AHRQ’s Effective Health Care AHRQ’s Effective Health Care Program: Applying Existing Program: Applying Existing Evidence to Diabetes CareEvidence to Diabetes Care

Tuesday, December 14, 2010Tuesday, December 14, 2010

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AgendaAgenda

Brief Overview of Patient-Centered Brief Overview of Patient-Centered Outcomes Research and AHRQ’s Outcomes Research and AHRQ’s Effective Health Care Program-Effective Health Care Program- Sonia Sonia Nagda, moderatorNagda, moderator

Comparative Effectiveness, Safety, and Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Indications of Insulin Analogues in Premixed Formulations for Adults With Premixed Formulations for Adults With Type 2 Diabetes- Type 2 Diabetes- Rehan Qayyum, Rehan Qayyum, M.D., M.H.S.M.D., M.H.S.

Q&A from Audience Q&A from Audience 33CALL-IN NUMBER: (888) 632-5065 ACCESS CODE: 25848872CALL-IN NUMBER: (888) 632-5065 ACCESS CODE: 25848872 ##

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at the bottom of the screen. at the bottom of the screen.

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Patient-Centered Outcomes Patient-Centered Outcomes Research and AHRQ’s Effective Research and AHRQ’s Effective

Health Care ProgramHealth Care Program

Sonia Nagda, M.D., M.P.H.Sonia Nagda, M.D., M.P.H.

AHRQ’s Office of Communications and AHRQ’s Office of Communications and Knowledge TransferKnowledge Transfer

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Patient-Centered Patient-Centered Outcomes ResearchOutcomes Research

Benefits

Harms

Also known as comparative effectiveness researchAlso known as comparative effectiveness research

Unbiased and practical, evidence-based Unbiased and practical, evidence-based information information

Compares drugs, devices, tests and surgeries, and Compares drugs, devices, tests and surgeries, and approaches to health care approaches to health care – Benefits and harms Benefits and harms – What is known and what isn’tWhat is known and what isn’t

Descriptive, not prescriptiveDescriptive, not prescriptive 66

Horizon Horizon ScanningScanning

EvidenceEvidence NeedNeed

IdentificationIdentification

Evidence Evidence SynthesisSynthesis

EvidenceEvidence GenerationGeneration

StrategiesStrategiesInterventionsInterventionsConditionsConditionsPopulationsPopulations

DisseminationDisseminationTranslationTranslation

ImprovementsImprovements inin

Health CareHealth Care

Research PlatformResearch PlatformInfrastructure – Methods Development – Training Infrastructure – Methods Development – Training

A Framework for A Framework for Patient-Centered Outcomes Patient-Centered Outcomes

ResearchResearch

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Research Focus: Research Focus: 14 Priority Conditions14 Priority Conditions

Arthritis and nontraumatic joint Arthritis and nontraumatic joint disordersdisorders

CancerCancer

Cardiovascular disease, Cardiovascular disease, including stroke and including stroke and hypertensionhypertension

Dementia, including Dementia, including Alzheimer’s diseaseAlzheimer’s disease

Depression and other mental Depression and other mental health disordershealth disorders

Developmental delays, ADHD Developmental delays, ADHD and autismand autism

Diabetes mellitusDiabetes mellitus

Functional limitations and Functional limitations and disabilitydisability

Infectious diseases, Infectious diseases, including HIV/AIDSincluding HIV/AIDS

ObesityObesity

Peptic ulcer disease and Peptic ulcer disease and dyspepsiadyspepsia

Pregnancy including Pregnancy including preterm birthpreterm birth

Pulmonary disease/asthmaPulmonary disease/asthma

Substance abuseSubstance abuse

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Effective Health Care Program Effective Health Care Program Translation ProductsTranslation Products

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Executive Summary

Web Site

ClinicianGuide

ConsumerGuide Policymaker

Summary

Interactive Case Study

CE Modules

Faculty Slides

Patient Decision Aid(available soon)

Systematic Review Report

Diabetes ResourcesDiabetes Resources

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Public InvolvementPublic Involvement

Topic Topic GenerationGeneration

Topic Topic DevelopmentDevelopment

Topic Topic RefinementRefinement

Research Research ReviewReview

Research Research Needs Needs

DevelopmentDevelopment

Report Report Translation & Translation & DisseminationDissemination

During the Research ProcessDuring the Research Process

Web Web linkslinks

Newsletter Newsletter blurbsblurbs

Articles Articles or or

commentariescommentaries

Web Web conferencesconferences

Continuing Continuing EducationEducation

Disseminating the FindingsDisseminating the Findings

• Nominate topics using the online Nominate topics using the online formform• Participate in key question Participate in key question refinementrefinement• Comment via the web on draft key Comment via the web on draft key questions and reportsquestions and reports

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Comparative Effectiveness, Safety, and Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Indications of Insulin Analogues in

Premixed Formulations for Adults with Premixed Formulations for Adults with Type 2 DiabetesType 2 Diabetes

Rehan Qayyum, M.D., M.H.S.Rehan Qayyum, M.D., M.H.S.

Prepared for: Agency for Healthcare Research Prepared for: Agency for Healthcare Research

and Qualityand QualityContract No. #290-02-0018Contract No. #290-02-0018Prepared by: Evidence-based Practice Center, Prepared by: Evidence-based Practice Center,

The Johns Hopkins UniversityThe Johns Hopkins University 1212

Insulin AnaloguesInsulin Analogues

Insulin analoguesInsulin analogues are altered forms of are altered forms of human insulin with minor structural human insulin with minor structural changes without affecting glycemic changes without affecting glycemic controlcontrol

These structural changes impart These structural changes impart pharmacokinetic properties that allow pharmacokinetic properties that allow better control of the onset and duration of better control of the onset and duration of insulinlike activity. insulinlike activity.

These analogues are produced using These analogues are produced using recombinant DNA technology.recombinant DNA technology.

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Insulin AnaloguesInsulin Analogues

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Premixed Insulin AnaloguesPremixed Insulin Analogues

Mixture of rapid-acting and intermediate-Mixture of rapid-acting and intermediate-acting insulin analoguesacting insulin analogues

Intermediate-acting insulin is prepared Intermediate-acting insulin is prepared by mixing insulin analogues with by mixing insulin analogues with protamine sulfateprotamine sulfate

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Key Questions

1.1. In adults (age ≥ 18 years) with type 2 diabetes, what is the In adults (age ≥ 18 years) with type 2 diabetes, what is the effectivenesseffectiveness of of premixed insulin analogues (insulin aspart 70/30, insulin lispro 75/25, insulin premixed insulin analogues (insulin aspart 70/30, insulin lispro 75/25, insulin lispro 50/50) in achieving optimal glycemic control, as compared to insulin lispro 50/50) in achieving optimal glycemic control, as compared to insulin regimens including, but not necessarily limited to, the following preparations?regimens including, but not necessarily limited to, the following preparations? Premixed human insulin preparations (neutral protamine Hagedorn Premixed human insulin preparations (neutral protamine Hagedorn

[NPH]/regular 70/30, NPH/regular 50/50)[NPH]/regular 70/30, NPH/regular 50/50) Long-acting insulin analogues (insulin detemir, insulin glargine) Long-acting insulin analogues (insulin detemir, insulin glargine)

administered aloneadministered alone Intermediate-acting human insulin (NPH insulin) administered aloneIntermediate-acting human insulin (NPH insulin) administered alone Short-acting human insulin (regular insulin) administered prandiallyShort-acting human insulin (regular insulin) administered prandially Rapid-acting insulin analogues (insulin aspart, insulin glulisine, insulin Rapid-acting insulin analogues (insulin aspart, insulin glulisine, insulin

lispro) administered separately (prandially) with a long-acting insulin lispro) administered separately (prandially) with a long-acting insulin analogue (insulin detemir, insulin glargine)analogue (insulin detemir, insulin glargine)

2.2. For adults with type 2 diabetes, do premixed insulin analogues differ from other For adults with type 2 diabetes, do premixed insulin analogues differ from other commonly used insulin preparations with regard to commonly used insulin preparations with regard to safety, adverse effects, or safety, adverse effects, or adherenceadherence? The adverse effects of interest include, but are not limited to, ? The adverse effects of interest include, but are not limited to, hypoglycemia (nocturnal and daytime), weight gain, and interactions with other hypoglycemia (nocturnal and daytime), weight gain, and interactions with other medications.medications. 1616

Key Questions (cont.)Key Questions (cont.)

3. Does the effectiveness or safety of the new premixed insulin 3. Does the effectiveness or safety of the new premixed insulin analogue regimens vary across the following analogue regimens vary across the following subpopulationssubpopulations of of patients with type 2 diabetespatients with type 2 diabetes The elderly (≥ 65 years), very elderly (≥ 85 years)The elderly (≥ 65 years), very elderly (≥ 85 years) Other demographic groups (ethnic or racial groups, genders)Other demographic groups (ethnic or racial groups, genders) Individuals with comorbid medical conditionsIndividuals with comorbid medical conditions Individuals with limited life expectancyIndividuals with limited life expectancy Individuals with disabilitiesIndividuals with disabilities

4. What is the 4. What is the effectiveness and safetyeffectiveness and safety of the new premixed of the new premixed insulin analogue regimens in individuals insulin analogue regimens in individuals on oral antidiabetic on oral antidiabetic agents agents and individuals with and individuals with different blood glucose patterns different blood glucose patterns (such as fasting hyperglycemia or postprandial hyperglycemia) (such as fasting hyperglycemia or postprandial hyperglycemia) or or types of control types of control (such as tight control, usual control, good (such as tight control, usual control, good fasting or postprandial control)? fasting or postprandial control)? 1717

MethodsMethods

Search StrategySearch Strategy– Electronic database (February 2008)Electronic database (February 2008)

– Hand search of literature and Web sitesHand search of literature and Web sites

– Scientific information submitted by the pharmacy Scientific information submitted by the pharmacy industryindustry

Study Inclusion CriteriaStudy Inclusion Criteria– Clinical trials and observational studies Clinical trials and observational studies

Two reviewers independently selected studiesTwo reviewers independently selected studies

Data AbstractionData Abstraction– For relevant outcomesFor relevant outcomes

– Crossover studies excluded from progressive Crossover studies excluded from progressive outcomesoutcomes

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Statistical MethodsStatistical Methods

Intermediate outcomes Intermediate outcomes (Fasting and postprandial glucose, A1c)(Fasting and postprandial glucose, A1c)

– Random effects modelRandom effects model Adverse Effects Adverse Effects (Hypoglycemia, weight change)(Hypoglycemia, weight change)

– Random effects modelRandom effects model Clinical Outcomes Clinical Outcomes (rare-event data)(rare-event data)

– Fixed effects model (Mantel-Haenszel)Fixed effects model (Mantel-Haenszel)– Sensitivity analysis with Peto’s method and Bayesian Sensitivity analysis with Peto’s method and Bayesian

random-effects modelrandom-effects model

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ResultsResults

Qayyum et al. Ann Intern Med. 2008; 21:549-559 2020

ResultsResults- Fasting Glucose -- Fasting Glucose -

Qayyum et al. Ann Intern Med. 2008; 21:549-559 2121

ResultsResults- Postprandial Glucose -- Postprandial Glucose -

Qayyum et al. Ann Intern Med. 2008; 21:549-559 2222

ResultsResults - Hemoglobin A1C -- Hemoglobin A1C -

Qayyum et al. Ann Intern Med. 2008; 21:549-559 2323

ResultsResults- Hypoglycemia -- Hypoglycemia -

Qayyum et al. Ann Intern Med. 2008; 21:549-559 2424

ResultsResults- Weight Change -- Weight Change -

Mean 95%CI P-value

Long-acting insulin analogues vs.

All premixed insulin analogues

1.97 1.22 to 2.73 < 0.001

Insulin Aspart 70/30 2.5 1.6 to 3.4 < 0.001

Insulin Lispro 75/25 No data

Insulin Lispro 50/50 1.58 0.99 to 2.18 < 0.001

Non-insulin antidiabetic agents vs.

All premixed insulin analogues

2.35 0.84 to 3.86 0.002

Insulin Aspart 70/30 2.82 0.61 to 5.02 0.012

Insulin Lispro 75/25 1.88 1.35 to 2.41 < 0.001

Insulin Lispro 50/50 No data

Premixed Human insulin vs.

All premixed insulin analogues

Not enough data

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ResultsResults- Other Comparisons -- Other Comparisons -

No or scant data for other comparisonsNo or scant data for other comparisons

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ResultsResults- Clinical Outcomes -- Clinical Outcomes -

Qayyum et al. Ann Intern Med. 2008; 21:549-559 2727

ResultsResults- Quality of Life -- Quality of Life -

Six studies evaluated this outcome.Six studies evaluated this outcome. In four studies using validated measurement In four studies using validated measurement

tools, only one of six quality of life outcomes tools, only one of six quality of life outcomes (psychological distress) showed a statistically (psychological distress) showed a statistically significant difference, in favor of premixed significant difference, in favor of premixed insulin analogues over other antidiabetic insulin analogues over other antidiabetic agents.agents.

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ResultsResults- in combination with oral agents -- in combination with oral agents -

Fasting glucose, Postprandial glucose, and Fasting glucose, Postprandial glucose, and HypoglycemiaHypoglycemia– 3 studies; no significant difference3 studies; no significant difference

Hemoglobin A1cHemoglobin A1c– 3 studies, combination better than premixed analogues alone 3 studies, combination better than premixed analogues alone

Weight change and Clinical outcomesWeight change and Clinical outcomes– 2 studies, no significant difference2 studies, no significant difference

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ResultsResults

No evidence forNo evidence for– adherence to treatment regimenadherence to treatment regimen– effectiveness and safety in subpopulations of effectiveness and safety in subpopulations of

interestinterest– different intensity of glucose controldifferent intensity of glucose control– targeting fasting versus postprandial glucose targeting fasting versus postprandial glucose

controlcontrol

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Case Study 1Case Study 1

50-year-old obese diabetic male comes 50-year-old obese diabetic male comes in for his regular clinic visitin for his regular clinic visit– HbA1C = 8.7HbA1C = 8.7

– Fasting glucose = 160-190Fasting glucose = 160-190

– On glipizide 10 mg twice daily and On glipizide 10 mg twice daily and metformin XL 1000mg twice dailymetformin XL 1000mg twice daily

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Case Study 2Case Study 2

56-year-old diabetic female comes in for her 56-year-old diabetic female comes in for her regular clinic visitregular clinic visit– HbA1C = 7.4HbA1C = 7.4

– Fasting glucose = 120-140Fasting glucose = 120-140

– Postprandial glucose = 180-220Postprandial glucose = 180-220

– On glyburide/metformin 5/500 BID and sitagliptin On glyburide/metformin 5/500 BID and sitagliptin 100mg QD100mg QD

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SummarySummary

Long Long actingacting

Rapid Rapid ActingActing

Long + Long + RapidRapid

NPH + NPH + RapidRapid PremixedPremixed NPHNPH Noninsulin Noninsulin

antidiabeticantidiabetic

FBGFBG

IA70/30IA70/30 ↔↔ ↓↓ ↔↔ XX ↑↑ ↔↔ ↓↓IL 75/25IL 75/25 ↑↑ XX XX XX ↔↔ XX ↓↓IL 50/50IL 50/50 ↑↑ ↔↔ ↑↑ XX ↑↑ XX XX

PPBGPPBG

IA70/30IA70/30 ↓↓ ↑↑ ↔↔ XX ↓↓ ↔↔ ↓↓IL 75/25IL 75/25 ↓↓ XX XX XX ↓↓ XX ↓↓IL 50/50IL 50/50 ↓↓ ↔↔ ↑↑ XX ↓↓ XX XX

HbA1cHbA1c

IA70/30IA70/30 ↓↓ ↔↔§§ ↓↓* * ↔↔ ↔↔ ↔↔ ↓↓IL 75/25IL 75/25 ↓↓ XX XX XX ↔↔ XX ↔↔IL 50/50IL 50/50 ↓↓ ↔↔ ↑↑ XX ↔↔ XX XX

Hypogly-Hypogly-cemiacemia

IA70/30IA70/30 ↑↑ ↔↔ ↓↓* * ↔↔ ↔↔ ↔↔ ↑↑IL 75/25IL 75/25 ↑↑** XX XX XX ↔↔ XX ↔↔IL 50/50IL 50/50 ↑↑ ↔↔ ↔↔ XX ↔↔ XX XX

Weight Weight ChangeChange

IA70/30IA70/30 ↑↑ ↓↓ ↔↔ ↑↑ ↔↔ ↔↔ ↑↑IL 75/25IL 75/25 XX XX XX XX ↔↔ XX ↑↑IL 50/50IL 50/50 ↑↑* * ↓↓** ↔↔ XX ↔↔ XX XX

↑ = variable increases with premixed analogue versus comparator↓ = variable decreases with premixed analogue versus comparator↔ = premixed analgoue and comparator has same effect on variableX = No studies have looked at the comparison* = Overall evidence is not of sufficient strength§ = benefit with premixed insulin analogue almost reached statistical significance

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