The ADOPT Study: Implications for the Choice of Initial Oral Hypoglycemic Therapy
The recently published ADOPT (A Diabetes Outcome Progression Trial¹) trial reports a decreased cumulative incidence of monotherapy failure at five years with rosiglitazone (Avandia®) as compared to metformin and glyburide.  This trial evaluated rosiglitazone, metformin, and glyburide head-to-head comparing time to monotherapy failure for each medication.  Monotherapy failure was defined as a fasting plasma glucose of >180mg/dL after at least 6 weeks of treatment at maximum indicated or tolerated doses.  Based on this definition of failure, the results reflected that rosiglitazone slowed time to treatment failure as compared to metformin and glyburide.²  At five years, the reported cumulative incidence of monotherapy failure was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide (P<0.001 for all three therapies).³

Some physicians have questioned the implications of these results for selection of a first line oral agent for type II diabetes.⁴  Although the difference in “time to monotherapy failure” between medications may have been statistically significant, the clinical significance of these results is unclear.⁵  Time to monotherapy failure has not been shown to correlate to any decrease in risk of complications associated with type II diabetes. 

When looking at the HbA1c, a secondary endpoint in ADOPT, results in favor of rosiglitazone were not impressive. After four years, 40% of the patients in the rosiglitazone group had met goal (an HbA1c level of less than 7%), as compared with 36% in the metformin group (P=0.03) and 26% in the glyburide group (P<0.001).⁶  Based on these results, a provider would need to treat 25 patients with rosiglitazone instead of metformin for four years to achieve HbA1c goal in only one patient. 

When determining how to apply ADOPT results to clinical practice, providers should consider the following:

• As discussed above, the clinical significance of time to monotherapy failure as defined by fasting plasma glucose is unclear.⁷  It is unknown how this endpoint correlates to a decrease in risk of complications seen in type II diabetes.
• The clinical significance of the observed differences in HbA1c values between the rosiglitazone and metformin groups is also unclear.  It is unknown what this modest difference may mean in terms of a decreased overall risk of complications for the two treatments.⁸
• The Number Needed to Treat (NNT) to prevent one monotherapy failure equaled 17.  In other words, a provider would need to treat 17 patients with rosiglitazone instead of metformin for 5 years to prevent one monotherapy failure.⁹ 
• Approximately 40% of enrolled patients did not complete the study. Reasons for discontinuation varied and included adverse events, insufficient treatment response, protocol violation, loss to follow-up, and withdrawal of consent.¹⁰  Large drop out rates such as these in clinical trials may erode randomization and lead to erroneous conclusions regarding potential harms and efficacy.
• ADOPT Reported Adverse Effects
• Patients who were randomized to rosiglitazone experienced greater weight gain (+4.8kg) and edema, than those patients randomized to metformin (-2.9kg) or glyburide (+1.6kg).
• Patients in the rosiglitazone group also had a higher use of loop diuretics and statins.¹¹
• Patients taking metformin reported a higher incidence of GI upset.  Patients on glyburide reported a higher incidence of hypoglycemia than the other groups.¹²  
• Unexpectedly, female patients in the rosiglitazone group reported a greater number of fractures of the upper arm, hand, or foot, than did female patients who received either metformin or glyburide.¹³  In February 2007, Glaxo SmithKline (GSK) notified healthcare professionals to consider the risk of fracture when initiating or treating female patients with type 2 diabetes mellitus with rosiglitazone.¹⁴

The American Diabetes Association guidelines, published prior to the ADOPT study, currently recommend metformin for initial treatment in newly diagnosed type 2 diabetes. The guidelines recommend that insulin, a sulfonylurea, or a thiazolidinedione be added to metformin if additional pharmacotherapy is required to control blood glucose.¹⁵

The authors concluded that “the potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes.”¹⁶  

• Thiazolidinediones are considerably more expensive than metformin (averaging $132 more/month) and do not have a superior safety profile over metformin. 
• At this time, there does not appear to be a clear clinical advantage to using rosiglitazone as a first line agent over metformin in newly diagnosed type 2 diabetes. 
• Rosiglitazone continues to require prior authorization for Regence members. 

Rosiglitazone may be considered medically necessary for the treatment of diabetes where metformin has failed to reduce the HbA1c to goal after at least 90 days of treatment or where metformin is not tolerated or is contraindicated.¹⁷

Food and Drug Administration (FDA) Alert – Orlistat (Alli®) Approved for OTC Use
On February 7, 2007, the FDA approved orlistat capsules as an over-the-counter (OTC) weight loss aid for overweight adults.  Orlistat was initially approved in 1999 as a prescription drug to treat obesity, and remains a prescription drug for obesity at a higher dose than the OTC version.  Alli® is indicated for use in overweight adults ages 18 years and older along with a reduced-calorie, low-fat diet, and exercise program. 

If your patients ask you about using this OTC product for weight loss, here are some things to consider:

• The most common side effect of Alli® is a change in bowel habits, which may include loose stools.  Eating a low fat diet will reduce the likelihood of this side effect.¹⁸  
• Alli® may also reduce the absorption of fat soluble vitamins, including vitamin K, which may lead to an increased bleeding risk for your patients on warfarin.¹⁹ 
• Alli® may also decrease the absorption of cyclosporine and should not be used by patients who are taking this medication.²⁰ 

Clinical trials of medications used for weight loss are frequently of short duration with limited follow up periods.²¹  There are no long term clinical trials showing that people using weight loss medications are more likely to enjoy long term clinical benefits.²²  Finally, as indicated in the Alli® patient information packet, diet and exercise play an important role in any weight loss strategy.²³
 
More information on this over-the-counter medication can be found at:  http://www.fda.gov/bbs/topics/NEWS/2007/NEW01557.html

Food and Drug Administration (FDA) Alert – Ketek®
On February 12, 2007, the FDA announced revisions to the labeling for the antibiotic Ketek® (telithromycin.)  Two of the three previously approved indications -- acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis – have been removed from the drug's label. The FDA determined that the balance of benefits and risks no longer support approval of the drug for these indications. Ketek® will remain on the market for the treatment of community acquired pneumonia of mild to moderate severity (acquired outside of hospitals or long-term care facilities).  A black boxed warning will also be added to the product’s labeling stating that Ketek should not be used in patients with myasthenia gravis, a disease that causes muscle weakness.

RegenceRx released a PhysicianRxSM on the safety concerns with Ketek® in December of 2005 compared to other antibiotics indicated for upper respiratory infections.  To read the Ketolide PhysicianRx,SM please see the RegenceRx website at:  http://www.regencerx.com/learn/physicianRx/index.html

For the full FDA Ketek® news release, please see:  http://www.fda.gov/bbs/topics/NEWS/2007/NEW01561.html

The above FDA alerts and other MedWatch Safety Summaries can be found at: http://www.fda.gov/medwatch/safety/2006/safety06.htm

Evidence Based Medicine

Quick Review: Number Needed to Treat (NNT)
It has been called one of the “best-kept statistical secrets in medicine.”²⁴  The Number Needed to Treat or NNT answers the question “How many people need to take this medication in order to achieve a benefit in one person?”  This term can help providers decide whether the risks and benefits of a treatment are worthwhile. 

The NNT is often not reported in clinical trials.  Instead, pharmaceutical manufacturers often report clinical study results in terms of relative risk reduction or RRR.  Relative risk reduction may be misleading as it may not take into account a patient’s baseline risk for the outcome the treatment is meant to prevent.

Listed below are examples of different formats used to report a trial’s results:

• Active treatment led to a 30% reduction in mortality as compared to placebo.²⁵ (RRR)
• Active treatment reduced mortality by 3.4% as compared to placebo.²⁶  (ARR)
• One death was avoided for every 30 patients treated.²⁷  (NNT)

The above formats are simply different ways of reporting the results of the 4S (Scandinavian Simvastatin Survival Study) trial.²⁸  The first format reports relative risk reduction (RRR), the second the absolute risk reduction (ARR), and the third the number needed to treat (NNT).  As shown, reporting the results using relative risk reduction may make a medication’s efficacy appear more impressive.

The next time you evaluate a clinical trial for application to your practice, ask yourself if the results have been reported in clinically significant format.  Taking the time to quickly calculate the NNT may make the results easier to evaluate for application to your practice.²⁹  NNT can be calculated from the absolute risk reduction reported for a treatment.  NNT is the inverse of the absolute risk reduction (NNT=1/ARR). 

Next issue -  Quick Review: Number Needed to Harm (NNH)

(Please note, the 4S trial calculation of NNT=30 where RRR=30% is an anomaly.  Don’t assume from this example that the calculated NNT and RRR will always be the same number.)

For more information on RegenceRx’s commitment to Evidence Based Medicine, please see:
http://www.delfini.org/page_Project_Regence.htm

RegenceRx P&T Decisions

The following medications will remain Non-Preferred/Non-Formulary at this time:
CesametTM indicated for chemotherapy-induced nausea and vomiting where conventional antiemetics have failed.  For Preferred Medication List/Formulary alternatives for this indication, please see:  http://www.regencerx.com/learn/covered/therapeutic/index.html

JanuviaTM indicated for the treatment of Type II Diabetes Mellitus.  JanuviaTM will remain non-formulary/non-preferred at this time. 

Levemir® indicated for adult and pediatric patients with Type I Diabetes Mellitus, and adult patients with Type II Diabetes requiring basal (long acting) insulin for control of hyperglycemia.  Levemir® will remain non-preferred/non-formulary at this time.

For Preferred Medication List/Formulary alternatives for oral hypoglycemics and long acting insulins, please see our RxPrice Guide at:  http://www.regencerx.com/learn/physicianResearch/rxPriceGuide/index.html

Fentora® indicated for the treatment of cancer breakthrough pain.  Fentora® will remain non-formulary/non-preferred at this time.

Azilect® indicated as initial monotherapy for the treatment of Parkinson’s disease and as adjunct therapy to levodopa. Azilect will remain non-preferred/non-formulary at this time. For Preferred Medication List/Formulary alternatives for this indication, please see:  http://www.regencerx.com/learn/covered/therapeutic/index.html

Angeliq® an oral combination hormone replacement therapy indicated for the treatment of menopausal symptoms.  For Preferred Medication List/Formulary alternatives for oral contraceptives, please see our RxPrice Guide at:  http://www.regencerx.com/learn/physicianResearch/rxPriceGuide/index.html

P&T Committee Recommended Provider Alerts:
After requesting and receiving an update on Ortho-Evra® and desogestrel-containing oral contraceptives, the P&T committee recommended that safety information on these products be sent to providers.  More information is available at:
http://www.regencerx.com/meet/physicianNews/index.

For more information on our Preferred Medication List/Formulary, please see:
http://www.regencerx.com/learn/physicianResearch/covered/index.html

Medication Policy Updates

The following medications have new or updated Medication Policies:

Brand Name Statins - Crestor®, Vytorin,® and Lipitor.®  RegenceRx has introduced a generics first initiative for the statin medication class.  As a result, new start prescriptions for Crestor®, Vytorin,® and Lipitor® will need prior authorization and will be only be authorized if a generic statin is not an option. 

For New Start Statin Patients:

• Consider a generic statin first.  Generic lovastatin, pravastatin and simvastatin do not require prior authorization and these newly available, high quality generics are able to provide up to 40% LDL-C lowering.
• If your patient needs a brand name statin, prior authorization will be required.  To ensure your prior authorization request is complete, please indicate the patient’s current LDL-C, the patient’s goal LDL-C, and any known prior statin therapy on the prior authorization form.
• Write for a preferred/formulary statin first.  Crestor® and Vytorin® are the RegenceRx preferred/formulary brand statins and will only be approved where the patient requires greater than 40% LDL-C lowering OR where generic statins have not been effective in reaching the LDL-C goal. 
• Non-Preferred/Non-Formulary Statins.  New start Lipitor® prescriptions will only be approved where the patient requires greater than 40% LDL-C reduction AND the formulary brand statins have not been effective in getting the patient to his or her LDL-C goal.

For more information, please see our medication policies and coverage criteria at:  www.regencerx.com/learn/policy/index.html

A copy of the prior authorization form can be found at:  www.regencerx.com/docs/forms/priorAuth/priorAuthorization.pdf

For Washington members, the generics first statin initiative will begin on April 3, 2007.  This program is already in place for other Regence members.

Generic Medications

New Generic Medications at the Pharmacy or Coming Soon! ³⁰
Consumers stand to save billions of dollars in prescription drug costs in the next few years as a wave of brand name medications come off of patent.  The chart below includes a list of generic medications already at the pharmacy or coming soon to a pharmacy near you!

Asthma/Allergy cetirizine (Zyrtec®) – Fall/Winter 2007 desloratadine (Clarinex®) - Fall/Winter 2007 fexofenadine/pseudoephedrine –(Allegra D®) Fall/Winter 2007 nedocromil (Tilade®) – Spring/Summer 2007 olopatadine (Patanol®) – Spring/Summer 2007	Mental Health/Sleep Disorders bupropion XL (Wellbutrin XL®) – on shelves olanzepine (Zyprexia Zydis®) – Fall/Winter 2007 risperidone (Risperdal®) - Fall/Winter 2007 zolpidem (Ambien®) – Spring/Summer 2007
Cardiology amlodipine (Norvasc®) – Spring/Summer 2007 metoprolol XL (Toprol XL®) –  Spring/Summer 2007 ramipril (Altace®) - Fall/Winter 2007	Other Latanoprost (Xalatan®) - Fall/Winter 2007 methylphenidate ER (Concerta®) – Fall/Winter 2007 ondansetron (Zofran®) – on shelves oxybutynin XR (Ditropen XR®) – on shelves terbinafine (Lamisil®) – Fall/Winter 2007
Women’s Health estradiol transdermal (Climara®) – on shelves

Special Member Program Spotlight

RegenceRx Half-Tablet Program
This voluntary program permits eligible members to receive a two month supply of medication for one copayment by splitting a higher strength medication in half.  Members may save time as well as money by only having to pick up these medications at the pharmacy every other month.  The program applies only to prescriptions filled at retail pharmacies, not to mail order prescriptions. 

The following medications are included under the program:

Benicar® / Benicar HCT® citalopram (Celexa®) Crestor® enalapril (Vasotec®) Lamictal® leflunomide (Arava®)

Lexapro®* Lipitor®* mirtazapine (Remeron®) nefazodone (Serzone®) paroxetine (Paxil®)

Risperdal® sertraline (Zoloft®) simvastatin (Zocor®) Valtrex® Zyprexa®

    *Non-preferred/non-formulary brands.

For more information on the Half-Tablet Program, and all of the RegenceRx special member programs, please see:
http://www.regencerx.com/programs/physicianPrograms/index.html

Provider Feedback

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