1. New Drugs 2016 The Good, the Bad, & the Worthless
Bill Origer MD
OAFP
March 11, 2016

2. Disclosure No commercial financial support
After the talk, you will understand why

3. Disclaimers Not a comprehensive study of diseases
Based on high quality published research
References & boring details available
Prices are approximate & may vary
New information is continuous
anything could change
I could be wrong

4. Another disclaimer Research applies to populations
Physicians treat individuals
Medicine has thousands of unique & unusual people and situations
Do the right thing for each patient
There are times when a 4th or 5th choice is the best option for that patient

5. How did I get into this?? 20 yrs private practice Albany, 1977 – 1996
Variety of admin jobs & part-time practice
Faculty, Samaritan Family Medicine Residency, Corvallis
Oregon Health Resources Commission ,
Chair, Pharmaceutical Subcommittee ‘08-’11
Oregon Preferred Drug List Committee 2010
Oregon P & T Committee, Chair,
My credibility in this world is the strength of evidence
If it’s evidence based, it’s not you vs me, but a discussion of the evidence
In 2000, “Bill, put this drug on the formulary, it works better.”
“What’s the evidence for that?”
“ Ummmm.”
In 2006, “ Bill I’ve got an article I want you to read.”

6. Same efficacy & toxicity within category May be differences in side effects, dosing, duration of action, price
Alzheimer’s drugs
ACE Inhibitors
Angiotensin receptor blockers
ADHD stimulant drugs
Inhaled steroids for asthma
Inhaled anti-cholinergics
β agonists for asthma
Inhaled nasal steroids
α blockers for PBH
5 α-reductase inhibitors- BPH
Estrogens for menopause
Oral contraceptives
Muscle relaxants
NSAIDS
Ophthalmic steroids
Ophthalmic anti-inflammatories
Growth hormone products
Benzodiazepine receptor agonist sedatives
Opioids for long term use
H2 blockers
PPIs
Statins (adjusted for potency)
Triptans for migraine
Anticholinergics & others for overactive bladder
DPE-5 inhibitors for erectile
2nd generation antidepressants
Based on rigorous evidence reviews by Oregon Health Resources Commission &
Oregon P & T Committee, there are no major difference in efficacy or toxicity among drugs in the following categories. There may be differences in side effects, dosing, and duration of action, and price\
Growing evidence of class effect of beta blockers, but not yet conclusive

7. The Good

8. Newer anticoagulants
Safety & efficacy same as warfarin for stroke prevention with atrial fib, and acute DVT in uncomplicated patients
Concerns: no way to monitor, bid dose (dabigatran & apixaban) caution w renal impairment, high cost (~$300/mo)
Edoxaban (Savaysa) no comparative data to others
Only dabigitran is reversible
90% of OHP patients still on warfarin
Oregon P & T Sept 2015; Medical Letter 3/15/2015
dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) 
Edoxaban (Savaysa) - The Fourth New Oral Anticoagulant

9. Idarucizumab (Praxbind) Antidote for dabigatran (Pradaxa)
Human monoclonal antibody
Binds to dabigatran w higher affinity than dabigatran binds to thrombin
Works only for dabigitran.
Immediate onset, blood levels <20 ng/ml
93% at 12 hr, 79% at 24 hrs.
Dose - IV bolus 5 gm, $3500/dose
Limited data – single arm trial, 90 patients, 92% had normal hemostasis for surgery
The Medical Letter 11/23/2015

10. Drugs past expiration date
Dates written by legal department
Single episode of toxicity of expired drug – tetracycline 1963
Dept Defense Study: 3005 lots of 122 meds, ave. 66 mo. past date
Solid drugs, unopened container, room temperature >90% of potency 5 yrs past date
Heat & humidity speed aging
Solutions, suspensions less stable, especially to freezing
Epi-pens loose potency after expiration
The Medical Letter 12/7/2015

11. Albuterol powder MDI (ProAir RespiClick)
Existing albuterol inhalers - dilute solution w propellant. Requires coordination between actuation of the device and inspiration, or the use of a spacer
Dry powder inhalers are breath-actuated, and do not require an initial priming dose. The patient must be able to take a rapid deep inhalation to activate the inhaler.
Contains a dose counter
Opening the mouthpiece prepares a dose for use & causes the counter to count down one dose. Closing the cap without inhalation wastes that dose.
Price $50 per inhaler (200 doses,) similar to other albuterol MDIs. This device may be easier for some patients to use.
The Medical Letter 10/26/2015

12. Hepatitis C Facts Of 100 persons infected with HCV, approximately
75–85 will go on to develop chronic infection
60–70 will go on to develop chronic liver disease
5–20 will go on to develop cirrhosis over a period of 20–30 years
1–5 will die from the consequences of chronic infection (liver cancer or cirrhosis)
CDC website accessed 2/22/2015

13. Beware of Hep C Guidelines
American Association for the Study of Liver Diseases (AASLD) Infectious Disease Society of America (IDSA) Hepatitis C Guidelines
Not evidence based
Majority of members with conflict of interest

14. Levels of evidence 1A Meta-analysis of randomized controlled trials
1B At least one randomized controlled trial
2A At least one controlled study without randomization
2B At least one type of quasi-experimental study
3 Descriptive studies, such as comparative studies, correlation studies, or case-controlled studies
4 Expert committee reports or opinions and/or clinical experience of respected authorities

15. American Association for the Study of Liver Diseases (AASLD) Infectious Disease Society of America (IDSA) Definitions of Evidence
Classification
Description
Class I
Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective
Class II
Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness and efficacy of a diagnostic evaluation, procedure, or treatment
Class IIa
Weight of evidence and/or opinion is in favor of usefulness and efficacy
Class IIb
Usefulness and efficacy are less well established by evidence and/or opinion
Class III
Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful and effective or if it in some cases may be harmful

16. Guideline Myths Myth - Treat everyone
<20% get cirrhosis over yrs; <5% die from disease
Cost would double total annual drug budget for OHP open card
Myth - treat early
Based on “modeling studies” – IE speculation
Myth - Active drug abuse not a barrier
Only study done on opioid addicts in treatment with suboxone or methadone – they did well, but can’t extrapolate
Anecdotal reports of re-infection in addicts after tx
Myth – alcohol abuse not an obstacle
Studies exclude active drug or alcohol users – no data

17. Priority - sickest
Advanced fibrosis (METAVIR F3),compensated cirrhosis (METAVIR F4) OR radiologic, lab, or clinical evidence of cirrhosis without ongoing progressive decompensation (MELD score 8 -11),
Expected survival from other conditions >5 years
Extrahepatic manifestations of hepatitis C
Type 2 or 3 cryoglobulinemia with end-organ manifestations (vasculitis)
Proteinuria, nephrotic syndrome, or
membranoproliferative glomerulonephritis

18. Priority - sickest
Patient is listed for a transplant and it is essential to prevent recurrent hepatitis C infection post-transplant
Post-transplant patients with Stage 4 fibrosis
Post-transplant patients with fibrosing cholestatic hepatitis due to HCV infection
Oregon P & T Jan 2016

19. Priority – best chance for success
Abstinent from illicit drug, marijuana use, AND alcohol abuse for 6 months or longer
Able to participate & cooperate in treatment
Consultation with hepatologist, GI or ID specialist, or other physician with experience in treatment of Hepatitis C

20. Hep C summary New drugs are better & less toxic
Studies are poor quality & short
Guidelines are not scientific
Competition dropping prices, but still outrageous
More drugs in the pipeline
Treat the sickest, no hurry for most
Cost still $40,000 – 80,000

21. Naloxone auto injector (Evzio)
Auto-injector syringes containing 0.4 mg naloxone for opioid overdose
Original price $250/pkg
As of 2/24/2016: pkg of 2 syringes: $820
Off-label: a standard dose, 0.4mg of injectable naloxone ($17-22) may be used intranasally.
The Medical Letter 6/9/2014; goodrx.com

22. Platelet inhibitors after PCI
Dual antiplatelet therapy (DAPT) consisting of aspirin plus a P2Y12 receptor antagonist is after drug‐eluting stent (DES)
12 months by the Am Coll of Cardiology/Am Heart Asso (ACC/AHA)
6-12 months by European guidelines
followed by aspirin monotherapy
extended therapy (>12 months) compared with 12‐month therapy
reduction in stent thrombosis (NNT 100‐250) and MI (NNT 50‐125), but increased risk of major bleeding (NNH 111‐325).
increase in all‐cause mortality with extended DAPT beyond one year 2.0% vs. 1.5%; NNH 200 driven by non‐cardiovascular events.
Further studies are needed the optimal duration of therapy
DAPT one year in most patients receiving a DES
high CV risk patients considering longer term use (up to 30 months)
high bleeding risk consider <6 months.
Oregon P & T July 2015

23. Newer drugs for Diabetes
A recent systematic review found insufficient evidence to compare health outcomes of the newer diabetes medications and combinations
Studies underway
Be skeptical of single studies
CV benefit of metformin, insulin, sulfonylureas based on meta-analysis of large studies
Evidence‐based Practice Center for the Drug Effectiveness Review Project. OHSU Portland, OR
CV benefit of metformin, insulin, sulfonylureas based on meta-analysis of large studies.

24. Ophthalmic steroids & anti-inflammatories
High quality evidence - no difference in efficacy/effectiveness or in safety between ophthalmic corticosteroid agents
High quality evidence - no difference in efficacy/effectiveness or in safety among ophthalmic nonsteroidal anti‐inflammatory drugs
Oregon P & T 5/28/2016
Current Preferred Agents Current Non‐Preferred Agents
Ophthalmic Corticosteroids
Dexamethasone (MAXIDEX) suspension
Dexamethasone sodium phosphate suspension
Fluorometholone (FML; FML S.O.P.; FLUOR‐OP) suspension
Loteprednol etabonate (LOTEMAX) suspension
Prednisolone (OMNIPRED; PRED FORTE) suspension
NON PREFERRED
Dexamethasone sodium phosphate (DECADRON) ointment
Difluprednate (DUREZOL) emulsion
Fluorometholone (FML FORTE) suspension
Fluorometholone acetate (FLAREX) suspension
Loteprednol etabonate (ALREX) suspension
Loteprednol etabonate (LOTEMAX) gel and ointment
Prednisolone acetate (PRED MILD) suspension
Prednisolone sodium phosphate (INFLAMASE MILD; INFLAMASE FORTE) suspension
Rimexolone (VEXOL) suspension
Ophthalmic Non‐steroidal Anti‐inflammatory Drugs (NSAIDs)
PREFERRED
Diclofenac sodium (VOLTAREN) solution
Flurbiprofen (OCUFEN) solution
Ketorolac tromethamine (ACULAR; ACULAR LS) solution
Bromfenac (PROLENSA) solution
Ketorolac (ACUVAIL) solution
Nepafenac (ILEVRO; NEVANAC) suspension

25. Asthma/COPD
Tiotropium/olodaterol (Stiolto™ Respimat®) insufficient evidence of comparative efficacy or safety between tiotropium-olodaterol and other drugs for the management of COPD
Olodaterol - lack of quality evidence for clinical effectiveness.
Fluticasone furoate (Arnuity™ Ellipta®) same as any other inhaled steroid
Oregon P & T Sept 24, 2015

26. Insulin glargine (Lantus) Insulin detemir (Levemir)
Insufficient comparative evidence that evaluates long‐term outcomes (ie, vascular outcomes, mortality or cancer) between insulin detemir and glargine products
No clinically relevant difference in efficacy or safety of the two long acting agents
Insulin degludec (Tresiba) is noninferior to insulin glargine & insulin detemir in lowering HbA1c
Oregon P & T Nov 2015; Medical Letter 12/7/2105

27. Insulin degludec (Tresiba)
8 open‐label, randomized controlled trials
Comparisons included insulin glargine, insulin detemir, and sitagliptin
Low strength evidence - non‐inferior to insulin glargine or detemir at A1c reduction
Open‐label study design prohibits a fair comparison for adverse effects
Insufficient evidence to show any effect on mortality, or vascular outcomes.

28. Insulin degludec and insulin aspart Ryzodeg®
Similar A1c lowering as detemir/aspart
Insufficient evidence to determine the effect of degludec/aspart on mortality, & vascular outcomes
Oregon P & T Dec 2015

29. Fluoroquinolones
Moderate quality evidence: no difference in effectiveness of fluoroquinolones to susceptible bacteria
Ofloxacin - highest risk of tendon injury levofloxacin - least risk
Oregon P & T 5/28/2015

30. Topical analgesics
Moderate quality evidence: topical NSAIDs are safe and effective for acute musculoskeletal pain over 1 to 2 weeks
Insufficient evidence to compare efficacy or safety among topical analgesics.
Topical 8% capsaicin improves neuropathic pain more than lower concentrations
Evidence of long‐term safety is insufficient
Insufficient evidence exists for efficacy of 5% topical lidocaine patches for neuropathic pain
Insufficient evidence to compare topical VS oral NSAIDS for efficacy or safety
Oregon P & T Nov 2015

31. Maybe good

32. Flibanserin (Addyi) Hypoactive sexual desire in menopausal women
Mechanism unknown
Agonist serotonin-HT1A Antagonist serotonin-HT2A
100mg daily at hs, $800/month
Somnolence, sedation, fatigue 21%
Hypotension & syncope, worse w alcohol
Concurrent alcohol use contraindicated

33. Flibanserin (Addyi) Three 24-week studies, DAISY, VIOLET, BEGONIA
End points on self-rating scales:
Increase in satisfying sexual events over 4 wks:
0.8 to 1.0 compared to placebo (p<0.05)
Mean increase in peak sexual desire score at 24 wks: not significant 2 studies, 3rd study: increase over placebo 0.3 on 6 point scale (p<0.05)
Overall response rate 8-13% compared to placebo
Long term safety & efficacy unknown
Medical Letter 9/28/2015

34. Sacubitril/valsartan (Entresto)
New category of drug neprilysin inhibitor
Neprilysin degrades natriuretic peptides
Natriuretic peptides prevent progression of ventricular dysfunction & remodeling in animals
Neprilysin also degrades angiotensin, endothelin- 1, opioids, bradykinin, & amyloid-β peptide.
JAMA 12/7/2015

35. Sacubitril/valsartan Theoretical risks
Neprilysin also degrades angiotensin, opioids, endothelin- 1, bradykinin, & amyloid-β peptide
Used with ARB due to degradation of angiotensin
Amyloid-β peptide has protective effects on Alzheimer's & macular degeneration
Long term studies of neurocognitive effects due in I think we can wait.

36. Sacubitril/valsartan Clinical study
8399 pts randomized, CHF, EF 29%, NYHA Class II or III, on diuretic and β blocker
Comparison: enalapril 10 mg bid
End points at 27 months: composite CV death or admission for CHF; all cause mortality
Single blind run-in for dose toleration. 20% of subjects eliminated before randomization.
NEJM 9/11/2014
NYHA
I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath).
II Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath).
III Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea.
IV Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest.  If any physical activity is undertaken, discomfort increases.

37. Sacubitril/valsartan Clinical study
Terminated early, 27 vs 36 months
CHF admission: 12.8% vs 15.6% control
Absolute risk reduction 2.8% NNT 36
CV mortality: 16.5% vs 13.3% control
Absolute risk reduction 3.2% NNT 31
NNT similar to ACE I alone
NNT for beta blockers alone much better about half

38. Sacubitril/valsartan Clinical study- Problems
Not comparable dose of enalapril – should be 20 mg bid
Higher ARB dose could be reason for benefit
20% of both arms dropped out due to drug intolerance (in addition to 20% eliminated at run-in)
Large single study, not replicated
Long term toxicity unknown
Similar

39. Sacubitril/valsartan analysis
NNT 36 patients for 27 months to prevent one admission and one death. Assume $375/mo cost
36 pt x 27mo = 972 months x $375/mo = $364,500 – drug cost to prevent one hospitalization
 Medicare 2015 DRG payments for CHF hospitalization $3,966 to $8,855
Total drug cost is 41-92X more than cost of hospitalization.
Oregon State Drug Review Dec 2015; cost: Goodrx.com 2/16/2016

40. Sacubitril/valsartan Summary
Interesting concept
Not ready for general use
Need more/better studies
Standard therapy better studied, costs 100X less

41. Rifaximin for hepatic encephalopathy
Low quality evidence - adding rifaximin 550 mg bid to lactulose is superior to lactulose alone at preventing HE
Low quality evidence -adding rifaximin to lactulose in hospitalized patients with HE is superior to lactulose alone
Studies have not been conducted in the U.S. - off label use
Insufficient evidence for the use of rifaximin without lactulose for prevention or treatment
Cases reports of Clostridium difficile infection - uncommon, but incidence unknown.
$1,800/month, lactulose $50/mo
Oregon P & T 5/28/2105

42. Fidaxomicin (Dificid) for C diff
Moderate evidence - oral vancomycin is superior to oral metronidazole in mild and severe C difficile infection (CDI)
Moderate evidence - oral vancomycin and oral fidaxomicin same for first episode of CDI
Insufficient evidence to compare metronidazole and fidaxomicin.
Insufficient evidence to support fidaxomicin alone for complicated or fulminant CDI
First recurrence – repeat previous tx
Moderate quality evidence fidaxomicin is superior to oral vancomycin at preventing recurrences of CDI
Insufficient evidence for the combination of 2 oral antibiotics
Fidaxomicin $3,500 - $3,700 for 10 days
Oregon P & T 5/28/2016

43. The BAD

44. Ivabradine (Corlanor) for CHF
Slows heart rate by inhibiting cardiac pacemaker If  current. No effect on ventricular repolarization or myocardial contractility
Does not reduce all‐cause or CV mortality compared to placebo
Low quality evidence - ivabradine may reduce hospitalizations for CHF by 4.7% compared to placebo (15.9% vs. 20.6%.)
Majority of patients were in Eastern European countries with higher rate of hospitalization for CHF than USA. Cannot extrapolate results to US.
Increases risk for atrial fibrillation. Do not use in patients with atrial fibrillation, discontinue if a fib develops
$380 - $400/month
Oregon P & T July 2015
60 tablets of Corlanor 5mg $
In a trial in 10,917 patients with coronary artery disease and stable heart failure (BEAUTIFUL), ivabradine did not significantly affect the primary composite endpoint of cardiovascular death, hospitalization for acute MI, or hospitalization for new-onset or worsening heart failure, compared to placebo.3
In another placebo-controlled trial in 19,102 patients who had coronary artery disease without clinically evident heart failure (SIGNIFY), ivabradine also did not significantly affect the primary endpoint, a composite of cardiovascular death or nonfatal MI. Moreover, a prespecified subgroup analysis in patients with more than minimal angina pectoris found a significantly higher incidence of the primary endpoint with ivabradine (7.6% vs 6.5% with placebo).4

45. Eluxadoline (Viberzi) for irritable bowel
Mu-opioid receptor, Schedule IV narcotic $960/mo
2 unpublished studies weeks, vs placebo reported 12 week endpoints, 75 & 100 mg doses
Primary endpoint: improvement in the daily worst abdominal pain score by ≥30% as compared to the baseline weekly average AND a reduction in the Bristol Stool Score to <5 on at least 50% of the days in a 12-week time interval. Improvement in daily worst abdominal pain in the absence of a concurrent bowel movement was also considered a response day.

46. Eluxadoline (Viberzi) for irritable bowel
Even if you understand what that means, it did not work very well. At 12 weeks:
Study 1: 24-25% responded to drug, 17% pcbo
Study 2: 29-30% responded to drug, 16% pcbo
26 wks, 75 mg worse than placebo, 100 mg similar to placebo
No improvement in abd pain vs pcbo at 12 wks
Medical Letter 1/4/2016; Viberzi package insert

47. Eluxadoline (Viberzi) for irritable bowel
High dose - euphoria in 14-28% of patients, 0-5% on placebo
Sphincter of Oddi spasm 1%, if no gallbladder 4%
Risk of pancreatitis if >3 drinks/day
This drug has it all: High cost, high toxicity, addiction risk, low efficacy!!

48. SGLT2 Inhibitors risks
Induce renal glycosuria – risks: dehydration, hypotension, hyperkalemia, mycotic genital infections, renal failure, especially in elderly
New FDA warnings - case reports of:
Ketoacidosis, some with normal blood glucose. Mechanism- increased fat metabolism
Pyelonephritis & urosepsis. Mechanism - glucosuria
Loss of bone density & increased fractures. Mechanism – increased renal reabsorption of phosphate
Incidence & long term risk unknown
Oregon State Drug Review Feb Medical Letter 10/12/2015

49. SGLT2 Inhibitors ? CV benefit
Single study 7020 pts with DM-2 & CV disease
590 sites, 42 countries
Empagliflozin 10 or 25 mg vs placebo, 2.6 yrs
Same incidence of MI & stroke
Reduced CV death 3.7% vs 5.9 % placebo
Reduced hospitalization for CHF 2.7% vs 4.1%
Mechanism unknown
Remain skeptical. NEJM 11/26/2015
Lots of patients in E Europe & Russia, Mexico, Brazil, Peru, Indonesia, Malaysia, India, Japan, Korea, Hong Kong, W Europe & USA

50. The Worthless

51. Rifaximin for irritable bowel
Non-absorbable antibiotic mg tid 14 days vs placebo, 12 week study
Primary endpoint is squishy:
Self reported relief of symptoms 2 of the first 4 weeks of tx. Would we use that for angina?
40.8% drug % pcbo
Difference between tx & pcbo decreased w time. Gone at 12 weeks in 4/5 endpoints
$1,176
Medical Letter 8/3/2015; NEJM 1/6/2011
Self reported relief of symptoms 2 of the first 4 weeks of tx. (would this endpoint be OK for Htn?)
Recurrence rate 59%
Remember CV benefits metformin, sulfonylurea, insulin well documented

52. Calcium & Vitamin D Mythology outweighs good studies by wide margin
Insufficient evidence on comparative efficacy among the different calcium formulations and among the different vitamin D formulations
(USPSTF) recommends against routine screening of vitamin D levels in asymptomatic adults
Calcium and vitamin D supplements lack evidence to support routine use
Insufficient evidence to make strong conclusions
Many references, me if you want specifics
Vitamin D plus calcium had a small effect in reducing hip fractures (RR 0.84; 95% CI 0.74 to 0.96; p=0.01), which
translates into 1‐9 fewer fractures per 1000 patients per year compared to controls.

53. Calcium supplements
Small reduction in total fractures in women – 12 to 11%, vertebral fractures 1.5 to 1.3%. No benefit in hip or forearm fx
Small increase in bone density 0.7 to 1.8% in hip, spine, femoral neck & forearm
Decreases risk of pre-eclampsia & hypertension in pregnancy
Four systematic reviews and meta‐analyses were available for updated evidence on the role of calcium supplementation on fracture risk, bone mineral density (BMD), hypertensive disorders in pregnancy and maternal and child outcomes.
There is low strength of evidence from 26 trials that included mostly females that calcium supplementation may reduce total body fracture risk (RR, 0.89, 95% CI 0.81 to 0.96) and vertebral fractures (RR, 0.86; 95% CI, 0.74 to 1.00) regardless of dose. Absolute risk reduction for total body fractures was 1% favoring calcium over control (11% vs. 12%, respectively) and the absolute risk reduction for vertebral fractures was 0.2% (1.3% vs. 1.5%, respectively). No benefit was seen in hip or forearm fractures. Calcium supplements with vitamin D had similar results as calcium monotherapy. Studies of dietary calcium had no effect on fracture rates.
 There is low strength of evidence from a systematic review and meta‐analysis of 59 trials that BMD is increased 0.7‐1.8% in the hip, lumbar spine, femoral neck, forearm and total body with calcium supplementation dosed 250‐2,500 mg daily. 
There is moderate strength of evidence that calcium supplementation (≥1 g/day) decreases risk of pre‐eclampsia during pregnancy (RR 0.45; 95% CI, 0.31 to 0.65), with an incidence rate of 65/1000 in controls compared to a rate of 29/1000 in women treated with calcium. The risk of hypertension in this population is reduced with calcium supplementation compared to placebo (RR, 0.65; 95% CI, 0.53 to 0.81) as well as decreased incidence of preterm birth (79/1000 vs. 104/1000, respectively; RR, 0.76; 95% CI, 0.60 to 0.97).3 However, there is moderate strength of evidence that calcium supplementation in women not at increased risk for pre‐eclampsia does not lower risk of preterm birth. However, there is low quality evidence calcium supplementation may be associated with a low, but increased incidence of HELLP Syndrome (hemolysis, elevated liver enzymes, and low platelets) in pregnant females (16 vs. 6 with placebo).

54. Vitamin D Benefits May reduce incidence of falls in elderly women
may decrease the number of falls (RR 0.66; 95% CI, 0.50 to 0.88; I2=65%) in elderly women.
vitamin D may have no effect on cancer rates compared to controls but may decrease all‐cause mortality (75/1000 vs. 80/1000, respectively; RR, 0.93; 95% CI, 0.88 to 0.98) and may decrease cancer‐related mortality (25/1000 vs. 29/1000, respectively

55. Vitamin D does not
Reduce mortally in healthy patients regardless of baseline serum level
Benefit cystic fibrosis, chronic pain scores, depression or blood pressure
Prevent recurrent adenomas of colon
Reduce mortality in colon or any other cancer
Improve HgbA1C in diabetics
no effect on mortality in healthy patients regardless of dose or baseline 25(OH)D levels
vitamin D alone, compared to control, does not prevent hip fractures
insufficient evidence of benefit from vitamin D supplementation for the following outcomes: cystic fibrosis (CF), chronic pain scores, depression symptoms or blood pressure
vitamin D did not affect hemoglobin A1C (A1C) compared to placebo in patients with type 2 diabetes mellitus (T2DM);20 and one RCT in patients with a history of colorectal adenomas found no benefit of vitamin D, calcium or the combination of both, for prevention of recurrent adenomas.

56. Vitamin D risks
Increases risk of nephrolithiasis, hypercalcemia, and gastrointestinal effects

57. PCSK9 Inhibitors Alirocumab (Praluent) Evolocumab (Repatha)
Proprotein Convertase Subtilisin Kexin type 9 Inhibitor!
Human monoclonal antibodies inhibit PCSK9 enzyme, reducing degradation of the LDL receptor, lowering LDL‐C\
Alirocumab and evolocumab, FDA approved. Bococizumab - in phase 3 testing.
Lowers LDL-cholesterol by ≥ 40% unpublished studies
No studies of morbidly or mortality
Both are injectable, $13,000/year
Oregon P & T Nov 2015; Medical Letter 8/17/2015, 10/12/2015
17 clinical trials, of which 14 are placebo‐controlled. No completed trials have evaluated health outcomes (morbidity or mortality) as primary endpoints. Two ongoing studies, one for evolocumab and one for bococizumab, will evaluate health outcomes as a primary endpoint but are not expected to be completed until None of the 5 completed trials of bococizumab have been published. In addition, no completed or ongoing studies
directly compare different PCSK9 inhibitors.

58. Meloxicam (Vivlodex)
Generic meloxicam 7.5 & 15 mg, #30, $4.00 Vivlodex (meloxicam) 5 & 10 mg, #30, $ Scrabble Effect Names with unusual consonants are expensive Drugs.com; fda.gov

59. Sumatriptan Nasal (Onzetra Xsail)
Imitrex brand, 5mg, #6 unit dose $450
Generic, 5mg, #6 unit dose $150
New FDA approval Jan 2016
Onzetra Xsail nasal powder
No release date or price
Expect Scrabble Effect
Similar efficacy to existing products
Centerwatch website; Headache Jan 2015

60. Durlaza, $6 Aspirin For secondary prevention of MI or stroke
162.5-mg timed release capsules
Once daily, prescription only
No trials of clinical efficacy for preventing CV dz
Approval based on bioequivalence to regular ASA
“No evidence that Durlaza, is as safe or as effective as low-dose immediate-release aspirin.”
The Medical Letter 1/18/2016

61. Fluad –Influenza Vaccine for Older Adults
Vaccine to counteract lower immune response in elderly
Will be available for NEXT season
Surrogate endpoint – antibody response
Immunogenicity non-inferior to standard vaccine
Greater antibody response did not meet superiority criteria
More frequent tenderness at injection site
SUMMARY: works the same, but hurts more
Why bother?
FDA ADVISORY COMMITTEE BRIEFING DOCUMENT 9/15/2015; The Medical Letter 1/18/2016
immunogenicity of the new vaccine to be noninferior to that of an unadjuvanted trivalent seasonal influenza vaccine (Agriflu). Compared to Agriflu, Fluad elicited significantly greater antibody responses against all three strains 3 weeks after vaccination, but the differences did not meet the prespecified criteria for superiority. Pain and tenderness at the injection site occurred more frequently with Fluad than with the unadjuvanted vaccine.2

62. Alzheimer’s drugs
ACH inhibitors and memantine - modest improvements in cognition, activities of daily living, & behavior
None stop or reverse the disease or impact clinical outcomes - mortality, disability, or institutionalization
Combination memantine ER + donepezil (Namzaric) Mixed evidence - small improvement in cognition and behavior. Magnitude low, clinical significance is uncertain
No improvement in function compared to monotherapy. Generic formulations of both individual products are available
Aricept 23 mg increased risk of adverse drug events.
Anticholinergics decrease effectiveness of ACH inhibitors
Oregon P & T Sept 24, 2016
Memantine 10 mg #60 $30-$40
Donepezil 10 mg #30, $8-$12
Aricept 23, #30, $130-$150
Namzaric #30 caps $360 - $390

63. Alzheimer's drugs – cost/month
Namenda XR #30 (memantine 28mg) $
Namzaric #30 (memantine ER and donepezil) caps, $360 - $390
Aricept 23, #30 (donepezil) $130 -$150
Donepezil 10 mg #30, $8-$12
Memantine 10 mg #60, $30-$40
Goodrx.com 2/24/2016

64. Drugs for weight loss Strange selections & combinations
Lorcaserin (Belviq®) selective serotonin 2c agonist Psychiatric effects, headache, dizziness, and nausea
Phentermine/Topiramate (Qsymia®) Increased heart rate, paresthesias, and anxiety
Naltrexone/Bupropion (Contrave®) Not for patients on Vicodin or other opioids
Liraglutide (Saxenda®) glucagon-like peptide-1 agonist for DM-2 that never sold well- injection
OSU Drug review Nov 2015, Medical Letter 6/22/2015
Lorcaserin (Belviq®)
Lorcaserin is a selective serotonin 2c agonist previously reviewed in the December 2012 newsletter. Lorcaserin was approved based on 3 placebo controlled trials, each about one year in duration. Combined data (n=6139) demonstrated a modest percent reduction in body weight compared to placebo (-4.5 to -5.8% vs to -2.8%, p<0.001) It is still unknown whether this modest reduction is sustained over time and whether use of the drug improves comorbidities associated with obesity. Lorcaserin is also associated with a number of adverse effects and precautions such as adverse psychiatric effects, headache, dizziness, and nausea.
Phentermine/Topiramate (Qsymia®)
Phentermine/topiramate was also reviewed in the December 2012 newsletter. Drug approval was based on two 56-week placebo-controlled trials that demonstrated a moderate reduction in body weight with both the high (15/92 mg) and low (7.5/46 mg) doses as compared to placebo (-10.9% and -5.1%, respectively vs. -1.6%, p< for all comparisons). It is unknown whether this weight reduction is sustained over time and there is insufficient evidence that the drug improves comorbidities associated with obesity. The agents are also associated with a number of adverse effects and precautions, such increased heart rate, paresthesias, and anxiety.
Naltrexone/Bupropion (Contrave®)
Bupropion is an antidepressant that inhibits dopamine and norepinephrine reuptake and may promote satiety. Naltrexone augments the appetite suppressant effects of bupropion.5,8 Approval for naltrexone/bupropion was based on four 56-week randomized, placebo-controlled trials (n=4468). Results revealed statistically significant weight loss compared to placebo (- 5.0 to -9.3% vs to -5.1%). The proportion of patients who lost more than 5% and 10% of body weight with naltrexone/bupropion was significantly higher than with placebo (52% and 28%, respectively, vs. 24% and 10% with placebo).
Liraglutide (Saxenda®)
Liraglutide is an injectable glucagon-like peptide-1 agonist approved for T2DM that can promote satiety. The FDA approved liraglutide for weight loss based on three 56-week randomized, placebo- and active-controlled trials with up to 2 years of follow-up. Data from these 3 trials (n=4999) demonstrated statistically significant weight loss compared to placebo or orlistat (-6 to -8% vs to -2.9%, respectively). The proportion of patients who lost more than 5% and 10% of body weight with liraglutide was significantly higher than with placebo or orlistat (63-73% and 26-27% respectively with liraglutide, vs % and 6-11% with placebo and 44% and 14% with orlistat) Not surprisingly, liraglutide delayed the diagnosis of T2DM in nondiabetics and reduced the onset of pre-diabetes versus placebo at week 56 (30.8% vs. 67.3%; p<0.001).
OSU Drug Review Nov 2015

65. Drugs for weight loss- cost/benefit
Same story as previous drugs
Wt loss at 1 yr vs placebo: 3-8.5% Average ~ 5%
No long term studies of safety or efficacy
No studies on clinical outcomes (morbidity, mortality, disease prevention)
$200 - $240/month - oral meds
$1,000/month Saxenda
($1,000 per # lost - 240# with 5% loss at 1 yr)

66. Pioglitazone & stroke prevention
“Pill to prevent strokes also prevents diabetes, study shows” The Oregonian 2/22/2016
3876 patients, non-diabetic, with insulin resistance, recent new CVA or TIA.
Ave age 63.5, 65% male, 85% white
Exclude: CHF, liver dz, anemia, dependent edema
Pioglitazone vs placebo, ave. followup 4.8 yrs
Standard care for htn, other dz, & stroke prevention (statins, ASA, etc)
Primary endpoint: first fatal or non fatal stroke or MI
NEJM: 2/22/2016
HOMA-%B is a measure of beta cell activity, not of beta cell health or pathology. HOMA can be used in subjects on insulin secretagogues, but the results need to be interpreted with caution.
It should be recognized that HOMA is a measure of basal insulin sensitivity and beta-cell function and, in contrast
to clamps, is not intended to give information about the stimulated state.
It can be seen from the model that for individuals with normal glucose levels, HOMA solutions might indicate
100% beta-cell function and 100% insulin sensitivity, or, in the case of a thin, fit individual with high sensitivity, 50% beta-cell function and 200% insulin sensitivity. Within the context of reporting both results, these are appropriate solutions—sensitivity is doubled, so the beta-cells are functioning at 50% of normal. However, if the beta-cell data are reported in isolation, one might conclude erroneously that the subject had failing beta-cells, as opposed to appropriately low secretion, because the sensitivity of the body was high.

67. Pioglitazone & stroke prevention
Primary outcome: lower composite & individual rates of stroke & MI
BUT: Secondary outcomes:
Same rate: acute coronary syndrome
Same rate: composite of stroke, MI, or CHF hospitalization
Are you confused? You should be…
Risks: wt gain> 4.5 kg , edema, fracture

68. Pioglitazone & stroke prevention
Smoke & mirrors
Study included only the first event
Patients with multiple events - only the first one counted.
IE patient had MI, later had stoke, the stroke was not counted. Number w multiple events unknown.
Results depend on which order events occurred, not on total incidence of stroke or MI

69. Pioglitazone & stroke prevention
Adverse events
Fractures: 6.9% vs 4.9% w placebo
Edema: % vs 24.9% w placebo
Wt gain >4.5 kg % vs 33.7% w placebo
Wt gain >13.6 kg 11.4% vs 4.5% w placebo
Progression to diabetes 3.8% vs 7.7% w placebo

70. Pioglitazone & stroke prevention
Previous similar pioglitazone study – PROactive – showed no difference from placebo
Lancet 2005; 366:

71. Remain Skeptical