Trina LaPharmD. CandidateUniversity of GeorgiaCollege of pharmacy

OutlineIntroductionStudy 1: Glycemic control, complications, &

death in older diabetic patientsStudy 2: Combination of oral antibiabetic

agents with basal insulin versus premixed insulin ALONE in randomized elderly patients with Type 2 DM

Summary of oral antidiabetic agents and insulins

Conclusion

IntroductionDefinition

DM is a syndrome characterized by chronic hyperglycemia & disturbances of carbohydrate, fat & protein metabolism, associated with an absolute or relative deficiency in insulin secretion and/or insulin action

Associated problems affecting management in elderlyCerebral agingAtherosclerotic changesCompromised Cardio Respiratory ReserveCataractNeuropathyCerebral Vascular Disease

Diabetic Complications

4

Amputation

Microvascular Complications

Neuropathy

CerebrovascularDisease

Peripheral Vascular Disease

Macrovascular Complications

Retinopathy

Nephropathy

Heart Disease

Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986. Stratton IM et al. BMJ. 2000;321:405-412 with permission from the BMJ Publishing Group www.cdc.gov.

Amputation

ELBERT HUANG, JENNIFER LIU, HOWARD MOFFET, ET AL

Diabetes care 2011;34: 1329-1335

Funded by the institute of diabetes & digestive & kidney diseases

BackgroundPeople aged > 60 years comprise > 40% of the type

2 diabetic population in the U.S, yet identifying the optimal glucose control level for older patients with diabetes remains a significant challenge

Recommended glycemic targetsA1C <6.5% from American Association of Clinical

EndocrinologistsA1C <7.0% from the American Diabetes AssociationA1C < 8.0% from geriatric diabetes care guidelines for

older patients with limited life expectancyHowever, there has been limited evidence for any of

these targets of glycemic control for elderly patients

ObjectiveTo identify the range of glycemic levels

associated with the lowest rates of complications & mortality in older diabetic patients

OutcomesAcute metabolic events

Hospitalizations for diabetes with other comaDiabtes with hyperosmolarityDiabetes with ketoacidosisUncontrolled diabetes

Chronic microvascular eventEnd-stage renal diseaseAmputation Severe diabetic eye disease

Chronic cardiovascular eventsCoronary artery diseaseCongestive heart failureCerebralvascular diseasePeripheral vascular disease

Research Design & MethodsInclusion Criteria Exclusion Criteria

Type 2 diabetesAged ≥60 years Continuous Kaiser

membership & pharmacy benefits for at least 12 months before baseline

Type 1 diabetes or unknown diabetes

End-stage renal disease No A1C test result

during the year prior to baseline

Research Design & MethodsA restrospective cohort study (2004-2008) of

71,092 patients with type 2 diabetes, age ≥60 years, enrolled in Kaiser Permanente Northern California

Registry eligibility is based onPharmacy recordsLaboratory dataOutpatient Emergency roomHospitalization diagnose of diabetes

Research Design & MethodsA restrospective cohort study (2004-2008) of

71,092 patients with type 2 diabetes, age ≥60 years, enrolled in Kaiser Permanente Northern California

Registry eligibility is based onPharmacy recordsLaboratory dataOutpatient Emergency roomHospitalization diagnose of diabetes

A1C & Assessment of covariatesFor stratified analyses

A1CAssessment of covariates

DemographicsDuration of diabetesSystolic blood pressureLab findings within 1 year prior to baseline:

eGFR, urinary albumin excretion, BMI; prevalent complications & comorbidities ( hx of lower extremitiy amputation, photocoagulation)

Hospitalization for acute metabolic event, MI, stroke, CHF, ect

SmokingBaseline use of glucose-lowering medications

ResultsThe mean age of population: 71 yearsPopulation: ethnically diverseThe mean A1C: 7.0%The mean duration of diabtes: 8.3 yearsPatients with lower baseline A1C values tend to

beOlderMore likely to be non-Hispanic whiteMore likely to have a shorter duration of diabetesBetter cholesterol controlLower GFRLess evidence of other microvascular complicationMuch less likely to be treated with insulin

Results: Baseline A1C, Complications, & mortality; Overall population results

Outcome Incidence Density (Events/1000 person-years)

Model A1C

<6.0 6.0-6.9 7-7.9 8.-8.9 9-9.9 10-10.9

≥11

Acute metabolic event

1.23 Adjusted HR95% CI

1 1.44.82-2.53

2.351.3-4.2

3.822.0-7.2

4.952.5-10

6.603-14.6

11.55.7-23.5

Chronic microvascular event

26.68 Adjusted HR95% CI

11

1.11.99-1.3

1.251.1-1.4

1.531.3-1.8

1.521.3-1.8

1.721.4-2.1

2.041.7-2.47

Chronic cardiovascular events

47.15 Adjusted HR95% CI

11

1.091.0-1.2

1.141.1-1.2

1.261.1-1.4

1.281.1-1.5

1.391.2-1.7

1.771.51-2.1

Mortality 40.42 Adjusted HR95% CI

11

0.840.8-0.9

0.830.7-0.9

0.900.8-1

1.020.9-1.2

1.211.0-1.45

1.311.09-1.6

Any complication 69.90 Adjusted HR95% CI

11

1.091.0-1.2

1.181.1-1.3

1.381.3-1.5

1.421.3-1.6

1.521.3-1.7

1.81.6-2.16

Any complication or Death

97.97 Adjusted HR95% CI

11

0.98.93-1.03

1.03.97-1.1

1.201.1-1.3

1.261.1-1.4

1.351.2-1.5

1.631.5-1.8

Age-stratified results Adjusted analyses

OutcomeBaseline A1C

<6.0 6.0-6.9 7.0-7.9 8.0-8.9 ≥9

Mortality Age-group 60-69 70-79 ≥80

111

0.920.830.83

0.830.850.83

0.910.861.05

1.171.111.20

Any complication 60-69 70-79 ≥80

111

1.121.081.11

1.201.211.18

1.441.351.28

1.581.501.43

Any complication 60-69 70-79 ≥80

111

1.040.980.94

1.081.070.96

1.281.181.13

1.431.361.25

ConclusionsObserved relationships between A1C &

combined end points support setting a target of A1C< 8.0% for older patients

A1C <6.0% were associated with increase mortality risk

Additional research is needed to evaluate the low A1C-mortality relationship

Ongoing research on care individualization in the elderly suggest that life expectancy, comorbid conditions, patient preferences are important consideration in glycemic control

Janka Hans, Plewe gerd, Busch klausJags 2007;55:182-188

Funded by a research grant from sanofi-aventis

BackgroundThe association between poor glycemic control &

the occurrence of micro-& macrovascular complications has been demonstrated in patients with type 1 & 2 DM

Tight glycemic control may be associated with greater frequency of hypoglycemic episodes; however it can have serious clinical consequences

Consensus opinion on how & when to initiate insulin tx in patients with type II DM is lacking

In older patients with type 2 DM, it is important that the insulin regimen be easy to apply, with optimal efficacy & safety.

Few studies have directly compared the leading methods of insulin initiation in this population

ObjectivesTo compare initiation of insulin therapy by

adding once-daily Lantus to oral antidiabetic agents(OAD) with premixed insulin alone

DesignA parallel-group, open-label, randomized,

multinational clinical trial with a 1 to 4 week screening phase & a 24-week treatment phase

A 1:1 randomization schedule stratified by center sequentially assigned treatment codes to eligible patients

Inclusion & Exclusion CriteriaInclusion Criteria Exclusion CriteriaAged 65 & olderType II DM for at least 1

yearTreated with a stable

dose of Sulfonylurea & Metformin for at least 1 month

BMI≤ 35 kg/m2

7.5 ≤A1C ≤10.5Fasting blood glucose(FBG)≥ 120mg/dL

Any additional use of other oral blood glucose-lowering agents

Prior use of insulin exceeding 3 days

A history of ketoacidosis

Study Protocol & TreatmentPrevious Sulfonylurea therapies were replaced

with 3 or 4 mg glimepiride during the screening phase

Metformin (≥850mg) administered during the study was provided & taken at the same dose as before study entry

The dose of Glimepiride & Metformin remained unchanged throughout the study

At the baseline visit, patients were randomly assigned to insulin Lantus given once daily in AM in combination with Glimepiride & Metformin or to human premixed insulin (70/30) BID

Study Protocol & TreatmentFor both groups, the FBG target was 100mg/dLFBG values & pre-dinner BG as well as

hypoglycemic episodes were recorded in a standardized diary

Hematological, clinical chemistry, & HbA1c values at baseline & 12, & 24 weeks were measured

The participating investigators noted any adverse events at every visit or telephone contact

Efficacy & Safety MeasurementsThe primary efficacy measure was change in A1C

level from baseline to endpointSecondary efficacy measurement:

Mean FBG levelsMean daytime BG levelsMean BG values from the 8-point profileThe proportion of patients with FBG levels of

100mg/dLThe proportion of patients with A1C levels of 7% or

less with no nocturial hypoglycemiaSafety measures were the proportion of patients

with hypoglycemia events & frequency of hypoglycemic events

Demographics & Baseline Characteristics of the Study Population

Characteristics Insulin Lantus+ OAD

Premixed Insulin

Patient, nMale/Female

Age, mean ± SDWeight, kg, mean ± SD

BMI, mean ± SDDuration of DM, years, mean

± SDDuration of OAD treatment,

years, mean ± SDC-peptide, ng/mL, mean ± SD

A1C, mean ± SDFasting blood glucose, mean

± SDmg/dL (range ≤100)mmol/L (range≤5.6)

6764/36

83.8±15.328.9±3.428.9±3.412.1± 6.78.9±5.9

3.5±2.08.84±1.06

165± 339.2±1.8

6348/52

69.6±4.180.5 ±13.028.9 ±3.311.1 ± 7.6

6.9±5.2

3.8±2.78.89±0.91

171±399.5 ± 2.2

ResultsGlycemic Control Blood glucose level Lantus + OAD

A1C decreased from 8.8% to 7.0%

Premixed insulin A1C decreased from 8.9% to

7.4% The mean adjusted decrease in

A1C was greater for Lantus +OAD than for premixed (P=0.03)

Overall, the proportion of patients that reached the target A1C level was significant higher in patients receiving Lantus+OAD (P=0.01)

Glargine +OADFBG decreased from

165 mg/dl to 111mg/dlPremixed insulin

FBF decreased from 171 mg/dl to 129 mg/dl

Decreases in mean adjusted FBG levels were significant greater with Lantus + OAD than premixed (P=0.02)

Rates of Confirmed Hypoglycemic Events per Patient-YearType of Hypoglycemia

Lantus+ Oral Antidiabetic Agents

Premixed Insulin

P-Value

All episodes of hypoglycemia (confirmed + unconfirmed)

5.59 11.39 0.01

All episodes of confirmed hypoglycemia

3.68 9.09 0.008

Confirmed symptomatic hypoglycemia

2.22 5.01 0.06

Confirmed nocturnal hypoglycemia

0.39 0.71 0.26

Severe hypoglycemia 0.00 0.09 0.21

Weight gain & Adverse EventsMean weight gain

Glargine + OAD: 1.3 ± 3 kgPremixed insulin: 2.2 ± 3.9 kgP value = 0.17

Adverse EventsSimilar between two groupsMost common AE

Respiratory, nervous system & GI disordersWithdraw from the study due AE

Lantus+ OAD: 1 patient Premixed insulin:2 patient

DiscussionThe results presented

Patients aged 65 & older with type II DM poorly controlled on oral therapy, adding a single injection of Lantusto glimepiride & Metformin can provide more effective glycemic control than stop OAD & starting BID 70/30

Lantus + OAD regimen enabled 55% of patients to reach A1C of 7% or less without experiencing nocturnal hypoglycemia

Some considerationsRisk of comorbidities in elderly patientsThe possibility that patients developed

contraindications to OADs over timeIndividual assessment with tailored therapy

is still importantMust consider the compromise between

achieving tight glycemic control & limiting the risk of hypoglycemia in this patient populations

ConclusionThis study demonstrated that, for elderly

patients with type II DM who are inadequately controlled with Metformin + a sulfonylurea, adding a Once daily injection of Lantus is a simple method that is more effective in improving glycemic control & less likely to cause hypoglycemia than starting BID injection of premixed insulin without oral agents

Oral Antidiabetic MedicationsDrugs Drugs Mechanism of

ActionComments

Glyburide Glipizide Glimipiride

Sulfonylureas

Increase insulin secretion

-Start low dose in elderly, renal adjustmnent- Most SE: hypoglycemia, N/V & skin reactions

PrandinStarlix

Meglitinides Stimulate insulin secretion

Rapid absorption, short duration of action, dose with meals

Precose Glyset

Alpha-glucosidase Inhibitors

Delay glucose absorption, decrease rate of carbohydrate digestion

No renal adjustmentContraindication: -Cirrhosis (Precose)-Colon ulceration-IBS/ bowel obstruction

Oral Antidiabetic MedicationsDrugs Drug class Mechanism of

ActionComments

Metformin Biguanides - Increase insulin sensitivity;-Decrease insulin resistance- Decrease glucogenesis

-Weight reduction- Lipid improvement (↑ TG & ↓LDL)-Contraindication: SCr(males) ≥1.5 & (female)≥ 1.4

Actos Avandia

Thiazolidinediones (TZD)

Insulin sensitizers -Good for fasting sugar & no renal adjustment- SE: Increase LFT, edema, weight gain-Actos: Risk for bladder cancer

JanuviaOnglyzaTradjenta

DPP4 Inhibitors -Increase insulin synthesis & secretion-Decrease glucagon-Delay gastric emptying , promotes b-cell proliferation

-Safe SE profile- Onglyza: drug interaction with CYP3A4

Insulin Type of Insulin

Onset Role in blood glucose management

HumalogNovologApidra

Rapid acting 15 to 30 minutes

-Cover insulin needs before or immediately after meals- Used with long acting insulin

Novolin RHumulin R

Short acting 30 minutes to 1 hour

- Given 30 to 60 minutes before meals

LantusLevemir

Long acting 30 minutes to 3 hours

-Cover insulin needs for one full day

Humalog mix Novolog mix

Pre-mixed 30 minutes -A combination of specific proportions of intermediate-acting & short acting insulin-Give twice daily before meals

GLP-1 Effects in HumanDrug class: Glucagon-Like Peptide Receptor

AgonistTherapeutic benefits:

Enhance glucose dependent insulin secretionPromote satiety & reduces appetiteDecreases post meal glucagon secretionDelays gastric emptying

Available:Byetta ®Victoza®

SummaryManagement of diabetes is a life-long

commitmentManagement of diabetes includes diet,

exercise and drugs Regular physicianConsiderations when developing or

recommending drug therapy planEfficacy therapySafety of therapyImpact on compliance Financial burden