↓ dose 20% to be conservative
Adapted from Pharmacist’s Letter 6/2014, www.PharmacistsLetter.com
Study: EDITION 1Toujeo® v Lantus®
• Multicentre, multinational, randomized, open-label, two-arm, parallel-group, phase 3a study
• 1:1 ratio– Insulin glargine U-100 (Lantus®) daily– Insulin glargine U-300 (Toujeo®) daily– Plus insulin aspart for meals
• Inclusion:– Adult patients with T2DM receiving basal/bolus insulin therapy– BMI ≤ 45 kg/m2– HbA1c between 7 and 10%
Diabetes Obes Metab 2015; 17: 835‐42.
Study: EDITION 1Toujeo® v Lantus®
Primary endpoint: A1C Lowering Effect
Diabetes Obes Metab 2015; 17: 835‐42.
0.17% more A1C lowering[‐0.17 (95% CI: ‐0.3 to ‐0.05)]
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Study: EDITION 1Toujeo® v Lantus®
Secondary Endpoint: Nocturnal hypoglycemia
Not Significantly Different[0.90 (95% CI: 0.70‐1.16)]
Diabetes Obes Metab 2015; 17: 835‐42.
Study: EDITION 1Toujeo® v Lantus®
Secondary Endpoint: Overall hypoglycemia
Not Significantly Different[1.06 (95% CI: 0.89‐1.27)]
Diabetes Obes Metab 2015; 17: 835‐42.
Study: EDITION 1Toujeo® v Lantus® Secondary Endpoint: Basal insulin dose
Diabetes Obes Metab 2015; 17: 835‐42.
Insulin Dose1.03 u/kg Toujeo ®
0.9 u/kg Lantus ®
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Summary - Insulin glargine U-300 (Toujeo®)
• Nocturnal hypoglycemia
– Less during titration period
– Possibly less overall
• Basal insulin dose
– Need 11-14% more insulin for same A1C lowering as Lantus
• Possibly less weight gain
Diabetes Obes Metab 2015; 17: 1142‐9.
Insulin Degludec (Tresiba)
http://mediacenter.novomedlink.com/v/tresiba‐mechanism‐of‐protraction
Insulin Degludec
• Ultra Long-Acting Insulin
• Human insulin analog (rDNA origin)
• Duration 42 hours
• Dose given once daily, any time of day
• Formulation:
– 100 units/ml
– 200 units/ml
• Stable 56 hours at room temp
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Switching Insulin ProductsSwitching TO Insulin Degludec
Dose Adjustment Comments
NPH Convert total daily dose unit‐per‐unit & give once daily
•Consider 20% dose reduction if switching from twice daily schedule•Consider dose reduction if switching from once daily schedule•Do not increase dose more than every 3‐4 days
Insulin glargine (Lantus, Toujeo)
Insulin detemir (Levemir)
To insulin detemir Limited information: Consider converting unit‐per‐unit
•Give glargine and detemir once daily (divide dose if necessary for control)
Adapted from Pharmacist’s Letter 6/2014, www.PharmacistsLetter.com
Switching Insulin Products
Switching FROM Insulin Degludec
Dose Adjustment Comments
To NPH Limited information: Consider converting unit‐per‐unit
•Give NPH twice daily
To insulin glargine •Give glargine and detemironce daily (divide dose if necessary for control)
To insulin detemir
Adapted from Pharmacist’s Letter 6/2014, www.PharmacistsLetter.com
Study: BEGIN Basal-Bolus Type 2Tresiba® v Lantus®
• Randomized, treat-to-target, parallel-group, open-label, multinational, non-inferiority, phase 3 trial
• 3:1 ratio– Insulin degludec (Tresiba®) vs insulin glargine(Lantus®) daily– Both in combination with insulin aspart for meals
• Inclusion:– Adult patients with T2DMfor on insulin for at least 6 months– BMI ≤ 40 kg/m2– HbA1c between 7 and 10%
Lancet 2012; 379: 1498‐507
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Lancet 2012; 379: 1498‐507
Primary Endpoint: A1C Lowering effect
Study: BEGIN Basal-Bolus Type 2Tresiba® v Lantus®
Non‐inferiority for A1C lowering
Lancet 2012; 379: 1498‐507
Secondary Endpoint: Nocturnal hypoglycemia
Study: BEGIN Basal-Bolus Type 2Tresiba® v Lantus®
25% lower rate of nocturnal hypoglycemia[0.75 (0.58‐0.99); p=0.0399]
Lancet 2012; 379: 1498‐507
Secondary Endpoint: Overall hypoglycemia
Study: BEGIN Basal-Bolus Type 2Tresiba® v Lantus®
18% lower rate of overall hypoglycemia[0.82 (0.69‐0.99); p=0.0359]
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Pharmacodynamic Variability between Lantus® and Tresiba®
Diabetes Obes Metab. 2012; 14: 859‐64.
4 fold decrease in variability seen in Tresiba
Summary - Insulin degludec (Tresiba®)
• Basal insulin dose – 11 to 14% LESS insulin needed
• U100 and U200 pens – max dose of 160units/injection
• Nocturnal hypoglycemia - Decreased rate by 25-40% compared
to Lantus
Diabetes Care. 2013; 36: 2536‐42.Lancet. 2012; 379: 1489‐97.Lancet 2012; 379: 1498‐507.
Final Thoughts
• Toujeo® use in patients:
– Concerned with weight gain
– Basal insulin wears off prior to redosing
• Tresiba® use in patients:
– Recurrent nocturnal hypoglycemia
– Requiring more than 80 units of basal insulin
– Basal insulin wears off prior to redosing
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SGLT-2 Inhibitors
SGLT-2 Inhibitors
• Sodium-Glucose Co-transporter Type 2 (SGLT2)
• Benefits:
– Decreases A1C by 0.5-1%
– Weight loss
– Lower blood pressure
Micromedex. Truven Health Analytics.
Brand Generic Initial Dose
Invokana® Canagliflozin 100 mg daily
Farxiga® Dapagliflozin 5 mg daily
Jardiance® Empagliflozin 10 mg daily
Empagliflozin
https://hcp.jardiance.com/clinical‐pharmacology.php#clinicalpharmacology
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Adverse Reactions
• Urinary Tract Infection (7.6-9.3%; 15% ≥ 75 years old)
• Hypoglycemia (0.4% monotherapy)
• Genital mycotic infections (5.4-6.4%)
• Dyslipidemia (2.9-3.9%)
• Precautions– Hypotension – renal impairment, elderly, concomitant diuretic– Impairment of renal function – dehydration, elderly– Ketoacidosis – post-market finding in majority of patients
EMPA-REG Outcome Trial
• Randomized, double-blind, placebo-controlled trial– 590 sites– 42 countries
• Patients– 7028 patients underwent randomization between 9/2010 and 4/2013– 7020 treated and included in primary analysis– 97% completed the study
• Median duration of treatment: 2.6 years• Median observation time: 3.1 years
N Engl J Med 2015; 373:2117‐2128
Inclusion Criteria
• Adult (≥ 18 years of age)
• BMI ≤ 45 kg/m2
• eGFR ≥ 30ml/min/1.73m2
• Established cardiovascular disease
• Standard blood glucose lowering treatment
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Study Procedure
• 2 week open-label, placebo run-in period during which background glucose lowering therapy was unchanged
• Patients then randomly assigned 1:1:1
– 10mg empagliflozin
– 25mg empagliflozin
– Placebo
Outcomes
Primary outcome:
• composite of death from cardiovascular causes, non-fatal MI (excluding silent MI), or non-fatal stroke
Key secondary outcome:
• composite of primary outcome + hospitalization for unstable angina
EMPA-REG OUTCOME TrialPrimary Outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
N Engl J Med 2015; 373: 2117‐28.
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EMPA-REG OUTCOME Trial
N Engl J Med 2015; 373: 2117‐28.
Secondary Outcome: Hemoglobin A1C Reduction
Mean A1C reduction: ‐0.24 % (95% CI, ‐0.4 to ‐0.08)
Mean A1C reduction: ‐0.54 % (95% CI, ‐0.58 to ‐0.49)
SafetyConfirmed hypoglycemia
• Blood glucose ≤ 70mg/dL• Event requiring assistance
Adverse effects reflecting:• UTI• Genital infection• Volume depletion• Acute renal failure• Bone fracture • Diabetic ketoacidosis• Thromboembolic events
Safety Analysis
• Genital infections reported in a significantly (p < 0.001) higher percentage of patients in the pooled empagliflozin group (6.4% vs. 1% placebo)– 5% empagliflozin group vs. 1.5% in men– 10% empagliflozin group vs 2.6% in women
• No imbalance in overall rates of UTI, complicated UTI, or pyelonephritis
• Rates of hypoglycemia similar (about 28%)
• Similar drop out rates
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Discussion
• Dosing of empagliflozin: 10m vs. 25mg
• Effect on HgA1C
• What caused the benefit in survival?
• Who might benefit from empagliflozin?
• Are there patients that should not use this drug?
• Is this a class effect?
Venous Thromboemoblism
VTE Treatment Decision Making
American College of Chest Physicians (ACCP) evidence-based antithrombotic therapy practice guideline
– 9th ACCP (AT9) released in 2012
– 10th ACCP (AT10) released in 2016
AT10 clarifies role of New Oral Anticoagulants (NOACs) based on trial data:– DABIGATRAN: RELY (NVAF); RECOVER (VTE)
– RIVAROXABAN: ROCKET-AF (NVAF); EINSTEIN PE/EINSTEIN DVT (VTE)
– APIXABAN: ARISTOTLE (NVAF); AMPLIFY (VTE); AMPLIFY-EXTENDED (VTE)
– EDOXABAN: ENGAGE-AF TIMI (NVAF); HOKUSAI VTE (VTE)
AT10 better identifies those patients at high risk of VTE recurrence who should be considered for extended therapy (i.e. no stop date)
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Review of Cascade & Target MOAs
Changing landscape of Oral Anticoagulants (OAC)
Warfarin– Benefits: highly effective when managed appropriately; affordable– Drawbacks: difficult to maintain in therapeutic range, which
increases risk of adverse outcomes; burden of INR monitoring; many interactions
NOAC Approval– Dabigatran: 2010 NVAF; 2014 prevention & Tx DVT/PE– Rivaroxaban: 2011 prevention & Tx DVT/PE, NVAF – Apixaban: 2012 NVAF; 2014 prevention & Tx DVT/PE– Edoxaban: 2015 NVAF & prevention/treatment DVT/PE
NVAF = nonvalvular atrial fibrillation Tx DVT/PE = treatment of deep vein thrombosis and pulmonary embolism
AT10: Duration of Therapy
Provoked DVT/PE : – 3 months DOT recommended over shorter period or over a longer period
Unprovoked DVT/PE (1st or 2nd event): Decision based on bleed risk– Low & Moderate bleed risk : extended therapy (no stop date) preferred– Very High bleed risk: 3 month DOT preferred with new role for ASA
therapy in this population.
DVT/PE in the setting of active cancer: – Extended therapy for all (no stop date) despite bleed risk
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AT10—NOAC Role More Clearly Defined
• NOACs take role of first line agents over warfarin for initial and long-term treatment of VTE in patients WITHOUT cancer
• NOACs and VKA have equal efficacy for recurrent VTE risk reduction
• NOACs considered safer as bleed risk, particularly intracranial bleeding
• VTE in setting of active cancer: LMWH remains preferred agent
Making The Choice Between Anticoagulants
History of GI Bleed:
– Apixaban may be preferred agent
Elderly (> 75 years age):
– Apixaban, Edoxaban or Rivaroxaban preferred
Extremes of body weight (< 60 kg or > 120 kg):
– Warfarin preferred agent
When is LMWH preferred?
1. Liver Disease
2. Active Cancer
3. Pregnancy
4. All of the above
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Clinical Scenarios where LMWH is Agent of Choice
• Liver Disease– NOACs contraindicated in severe liver disease– Warfarin remains an option, but INR is difficult to control
• Active Cancer– Ongoing trials are seeking to validate NOACs in setting of cancer
• Pregnancy– Warfarin is teratogenic – NOACs have potential to cross placenta
When is warfarin preferred?
1. Variable INR
2. Alcohol abuse
3. Breastfeeding
4. Non-adherence
5. All of the above
Clinical Scenarios Where Warfarin Preferred
Warfarin has advantage of using INR to estimate &
titrate anticoagulation response
Specific patient factors are present that lend concern about whether intensity of anticoagulation is appropriate
– Alcohol abuse
– Drug Interactions
– Medication adherence concerns
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AT10: New Role for Aspirin Therapy
Aspirin in extended treatment of VTE based on RCT data– Extended therapy reduces risk of VTE recurrence by one-third
– Benefits outweigh the increased risk of bleeding
– Consider ASA as an alternative for patient who does not want or unable to continue anticoagulation therapy
Unprovoked DVT/PE : if patient discontinues anticoagulation therapy and does not have contraindication to ASA:
– AT10 suggests aspirin over no aspirin to help prevent recurrent VTE
– ASA less effective at preventing VTE recurrence than anticoagulation therapy
– ASA provides some degree of protection for VTE recurrence
– Other potential ASA benefits:
• Stroke risk reduction
• Colon cancer risk reduction
AT10: VTE Occurrence while on AnticoagulationRecurrent VTE while on oral anticoagulant
– Evaluate if patient has been compliant with anticoagulation therapy– Consider the presence of underlying risk factor for hyper-coagulable
state– Stop oral anticoagulant and switch to LMWH for at least 1 month
Recurrent VTE while on LMWH therapy– Confirm compliance with LMWH– If compliance confirmed, increase dose of LMWH by ¼ to 1/3 – If patient was on a once-daily LMWH regimen, switch to BID
regimen to enhance efficacy
AT10: Additional Updates• Prevention of Post-Thrombotic syndrome
– AT10 no longer recommends use of compression stockings routinely to prevent Post-Thrombotic Syndrome
• Subsegmental PE Treatment Guidance Clarified
• Acute PE—Outpatient Treatment Prefered for Low-Risk PE
• Additional Management Guidance Per AT10: – Thrombolytic Therapy for PE– Catheter-Based Thrombus Removal– Pulmonary Thromboendarterectomy– Thrombolytic Therapy for Upper Extremity DVT
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Patient Case55 yo Caucasian female with type 2 DM who presents to clinic for evaluation of newly diagnosed PE secondary to proximal DVT. No provoking factors identified. The emergency room provider initiated LMWH anticoagulation therapy last evening and sends her to clinic for further anticoagulation therapy management.
Past medical history includes HTN, hyperlipidemia (TC 240, HDL 30, LDL 150, TG 175). She is a current smoker, 1 ppd. BP in clinic today is 130/78. Chem 7 reveals Scr 0.8 (estimated GFR > 60) and electrolytes WNL.
Current medications include Lisinopril, insulin glargine 80 units SQ nightly and metformin at target dose.
Recent A1c is 9.5% (Est Avg 220 mg/dL). She presents her BG log which reveals 3 episodes of nocturnal hypoglycemia in the last month however, the majority of her blood glucose readings are > 180 mg/dL.
Allergies include penicillin and a clearly documented intolerance to statins (she has tried multiple agents with equal intolerance)
Questions
1. How would you address therapy management of new VTE?
2. How would you address diabetes drug therapy management?
3. How would you address her CV risk? Would you consider additional therapy?
Cacophony To Harmony: A Composition of Chronic Disease State Updates
Northwest Pharmacy ConventionCoeur d’Alene, Idaho
June 2016
Sonia Allen, PharmD, BCACPAndrea Corona, PharmD, BCACP, CDEDaniela Dandridge, PharmD, BCACP