Barbara A. Bartman
[Scott Smith]
[Rehan Qayyum]
[Carmen Kelly]
Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults with Type 2 Diabetes
This activity was developed by the American Pharmacists Association and the Agency for Healthcare Research and Quality.
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Speakers
Moderator
Barbara A. Bartman, M.D., M.P.H.
Medical Officer
Agency for Healthcare Research and Quality
Effective Health Care
Speaker One
Scott Smith, R.Ph., M.S.P.H., Ph.D.
Director of Pharmaceutical Outcomes Research
Agency for Healthcare Research and Quality
Effective Health Care
Speaker Two
Rehan Qayyum, M.D.
Assistant Professor of Medicine
The Johns Hopkins University
School of Medicine
Investigator
Evidence-based Practice Center
The Johns Hopkins University
Baltimore, MD
Speaker Three
Carmen Kelly, Pharm.D, R.Ph.
Pharmacist Officer
Agency for Healthcare Research and Quality
Effective Health Care
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Accreditation
APhA is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. The ACPE Universal Activity Number assigned to the activity by the accredited provider is: 202-999-09-111-H01-P. This activity is approved for 1 contact hour of continuing pharmacy education credit (0.1 CEU).
To obtain continuing pharmacy education credit for this activity, participants must participate in the entire activity, and complete the online posttest and evaluation form located on www.pharmacist.com/education/. A Statement of Credit will be automatically generated upon achieving these requirements. There is no fee to participate in this activity.
ACPE Activity Type: Knowledge-Based
Initial Release Date: February 26, 2009
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Disclosures
Barbara A. Bartman, M.D., M.P.H., Scott Smith, R.Ph., M.S.P.H., Ph.D., and Carmen Kelly, Pharm.D, R.Ph. have no financial interests or relationships to disclose.
Rehan Qayyum, M.D. received grant support from the Agency for Healthcare Research and Quality (AHRQ) through contract #290-02-0018.
AHRQ’s Office of Communications and Knowledge Transfer staff, The Lewin Group project staff, and APhA’s editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.
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Learning Objectives
To discuss the effectiveness of premixed insulin analogues in achieving optimal glycemic control, as compared to insulin regimens
To compare the differences in premixed insulin analogues and other commonly used insulin preparations with regard to safety, adverse effects, or adherence
To evaluate the effectiveness and safety of the new premixed insulin analogue regimens in individuals on oral anti-diabetic agents and individuals with different blood glucose patterns or types of control.
To discuss practical and effective therapy options for patients with diabetes.
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Polling Question One
How would you describe your familiarity with AHRQ’s Comparative Effectiveness reports?
a. Very Knowledgeable
b. Somewhat Knowledgeable
c. Fairly Unfamiliar
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The Effective Health Care Program
Scott Smith, R.Ph., M.S.P.H., Ph.D.
Agency for Healthcare Research and Quality
Effective Health Care
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Effective Health Care Program 2003—Present
Authorized in 2003 by Section 1013 of the Medicare Prescription Drug, Improvement, and Modernization Act.
Conducts objective comparisons of the effectiveness of different health care interventions.
Goal: To support informed health care decisions by patients, clinicians, and policymakers and improve the quality, effectiveness, and efficiency of health care to support evidence-based practice.
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Effective Health Care Program
[Images] On the slide, there are three rows stacked on top of each other with a main heading. There is one row for Evidence Synthesis (EPC Network), one row for Evidence Generation (DEcIDE and CERTs Networks), and the bottom row for Evidence Communication/Translation (John M. Eisenberg Center). There are bullets in each row located horizontally across from the heading describing what each network or center is responsible for. The EPC network is responsible for systematically reviewing, synthesizing, and comparing existing evidence on treatment effectiveness. They are also responsible for identifying relevant knowledge gaps. The DEcIDE and CERTs Networks are responsible for the development of new scientific knowledge to address knowledge gaps. They are also responsible for accelerating practical studies. The John M. Eisenberg Center is responsible for translating evidence into improvements. They are also responsible for the communication of scientific information in plain language to policymakers, patients, and providers.
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Approaches to Research
Synthesizes existing scientific evidence.
Generates new scientific evidence to address gaps.
Translates research into plain-language guides.
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Available Products
[Images] On the slide, there are screen shots of a Research Review, a New Research Report, a Technical Brief, and a Summary Guide. Under each screen shot photo, there is the title of each: Research Reviews, New Research Reports, Technical Briefs, and Summary Guides. There is a long double-sided block arrow running under all titles.
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How Products Are Used
Inform clinical guideline development.
Identify future research priorities.
Inform policy, including coverage decisions.
Inform clinician and patient decisions.
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How to Obtain Reports
www.effectivehealthcare.ahrq.gov
Full reports and Summary Guides
Audio files
Spanish translations
AHRQ Publications: (800) 358-9295
Requests for free printed Summary Guides
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How to Stay Informed
EHC Web site.
E-mail notices.
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Contacts
AHRQ Effective Health Care E-mail:
effectivehealthcare@ahrq.gov
Speaker Contact:
Scott R. Smith, R.Ph., Ph.D.
Scott.Smith@ahrq.hhs.gov
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Polling Question Two
Are you currently using, or planning to use, AHRQ’s Comparative Effectiveness products in your setting?
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Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults with Type 2 Diabetes
Rehan Qayyum, M.D.
Johns Hopkins School of Medicine
Evidence-based Practice Center
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Scope of Problem
Diabetes—7th leading cause of death
as listed on death certificates; likely to be under-reported.
Patients with diabetes have twice the risk for death than those without diabetes.
Annual direct medical costs = $116 billion.
2.3 times higher expenditures in patients with diabetes than would be in its absence.
Source: National diabetes fact sheet 2007. CDC, Atlanta, GA. 2008.
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Glucose Control in Type 2 Diabetes
Optimal control of hyperglycemia prevents or delays diabetic complications.
10% decrease in mortality and 25% decrease in microvascular complications with intensive vs. conventional glucose control in patients with type 2 diabetes (UKPDS).
Suboptimal glucose control with oral hypoglycemic agents—insulin.
22% of type 2 diabetes patients take insulin.
Source: UKPDS. Lancet. 1998;352:837-853. National diabetes fact sheet 2007. CDC, Atlanta, GA. 2008.
[Images] On the slide, there is an image of the AHRQ logo, with the motto “Advancing Excellence in Health Care” on the image.
[Images] On the slide, there is an image of the Evidence-based Practice Centers logo.
Key Questions—1
In adults with type 2 diabetes, what is the effectiveness of premixed insulin analogues in achieving optimal glycemic control as compared to insulin regimens including the following preparations?
Premixed human insulin preparations.
Long-acting insulin analogues administered alone.
Intermediate-acting human insulin administered alone.
Short-acting (regular) human insulin administered prandially.
Rapid-acting insulin analogues administered separately (prandially) with a long-acting insulin analogue.
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Key Questions—2
For adults with type 2 diabetes, do premixed insulin analogues differ from other commonly used insulin preparations with regard to safety, adverse effects, or adherence?
The adverse effects of interest include, but are not limited to, hypoglycemia (nocturnal and daytime), weight gain, and interactions with other medications.
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Key Questions—3
Does the effectiveness or safety of the new premixed insulin analogue regimens vary across the following subpopulations of patients with type 2 diabetes?
The elderly (≥ 65 yrs), very elderly (≥ 85 yrs).
Other demographic groups (ethnic or racial groups).
Individuals with comorbid medical conditions.
Individuals with limited life expectancy.
Individuals with disabilities
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Key Questions—4
What are the effectiveness and safety of the new premixed insulin analogue regimens in individuals on oral anti-diabetic agents and individuals with different blood glucose patterns (such as fasting hyperglycemia or postprandial hyperglycemia) or types of control (such as tight control, usual control, good fasting or postprandial control)?
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Methods—Search Strategy
Electronic Databases (February 2008)
MEDLINE, EMBASE, CENTRAL (The Cochrane Central Register of Controlled Trials), CINAHL.
Hand Search
13 journals specific to the field.
References of included articles.
Web Sites
FDA, EMEA, clinicalstudyresults.org, clinicaltrials.gov.
Scientific information packets submitted by Eli Lilly, Sanofi-Aventis, Novo Nordisk
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Methods—Study Section
Included:
Controlled clinical trials, crossover trials, and observational studies published in English-language peer-reviewed journals.
Excluded:
Editorials, comments, letters, and abstracts.
Two reviewers independently selected studies.
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Methods—Data Synthesis
Intermediate outcomes (fasting and postprandial glucose, A1c)
Random effects model.
Adverse effects (hypoglycemia, weight change)
Random effects model.
Clinical outcomes (rare-event data)
Fixed effects model (Mantel-Haenszel).
Sensitivity analysis with Peto’s method and Bayesian random-effects model.
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Grading of Stretch of Evidence
Grading scheme of the GRADE Working Group
Focus was on
Study design.
Number of studies.
Quality of studies.
Consistency of evidence.
Graded as high, moderate, low, or no evidence
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Results
[Images] On the slide, there is a flow chart diagram of the literature search conducted. The chart first includes the number of articles retrieved by various search engines and hand searches, and then describes the process for refining the search by title review, abstract review, and article review. Once all duplicates and other exclusions were made, 45 studies in 50 articles were reported on at least one of the intermediate clinical outcomes or adverse events.
The following source citation is listed on the slide: Qayyum et al. Ann Intern Med. 2008; 149:549-559.
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Results—Fasting Glucose
[Images] On the slide, there is a chart that displays the comparison of long-acting insulin analogue, premixed human insulin, and noninsulin anti-diabetic agents with various types of glucose-lowering agents. The chart also contains the mean difference between these agents, including confidence intervals.
The following source citation is listed on the slide: Qayyum et al. Ann Intern Med. 2008; 149:549-559.
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Results—Postprandial Glucose
[Images] On the slide, there is a chart that displays the comparison of long-acting insulin analogue, premixed human insulin, and noninsulin anti-diabetic agents with various types of glucose-lowering agents. The chart also contains the mean difference between these agents, including confidence intervals.
The following source citation is listed on the slide: Qayyum et al. Ann Intern Med. 2008; 149:549-559.
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[Images] On the slide, there is an image of the Evidence-based Practice Centers logo.
Results—Hemoglobin A1C
[Images] On the slide, there is a chart that displays the comparison of long-acting insulin analogue, premixed human insulin, and noninsulin anti-diabetic agents with various types of glucose-lowering agents. The chart also contains the mean difference between these agents, including confidence intervals.
The following source citation is listed on the slide: Qayyum et al. Ann Intern Med. 2008; 149:549-559.
[Images] On the slide, there is an image of the AHRQ logo, with the motto “Advancing Excellence in Health Care” on the image.
[Images] On the slide, there is an image of the Evidence-based Practice Centers logo.
Results—Hypoglycemia
[Images] On the slide, there is a chart that displays compares long-acting insulin analogue with premixed analogue, premixed human insulin with premixed analogue, and noninsulin anti-diabetic agents with premixed analogue, in terms of various levels of hypoglycemia. The chart also contains the odd’s ratio between these agents, including confidence intervals.
The following source citation is listed on the slide: Qayyum et al. Ann Intern Med. 2008; 149:549-559.
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Results—Weight Change
[Images] On the slide, there is a chart that compares long-acting insulin analogue, premixed human insulin, and noninsulin anti-diabetic agents with various glucose-lowering agents and premixed analogues in terms of weight change, including confidence intervals.
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Results—Other Comparisons
No or scant data for other comparisons.
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Results—Clinical Outcomes
[Images] On the slide, there is a chart that compares premixed insulin analogues and comparators in terms of the following clinical outcomes-all-cause mortality, cardiovascular mortality, cardiovascular morbidity, and combined outcome.
The chart also contains the odd’s ratio between these agents, including confidence intervals.
The following source citation is listed on the slide: Qayyum et al. Ann Intern Med. 2008; 149:549-559.
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Results—Quality of life
6 studies evaluated this outcome.
In 4 studies using validated measurement tools, only one of six quality of life outcomes (psychological distress) showed a statistically significant difference, in favor of premixed insulin analogues over other anti-diabetic agents.
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Results—In Combinations with Oral Agents
Fasting glucose, postprandial glucose, and hypoglycemia.
3 studies; no significant difference.
Hemoglobin A1c.
3 studies; combination better than premixed analogues alone.
Weight change and clinical outcomes.
2 studies; no significant difference.
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Results
No evidence for:
Adherence to treatment regimen.
Effectiveness and safety in subpopulations of interest.
Different intensity of glucose control.
Targeting fasting versus postprandial glucose control.
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Summary
[Images] On the slide, there is a chart that summarizes several outcomes for long-acting, premixed, and noninsulin anti-diabetics compared with other glucose-lowering agents. Upward arrows in the columns indicate that the insulin at the top of the column is better than premixed analogues; downward arrows indicate the opposite; and, horizontal arrows indicate that both are similar.
The following source citation is listed on the slide: Qayyum et al. Comparative Effectiveness Review No. 14. AHRQ, 2008, Rockville, MD.
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Summary (cont’d.)
Premixed analogues vs. long-acting analogues.
Premixed better in lowering A1c and postprandial glucose.
Less effective in lowering fasting glucose.
Premixed analogues vs. premixed human insulin.
Better in lowering postprandial glucose.
Similar in lowering A1c and fasting glucose.
Risk of hypoglycemia.
Premixed analogue similar to premixed human insulin.
Long-acting insulin analogues better than premixed analogue
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Gaps in Evidence
Scant data on clinical outcomes.
No effectiveness data.
Insufficient data on several comparisons of interest—e.g., basal-bolus regimen.
Short duration of follow up.
Scant data on continued clinical efficacy.
No data on long-term harm
Scant data on quality of life or adherence
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Conclusion—Individualized Therapy
Problem—uncontrolled A1C.
Premixed analogues = Premixed human insulin.
Premixed analogues > Long-acting, oral anti-diabetic.
Problem—fasting hyperglycemia.
Premixed human insulin > Premixed analogues.
Long-acting > Premixed analogues.
Problem—postprandial hyperglycemia.
Premixed analogues > Premixed human insulin, long-acting.
Problem—hypoglycemia.
Premixed human insulin = Premixed analogues.
Long-acting > Premixed analogues.
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Premixed Insulin Analogue Team
Rehan Qayyum, M.D.
Shari Bolen, M.D., M.P.H.
Nisa Maruthur, M.D.
Leonard Feldman, M.D.
Lisa M. Wilson, Sc.M.
Spyridon S. Marinopoulos, M.D., M.B.A.
Padmini Ranasinghe, M.D., M.P.H.
Muhammad Amer, M.D.
Eric B. Bass, M.D., M.P.H.
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Utility and Value of the Systematic Review: The Unique Position of Pharmacists
Carmen Kelly, Pharm.D., R.Ph.
Agency for Healthcare Research and Quality
Effective Health Care
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Implications for Practice
Ensuring optimal adherence.
Help patients make informed choices.
Cost considerations.
Safety issues.
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Implications for Research
Comparative effectiveness research will further knowledge about which therapies work best for which individuals.
More research needed to “fill the gaps” identified in the report.
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Implications for Education
Capacity to answer patient questions regarding insulin analogues.
Capacity to assist physicians and other health care providers in choosing the right insulin therapy, especially insulin analogues.
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Questions and Answers
To submit any followup questions, please e-mail us at: AHRQScience2Practice@ahrq.hhs.gov
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Obtaining CE Credit
Instructions to Obtain CE Credit for this Activity:
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THANK YOU
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