Transcript Glycemic Control Blood glucose level

Trina La
PharmD. Candidate
University of Georgia
College of pharmacy
Outline
 Introduction
 Study 1: Glycemic control, complications, & death in
older diabetic patients
 Study 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
Introduction
 Definition
 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 elderly
 Cerebral aging
 Atherosclerotic changes
 Compromised Cardio Respiratory Reserve
 Cataract
 Neuropathy
 Cerebral Vascular Disease
Diabetic Complications
Microvascular Complications
Macrovascular Complications
Cerebrovascular
Disease
Retinopathy
Heart Disease
Nephropathy
Neuropathy
Peripheral Vascular
Disease
Amputation
Amputation
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.
4
ELBERT HUANG, JENNIFER LIU, HOWARD
MOFFET, ET AL
Diabetes care 2011;34: 1329-1335
Funded by the institute of diabetes & digestive & kidney diseases
Background
 People 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 targets
 A1C <6.5% from American Association of Clinical
Endocrinologists
 A1C <7.0% from the American Diabetes Association
 A1C < 8.0% from geriatric diabetes care guidelines for older
patients with limited life expectancy
 However, there has been limited evidence for any of these
targets of glycemic control for elderly patients
Objective
 To identify the range of glycemic levels associated with
the lowest rates of complications & mortality in older
diabetic patients
Outcomes
 Acute metabolic events
 Hospitalizations for diabetes with other coma
 Diabtes with hyperosmolarity
 Diabetes with ketoacidosis
 Uncontrolled diabetes
 Chronic microvascular event
 End-stage renal disease
 Amputation
 Severe diabetic eye disease
 Chronic cardiovascular events
 Coronary artery disease
 Congestive heart failure
 Cerebralvascular disease
 Peripheral vascular disease
Research Design & Methods
Inclusion Criteria
Exclusion Criteria
 Type 2 diabetes
 Type 1 diabetes or unknown
 Aged ≥60 years
diabetes
 End-stage renal disease
 No A1C test result during the
year prior to baseline
 Continuous Kaiser
membership & pharmacy
benefits for at least 12 months
before baseline
Research Design & Methods
 A 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 on
 Pharmacy records
 Laboratory data
 Outpatient
 Emergency room
 Hospitalization diagnose of diabetes
Research Design & Methods
 A 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 on
 Pharmacy records
 Laboratory data
 Outpatient
 Emergency room
 Hospitalization diagnose of diabetes
A1C & Assessment of covariates
 For stratified analyses
 A1C
 Assessment of covariates
 Demographics
 Duration of diabetes
 Systolic blood pressure
 Lab 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
 Smoking
 Baseline use of glucose-lowering medications
Results
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The mean age of population: 71 years
Population: ethnically diverse
The mean A1C: 7.0%
The mean duration of diabtes: 8.3 years
Patients with lower baseline A1C values tend to be
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Older
More likely to be non-Hispanic white
More likely to have a shorter duration of diabetes
Better cholesterol control
Lower GFR
Less evidence of other microvascular complication
Much less likely to be treated with insulin
Results: Baseline A1C, Complications, &
mortality; Overall population results
Outcome
Incidence
Density
(Events/1000
person-years)
Model
A1C
Acute metabolic
event
1.23
Adjusted HR
95% CI
1
1.44
.82-2.53
2.35
1.3-4.2
Chronic
microvascular
event
26.68
Adjusted HR
95% CI
1
1
1.11
.99-1.3
Chronic
cardiovascular
events
47.15
Adjusted HR
95% CI
1
1
Mortality
40.42
Adjusted HR
95% CI
Any complication
69.90
Any complication
or Death
97.97
9-9.9
1010.9
≥11
3.82
2.0-7.2
4.95
2.5-10
6.60
3-14.6
11.5
5.7-23.5
1.25
1.1-1.4
1.53
1.3-1.8
1.52
1.3-1.8
1.72
1.4-2.1
2.04
1.7-2.47
1.09
1.0-1.2
1.14
1.1-1.2
1.26
1.1-1.4
1.28
1.1-1.5
1.39
1.2-1.7
1.77
1.51-2.1
1
1
0.84
0.8-0.9
0.83
0.7-0.9
0.90
0.8-1
1.02
0.9-1.2
1.21
1.01.45
1.31
1.09-1.6
Adjusted HR
95% CI
1
1
1.09
1.0-1.2
1.18
1.1-1.3
1.38
1.3-1.5
1.42
1.3-1.6
1.52
1.3-1.7
1.8
1.6-2.16
Adjusted
HR95% CI
1
1
0.98
.93-1.03
1.03
.97-1.1
1.20
1.1-1.3
1.26
1.1-1.4
1.35
1.2-1.5
1.63
1.5-1.8
<6.0
6.0-6.9
7-7.9
8.-8.9
Age-stratified results Adjusted
analyses
Outcome
Baseline A1C
<6.0
6.0-6.9
7.0-7.9
8.0-8.9
≥9
Mortality
Age-group
60-69
70-79
≥80
1
1
1
0.92
0.83
0.83
0.83
0.85
0.83
0.91
0.86
1.05
1.17
1.11
1.20
Any
complication
60-69
70-79
≥80
1
1
1
1.12
1.08
1.11
1.20
1.21
1.18
1.44
1.35
1.28
1.58
1.50
1.43
Any
complication
60-69
70-79
≥80
1
1
1
1.04
0.98
0.94
1.08
1.07
0.96
1.28
1.18
1.13
1.43
1.36
1.25
Conclusions
 Observed 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 A1Cmortality 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 klaus
Jags 2007;55:182-188
Funded by a research grant from sanofi-aventis
Background
 The association between poor glycemic control & the
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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
Objectives
 To compare initiation of insulin therapy by adding
once-daily Lantus to oral antidiabetic agents(OAD)
with premixed insulin alone
Design
 A 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 Criteria
Inclusion Criteria
Exclusion Criteria
 Aged 65 & older
 Any additional use of other
 Type II DM for at least 1 year
oral blood glucose-lowering
agents
 Prior use of insulin exceeding
3 days
 A history of ketoacidosis
 Treated with a stable dose of
Sulfonylurea & Metformin for
at least 1 month
 BMI≤ 35 kg/m2
 7.5 ≤A1C ≤10.5
 Fasting blood glucose(FBG)≥ 120mg/dL
Study Protocol & Treatment
 Previous 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 & Treatment
 For both groups, the FBG target was 100mg/dL
 FBG 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 Measurements
 The primary efficacy measure was change in A1C level from
baseline to endpoint
 Secondary efficacy measurement:
 Mean FBG levels
 Mean daytime BG levels
 Mean BG values from the 8-point profile
 The proportion of patients with FBG levels of 100mg/dL
 The proportion of patients with A1C levels of 7% or less with
no nocturial hypoglycemia
 Safety 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, n
Male/Female
Age, mean ± SD
Weight, kg, mean ± SD
BMI, mean ± SD
Duration of DM, years, mean ± SD
Duration of OAD treatment, years,
mean ± SD
C-peptide, ng/mL, mean ± SD
A1C, mean ± SD
Fasting blood glucose, mean ± SD
mg/dL (range ≤100)
mmol/L (range≤5.6)
67
64/36
83.8±15.3
28.9±3.4
28.9±3.4
12.1± 6.7
8.9±5.9
63
48/52
69.6±4.1
80.5 ±13.0
28.9 ±3.3
11.1 ± 7.6
6.9±5.2
3.5±2.0
8.84±1.06
3.8±2.7
8.89±0.91
165± 33
9.2±1.8
171±39
9.5 ± 2.2
Results
Glycemic Control
Blood glucose level
 Lantus + OAD
 Glargine +OAD
 FBG decreased from 165
mg/dl to 111mg/dl
 Premixed insulin
 FBF decreased from 171
mg/dl to 129 mg/dl
 Decreases in mean adjusted
 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)
FBG levels were significant
greater with Lantus + OAD
than premixed (P=0.02)
Rates of Confirmed Hypoglycemic
Events per Patient-Year
Type of Hypoglycemia
All episodes of
hypoglycemia
(confirmed +
unconfirmed)
Lantus+ Oral
Antidiabetic Agents
Premixed
Insulin
P-Value
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 Events
 Mean weight gain
 Glargine + OAD: 1.3 ± 3 kg
 Premixed insulin: 2.2 ± 3.9 kg
 P value = 0.17
 Adverse Events
 Similar between two groups
 Most common AE

Respiratory, nervous system & GI disorders
 Withdraw from the study due AE
 Lantus+ OAD: 1 patient
 Premixed insulin:2 patient
Discussion
 The 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 considerations
 Risk of comorbidities in elderly patients
 The possibility that patients developed
contraindications to OADs over time
 Individual assessment with tailored therapy is still
important
 Must consider the compromise between achieving
tight glycemic control & limiting the risk of
hypoglycemia in this patient populations
Conclusion
 This 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 Medications
Drugs
Drugs
Mechanism of
Action
Comments
Glyburide Glipizide Sulfonylureas
Glimipiride
Increase insulin
secretion
-Start low dose in elderly,
renal adjustmnent
- Most SE: hypoglycemia,
N/V & skin reactions
Prandin
Starlix
Meglitinides
Stimulate insulin
secretion
Rapid absorption, short
duration of action, dose
with meals
Precose
Glyset
Alphaglucosidase
Inhibitors
Delay glucose
absorption,
decrease rate of
carbohydrate
digestion
No renal adjustment
Contraindication:
-Cirrhosis (Precose)
-Colon ulceration
-IBS/ bowel obstruction
Drugs
Drug class
Mechanism of Action
Comments
Oral Antidiabetic Medications
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
Januvia
Onglyza
Tradjenta
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
Humalog
Novolog
Apidra
Rapid acting
15 to 30 minutes
-Cover insulin needs before or
immediately after meals
- Used with long acting
insulin
Novolin R
Humulin R
Short acting
30 minutes to 1
hour
- Given 30 to 60 minutes
before meals
Lantus
Levemir
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 intermediateacting & short acting insulin
-Give twice daily before meals
GLP-1 Effects in Human
 Drug class: Glucagon-Like Peptide Receptor Agonist
 Therapeutic benefits:
 Enhance glucose dependent insulin secretion
 Promote satiety & reduces appetite
 Decreases post meal glucagon secretion
 Delays gastric emptying
 Available:
 Byetta ®
 Victoza®
Summary
 Management of diabetes is a life-long commitment
 Management of diabetes includes diet, exercise and
drugs
 Regular physician
 Considerations when developing or recommending
drug therapy plan
 Efficacy therapy
 Safety of therapy
 Impact on compliance
 Financial burden