Depression and Diabetes: Clinical Assessment and Pharmacotherapy

Sam Ellis, PharmD, CDEEllen Fay-Itzkowitz, LCSW, CDE

Barbara Davis Center for Childhood DiabetesUniversity of Colorado Health Sciences Center

Keystone 2008

Depression in Kids without Diabetes

• 2.5% of children (5-9) are depressed

• 8.3% of teens (12-17) are depressed(1)

• Early Onset Depression persist, recurs and may predict more severe depression and suicidal bxs later in life(2)

1) Birmaher, B. et.al. (1996) Journal of Child and Adolescent Psychiatry2) Weissman, MM. et.al. (1999) Journal of the American Medical Association

What Do we Know about Depression in Kids with Diabetes

Indicators of Depressive Symptoms in 12 to 17 year olds

with type 1 Diabetes

• 49 participants (12-17yo)

• Beck Depression Inventory (BDI)

• 36.7% with depressive symptoms

• Girls: problems with decision making and sleep

• Boys: change in appetite

Reviera, A. et.al. (2007) PR Health Science Journal

Role of Socioeconomic Status, Depression, QOL and Glycemic Control on Teens with Type 1

• 222 Participants (12-17yo)

• Children’s Depression Inventory (CDI)

• Poor glycemic control was associated with lower SES and increased depression

Hassan, K. et.al. (2006) Journal of Pediatrics

Depressive Symptoms in Children and Adolescents with

Type 1 Diabetes

• 145 Participants (10-18yo)

• Children’s Depression Inventory (CDI)

• 15.2% had depressive symptoms

- less SMBG

- increased A1C (>8.7%)

- increased family conflict

Hood, K. (2006) Diabetes Care

Prevalence and Correlates of Depressed Mood among Youth with

Diabetes: SEARCH• 2672 Participants (10-21yo)

– includes type 1 and type 2• Center for Epidemiologic Studies Depression

Scale (CES-D)• 14% Mild Depressive Symptoms• 8% Moderate to Severe A1C and ED visits• Depression among youth with diabetes = kids

without diabetes

Lawrence, J.M. (2006) Pediatrics

In Summary…

• Depression appears to be 2-3 times more prevalent among children and adolescents with diabetes

• Diabetes and Depression DON’T MIX A1c SMBG ED Admits Long Term Complications

So Now What?

Identifying Depression in Youth

• Routine Screening in Kids 10–Who?–How?

• Questionnaire vs. Clinical Interview

Silverstein, J. et. al. (2005) Care of Children and Adolescents with Type 1 Diabetes: A Statement of the ADA

First- Know the Symptoms

A1C• Frequent ED admissions SMBG• Persistent Sad or Irritable Mood• Appetite Disturbance • Problems with Concentration• Indecision • Sleep Disturbance • Poor School Performance

Symptoms (Cont.)

• Social Withdrawal• Guilt • Worthlessness• Physical Complaints • Lack of Enthusiasm or Motivation• Low Energy• Drug and/or Alcohol Abuse• Thoughts of Death or Suicide

Get Your Tools Out

WHO-5• Developed by the World Health Organization• 5 items • Measures emotional well-being• Easily scored• Validated for use with type 1 teens• < 50 = emotional well-being/further testing 29 = depression

– WHO recommends ICD-10

• No suicide question

De Wit, M. et.al. (2007) Diabetes Care

Children’s Depression Inventory (CDI)

• Approved for use in children and adolescents (ages 7-17)

• 27 items (CDI-Short- 10 items)• Parent/Child/Teacher versions• Suicide question• Validated in children and adolescents with T1D• Score 13 = clinical depression• Can be purchased for clinical use at:

http://www.pearsonassessments.com/tests/cdi.htm

The Clinical Interview

• Diagnostic Interview requires behavioral health specialist (LCSW, LPC, PhD or MD)

• Anyone can screen for depression– PHQ-2

• Primarily used in teens and adults

• 2 quick questions– Little interest or pleasure– Feeling down, depressed or hopeless

Suicide Screening

• Third leading Cause of Death in 15-24 year olds• Be Alert to Risk Factors

– Depression or Other Psychiatric Illness– Alcohol/drug abuse– Prior attempts– Relationship Break-Ups– Recent Bereavement

• Ask about Plan• Talk with Parents• Mental Health Referral/Hospitalization

Yep, Looks Like Depression!

The Next Step

Refer for Therapy1

Consider Medication

Facilitate Collaboration

1) Sherill, J., Kovacs, M. (2002) Nonsomatic Treatment of Depression. Child Adolescent Psychiatry

Managing Managing Depression in Depression in

DiabetesDiabetes

Sam Ellis, Pharm.D., BCPS, CDESam Ellis, Pharm.D., BCPS, CDE

Assistant Professor Assistant Professor

University of Colorado School of University of Colorado School of PharmacyPharmacy

ObjectivesObjectives

List the pros and cons of various List the pros and cons of various treatment strategies utilized in the treatment strategies utilized in the outpatient management of depression.outpatient management of depression.

Describe the differences among Describe the differences among pharmacologic agents used in the pharmacologic agents used in the management of depressionmanagement of depression

Describe the FDA advisory on SSRI Describe the FDA advisory on SSRI agents and suicidality and the impact on agents and suicidality and the impact on diagnosing, treatment and suicide risk.diagnosing, treatment and suicide risk.

Antidepressants and Antidepressants and SuicideSuicide

FDA Black Box WarningFDA Black Box Warning added for all added for all antidepressants in October 2004antidepressants in October 2004 Risk of suicidality in children, adolescents, and Risk of suicidality in children, adolescents, and

adults younger than 25 yearsadults younger than 25 years Based on Meta-analysis of industry-sponsored Based on Meta-analysis of industry-sponsored

trialstrials Suicidal behavior increased Suicidal behavior increased (RR=1.95, 95%CI 1.28-(RR=1.95, 95%CI 1.28-

2.98)2.98)

Sample Black Box WarningSample Black Box Warning““Antidepressants increased the risk compared to Antidepressants increased the risk compared to placebo of suicidal thinking and behavior in children, placebo of suicidal thinking and behavior in children, adolescents and young adults in short-term studies adolescents and young adults in short-term studies of MDD and other psychiatric disorders……..”of MDD and other psychiatric disorders……..”

FDA Mandate for FDA Mandate for Pediatric ADPediatric AD

black box warning designed to improve black box warning designed to improve monitoring of patients started on AD therapymonitoring of patients started on AD therapy Clearly warn the patient and family about riskClearly warn the patient and family about risk Patient Medication Guide distributed with each Patient Medication Guide distributed with each

new prescription and refillnew prescription and refill Risk appears greatest in the first few weeks of Risk appears greatest in the first few weeks of

therapytherapy Monitoring:Monitoring:

Weekly visits for first 4 weeksWeekly visits for first 4 weeks Biweekly until 12 weeksBiweekly until 12 weeks As clinically indicated beyond 12 weeksAs clinically indicated beyond 12 weeks

TADS: Fluoxetine ± CBTTADS: Fluoxetine ± CBT

TADS. JAMA292;807-20:2004

439 Randomized

107 Received

Fluoxetine + CBT

109 Received

Fluoxetine Alone

111 Assigned

CBT Alone

112 Assigned

Placebo

•RTC with blinded fluoxetine and open-label CBT

•Initial treatment of MDD in adolescents (12-17yo)

• 12 weeks of therapy (fluoxetine 10-40mg)

Fluoxetine ± CBTFluoxetine ± CBT

TADS. JAMA292;807-20:2004

Flu+CBT > plb; p=0.001

Flu+CBT > Flu OR CBT; p=0.02

Flu >CBT; p=0.01

Flu+CBT > plb; p=0.02

Flu OR CBT vs plb p=NS

Flu+CBT > flu or CBT; p<0.05

Children’s Depression Rating Scale

Suicidal Ideation Questionnaire-JHS

Decline in Treatment of Decline in Treatment of Pediatric Depression after Pediatric Depression after

FDA MandateFDA Mandate Pediatric Cohort with newly dx Pediatric Cohort with newly dx

depression (N=65,349)depression (N=65,349) Evaluation of rates of diagnosis and Evaluation of rates of diagnosis and

treatment after FDA changestreatment after FDA changes Time-series model using 5 years pre Time-series model using 5 years pre

and 2 years post mandateand 2 years post mandate

Libby AM, et al., Am J Psy. 2007; 164:884-91

Diagnosis and Treatment of Diagnosis and Treatment of Depression after the FDA Depression after the FDA

MandateMandateDiagnosis of Depression in Pediatrics

Prescribing of SSRIs before and after FDA Mandate

Libby AM, et al., Am J Psy. 2007; 164:884-91

Early Evidence of FDA Early Evidence of FDA Mandate on Suicide in Mandate on Suicide in

Children and AdolescentsChildren and Adolescents Evaluation of large pharmacy claims Evaluation of large pharmacy claims databasedatabase

Determined SSRI use by ageDetermined SSRI use by age Compiled suicide data from the CDCCompiled suicide data from the CDC

Gibbons, et al. Am J Psy. 2007;164:1356-63

SSRI Prescription Rates by Age

Suicide Rates in Children and Adolescents

Most often occurs early in treatment (acute Most often occurs early in treatment (acute

phase)phase) Occurs after dosing changes (both titration Occurs after dosing changes (both titration

up and down (within 1 month) up and down (within 1 month) Occurs in patients who are non-adherent to Occurs in patients who are non-adherent to

AD AD Diminishes the longer a person takes ADDiminishes the longer a person takes AD

Must monitor closely during acute phase Must monitor closely during acute phase and after titrationsand after titrations

Suicidality in RTC and in Cohort Studies

Jump Forward to 2008Jump Forward to 2008

“ “ The FDA advisories may have had the The FDA advisories may have had the unintended effect of discouraging the unintended effect of discouraging the prescription of antidepressants for pediatric prescription of antidepressants for pediatric patients and pediatric utilization of patients and pediatric utilization of antidepressants without compensatory antidepressants without compensatory increases in other specific treatments.”increases in other specific treatments.”

““A major concern missed in this controversy A major concern missed in this controversy is that less than 50% of children and is that less than 50% of children and adolescents with depression ever receive adolescents with depression ever receive treatment at all.”treatment at all.”

Cynthia Pfeffer, Am J Psy: June 2007

Graham Emslie, Am J Psy, Jan 2008

Antidepressant Antidepressant Treatment*Treatment*

All agents have similar efficacy when All agents have similar efficacy when comparablycomparably dosed dosed

Choices made empirically based on:Choices made empirically based on: Patient or family hx of responsePatient or family hx of response Concurrent conditions/medicationsConcurrent conditions/medications Depression subtypeDepression subtype Adverse effect profileAdverse effect profile Drug costDrug cost

*Fluoxetine is the only FDA approved AD for pediatrics

Drug ClassesDrug Classes

SSRISSRI SNRISNRI

Fluoxetine (Prozac)*Fluoxetine (Prozac)*++ Venlafaxine (Effexor) Venlafaxine (Effexor)

Sertraline (Zoloft) *Sertraline (Zoloft) * Duloxetine (Cymbalta) Duloxetine (Cymbalta)

Paroxetine (Paxil, CR)* Paroxetine (Paxil, CR)* Alpha-2 AntagonistAlpha-2 Antagonist

Fluvoxamine (Luvox)Fluvoxamine (Luvox) Mirtazapine (Remeron) Mirtazapine (Remeron)

Citalopram (Celexa)*Citalopram (Celexa)* Catacholamine reuptake Catacholamine reuptake inhinh

Escitalopram (Lexapro)*Escitalopram (Lexapro)* Bupropion (Wellbutrin) Bupropion (Wellbutrin)

*Commonly used in anxiety disorders; + only FDA approved drug for pediatrics

PharmacotherapyPharmacotherapy

Three (3) phases of therapyThree (3) phases of therapy AcuteAcute: achieve remission, 6-12 weeks: achieve remission, 6-12 weeks ContinuationContinuation: keep symptoms in remission using : keep symptoms in remission using

full-dose therapy, 6-12 monthsfull-dose therapy, 6-12 months MaintenanceMaintenance: long-term therapy for those at high : long-term therapy for those at high

risk for relapse (prior episodes, strong family risk for relapse (prior episodes, strong family history)history)

Adequate trialAdequate trial Full therapeutic doses for 6-8 weeks and in some Full therapeutic doses for 6-8 weeks and in some

cases up to 12 weeks (if no response, failure)cases up to 12 weeks (if no response, failure)

SSRI’sSSRI’s

MechanismMechanism selective reuptake inhibition of serotoninselective reuptake inhibition of serotonin

First-line therapy First-line therapy Fluoxetine only FDA approved agent for Fluoxetine only FDA approved agent for

children/adolescentschildren/adolescents Similar or superior efficacy to othersSimilar or superior efficacy to others Lower side effects, safer, convenient Lower side effects, safer, convenient

dosingdosing Generally choose cheapest availableGenerally choose cheapest available Recognize differences between agentsRecognize differences between agents

Dosing in Dosing in Children/AdolescentsChildren/Adolescents

SSRI titration ScheduleSSRI titration ScheduleDrugDrug Starting Dose Increments Effective dose Starting Dose Increments Effective dose

Max Dose Max Dose (mg)(mg) (mg) (mg) (mg) (mg) (mg) (mg)

CitalopramCitalopram 10 10 10 10 20 20 60 60

FluoxetineFluoxetine 10 10 10-20 10-20 20 20 6060

FluvoxamineFluvoxamine 50 50 50 50 150 150 300 300

ParoxetineParoxetine 10 10 10 10 20 20 60 60

SertralineSertraline 25 25 12.5-25 12.5-25 50 50 200 200

EscitalopramEscitalopram 5 5 5 5 10 10 2020

Cheung, et al. Pediatrics;2007:e1313-26

SNRI’sSNRI’s

MechanismMechanism selective serotonin and norepinephrine selective serotonin and norepinephrine

reuptake inhibitionreuptake inhibition Common side effects:Common side effects:

Nausea, dizziness, insomnia, constipation, Nausea, dizziness, insomnia, constipation, sweatingsweating

Venlafaxine can cause Venlafaxine can cause hypertensionhypertension

SNRI: VenlafaxineSNRI: Venlafaxine

Effexor (immediate release)Effexor (immediate release) DoseDose

25mg BID, increase by 25-50mg every week 25mg BID, increase by 25-50mg every week to max of 150mgto max of 150mg

Effexor XR (extended release)Effexor XR (extended release) DoseDose

37.5-75mg QD initially, increase by 37.5mg 37.5-75mg QD initially, increase by 37.5mg every week to maximum of 150mgevery week to maximum of 150mg

SNRI: DuloxetineSNRI: Duloxetine

Cymbalta (delayed release)Cymbalta (delayed release) Dosage forms: 20, 30, 60mg capsulesDosage forms: 20, 30, 60mg capsules Dose:Dose:

20mg BID initially, titrate up to 60mg daily 20mg BID initially, titrate up to 60mg daily (once daily or 30mg BID)(once daily or 30mg BID)

Also has indications for diabetic Also has indications for diabetic peripheral neuropathy and generalized peripheral neuropathy and generalized anxiety disorderanxiety disorder

BupropionBupropion MechanismMechanism

Weak inhibitor of norepinephrine and Weak inhibitor of norepinephrine and dopamine uptake, no effect on serotonindopamine uptake, no effect on serotonin

Lowers the Lowers the seizure thresholdseizure threshold, especially , especially in bulimic patientsin bulimic patients Contraindicated in bulimic and anorexic Contraindicated in bulimic and anorexic

patientspatients Immediate release higher incidence, may be Immediate release higher incidence, may be

due to peak concentrationsdue to peak concentrations Has mild stimulating propertiesHas mild stimulating properties

May be useful for patients presenting with May be useful for patients presenting with difficulty concentrating or fatiguedifficulty concentrating or fatigue

Does not cause Does not cause sexual dysfunctionsexual dysfunction

BupropionBupropion Dosage formsDosage forms::

Wellbutrin: 75, 100mg immediate release tabletWellbutrin: 75, 100mg immediate release tablet Wellbutrin SR: 100, 150, 200mg sustained-release Wellbutrin SR: 100, 150, 200mg sustained-release

tabletstablets Wellbutrin XL: 150mg, 300mg extended-release Wellbutrin XL: 150mg, 300mg extended-release

tabletstablets DoseDose::

Wellbutrin: 100mg BID x 3 days, then 100mg TID Wellbutrin: 100mg BID x 3 days, then 100mg TID (max = 450mg TID-QID) (max = 450mg TID-QID)

Wellbutrin SR: 150mg QD x 3 days, then 150mg Wellbutrin SR: 150mg QD x 3 days, then 150mg BID (max = 200mg BID) BID (max = 200mg BID)

Wellbutrin XL: 150mg QD x 3 days, then 300mg QD Wellbutrin XL: 150mg QD x 3 days, then 300mg QD (max = 450mg QD) (max = 450mg QD)

MirtazapineMirtazapine

MechanismMechanism: : Enhances the release of norepinephrine by Enhances the release of norepinephrine by

blocking blocking αα22-adrenergic autoreceptors and 5--adrenergic autoreceptors and 5-HTHT2A2A/5-HT/5-HT33 autoreceptors autoreceptors

Little affinity for Little affinity for αα11 and acetylcholine receptors and acetylcholine receptors High affinity for histamine-1 receptorsHigh affinity for histamine-1 receptors

Sedation, weight gain (appetite increase), Sedation, weight gain (appetite increase), and dry mouth are more prominent at lower and dry mouth are more prominent at lower dosesdoses

1:50 pediatrics/adolescents experience 1:50 pediatrics/adolescents experience suicidalitysuicidality

MirtazapineMirtazapine

Dosage formsDosage forms:: 7.5, 15, 30, 45mg tablets7.5, 15, 30, 45mg tablets 15, 30, 45mg disintegrating tablets15, 30, 45mg disintegrating tablets

DoseDose:: 7.5-15mg QHS initially, increase by 7.5mg 7.5-15mg QHS initially, increase by 7.5mg

weekly (max = 30mg)weekly (max = 30mg) Useful for the thin, depressed geriatric Useful for the thin, depressed geriatric

patient with insomniapatient with insomnia

Side Effects of Side Effects of AntidepressantsAntidepressants

Initial TherapyInitial Therapy

Considerations in agent selectionConsiderations in agent selection Cost, dosing convenienceCost, dosing convenience Co-morbidities (e.g. depression with Co-morbidities (e.g. depression with

insomnia)insomnia) Side effect profileSide effect profile Previous response to therapy, family members Previous response to therapy, family members

response to therapyresponse to therapy Drug-drug/drug-disease interactionsDrug-drug/drug-disease interactions

Prefer SSRI’s as first-line therapyPrefer SSRI’s as first-line therapy

Side Effects and Side Effects and SelectionSelection

Peripheral neuropathyPeripheral neuropathy Duloxetine, TCA’s, venlafaxineDuloxetine, TCA’s, venlafaxine

InsomniaInsomnia Mirtazapine, TCA’s, trazodoneMirtazapine, TCA’s, trazodone Paroxetine, citalopram, escitalopramParoxetine, citalopram, escitalopram

Concurrent anxietyConcurrent anxiety SSRI’s that cause more sedation: paroxetine, SSRI’s that cause more sedation: paroxetine,

citalopram, or escitalopramcitalopram, or escitalopram Erectile dysfunctionErectile dysfunction

Bupropion, mirtazapine, duloxetineBupropion, mirtazapine, duloxetine

Response vs. RemissionResponse vs. Remission ResponseResponse

Usually defined as a 50% reduction in symptomsUsually defined as a 50% reduction in symptoms RemissionRemission

A return to normal mood and normal functioningA return to normal mood and normal functioning

Use Ham-D (< 6 is remission) or other clinical Use Ham-D (< 6 is remission) or other clinical rating scale to monitor for response and rating scale to monitor for response and remissionremission

If a drug has given a If a drug has given a responseresponse, you can , you can possibly obtain possibly obtain remissionremission by adjusting the by adjusting the dose or augmenting the therapydose or augmenting the therapy

ResponseResponse

1 week: decreased anxiety, improved 1 week: decreased anxiety, improved sleep / appetitesleep / appetite

1-3 weeks: increased activity, self-care, 1-3 weeks: increased activity, self-care, concentration and memory, thinking concentration and memory, thinking normalizes, increased risk for suicide normalizes, increased risk for suicide (monitor closely)(monitor closely)

2-4 weeks: relief of depressed mood2-4 weeks: relief of depressed mood

Lack of ResponseLack of Response

OptimizationOptimization Maximize doseMaximize dose

Drug substitutionDrug substitution Can be difficult (titrations, length of Can be difficult (titrations, length of

time, loss of effect)time, loss of effect) CombinationCombination

Choose from a different class, Choose from a different class, monitor ADEsmonitor ADEs

Treatment DurationTreatment Duration Acute phaseAcute phase

Generally 6-12 weeksGenerally 6-12 weeks Goal: obtain remissionGoal: obtain remission Start low dose, titrate to max toleratedStart low dose, titrate to max tolerated

Augment or switch, if necessaryAugment or switch, if necessary

Continuation phaseContinuation phase:: After remission is obtained, 6-12 monthsAfter remission is obtained, 6-12 months GoalGoal: eliminate residual symptoms, restore level : eliminate residual symptoms, restore level

of functioning, self-care behaviors, prevent of functioning, self-care behaviors, prevent relapserelapse

Continue regimen that induced remissionContinue regimen that induced remission

Treatment DurationTreatment Duration Maintenance phaseMaintenance phase::

Continue therapy for 12-36 months or Continue therapy for 12-36 months or indefinitely to prevent relapseindefinitely to prevent relapse

Discontinuation phaseDiscontinuation phase:: If no relapse during continuation, gradual If no relapse during continuation, gradual

reduction in those with reduction in those with >> 6 months 6 months therapytherapy

Taper over several weeks to avoid Taper over several weeks to avoid discontinuation syndromediscontinuation syndrome Imbalance, GI, sleep, anxiety, agitation, Imbalance, GI, sleep, anxiety, agitation,

irritability, crying spellsirritability, crying spells

Zoloft Effects during Zoloft Effects during Maintenance in Adults with Maintenance in Adults with

DiabetesDiabetesRemission of Depression in maintenance

Effects of Depression control on A1c

Lustman PJ, et.al., Ach Gen Psychiatry. 2006

SummarySummary Decrease in diagnosing and prescribing for Decrease in diagnosing and prescribing for

depression has occurred since the FDA depression has occurred since the FDA MandateMandate

Fluoxetine is still the only FDA approved AD for Fluoxetine is still the only FDA approved AD for pediatric use and combination with CBT results pediatric use and combination with CBT results in decreased suicidalityin decreased suicidality

Other antidepressants can be used but exact Other antidepressants can be used but exact dosing is unclear. Tailor AD choice by taking dosing is unclear. Tailor AD choice by taking advantage of ADEs/symptoms of depression, advantage of ADEs/symptoms of depression, costs.costs.

Continue AD use for 6-12 months if achieved Continue AD use for 6-12 months if achieved remission and make sure to maximize dose and remission and make sure to maximize dose and augment or switch if partial responseaugment or switch if partial response

Monitor closely during acute 6-8 weeks and Monitor closely during acute 6-8 weeks and after dosing changes or discontinuationafter dosing changes or discontinuation

Assessment and Treatment of Assessment and Treatment of Children and Adolescents with Children and Adolescents with

DepressionDepressionScreen every visit

Mild Depression Moderate Depression

Major Depression

Initiate Medication and/or CBT

Active Support and

close monitoring q1-2 weeks

Partially Improved

Not Improved (reassess dx)

Consider consulting

Mental Health

1. Add or maximize therapy 2. Continue to assess closely for ADE/adherence and changes to self-care 3. Consult mental health

Monitor q 1-2 weeks

Continue to

follow

Improved

Not Improved

Future NeedsFuture Needs

Further data defining suicidality in Further data defining suicidality in peds/adolescentspeds/adolescents

Long term studies assessing differences in Long term studies assessing differences in acute vs maintenance suicidalityacute vs maintenance suicidality

Treatment algorithms designed Treatment algorithms designed specifically for the depressed patients with specifically for the depressed patients with diabetesdiabetes

Creating multidisciplinary treatment Creating multidisciplinary treatment approachesapproaches

ConclusionsConclusions The prevalence of depression is 2 fold The prevalence of depression is 2 fold

greater in patients with diabetesgreater in patients with diabetes Better detection/screening is essential to Better detection/screening is essential to

improving diabetes self-careimproving diabetes self-care Treatment with combined fluoxetine and Treatment with combined fluoxetine and

CBT is the preferred option in MDDCBT is the preferred option in MDD Suicidality is of concern immediately after Suicidality is of concern immediately after

initiating therapy and after dose titrationinitiating therapy and after dose titration Future multidisciplinary management Future multidisciplinary management

approaches are critical in the approaches are critical in the identification, treatment and follow up in identification, treatment and follow up in our diabetes patientsour diabetes patients