Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia

Report
BASAL INSULIN AND
CARDIOVASCULAR AND OTHER
OUTCOMES IN DYSGLYCEMIA
THE ORIGIN TRIAL
INVESTIGATORS
NEJM JULY 26, 2012: 367;4
Charles Wang
4th Year PharmD Candidate
University of Georgia College of Pharmacy
8/27/2012
OVERVIEW

ORIGIN Trial
Outcome Reduction with Initial Glargine
Intervention
Tested if sufficient basal insulin to normalize fasting
plasma glucose levels may reduce cardiovascular
events.


Funding
Sanofi
 BioPharma Norge


Study Dates

September 2003 – December 2011
BACKGROUND
Diabetes is a chronic metabolic disease in which
a person has high blood glucose levels.
 It involves either the body not producing enough
insulin or because the cells do not respond to the
insulin that is produced.
 Globally, as of 2012, an estimated 346 million
people have type 2 diabetes.
 Diabetes has many complications:






Cardiovascular disease
Ischemic heart disease
Stroke
Peripheral vascular disease
Diabetic retinopathy, nephropathy, and neuropathy
BACKGROUND
Elevated blood glucose indicates that there is not
enough endogenous insulin to regulate the
glucose levels or to overcome underlying insulin
resistance
 Correction of this deficiency may reduce
cardiovascular outcomes.
 United Kingdom Prospective Diabetes Study
(UKPDS)

15% reduction in myocardial infarction
 13% reduction in death among people with a newonset type 2 diabetes
 Normalizing fasting plasma glucose levels may safely
reduce incident CV outcomes
 Exogenous insulin may slow the decline in pancreatic
function with time

BACKGROUND

Insulin glargine
Brand name: Lantus
 Long acting basal insulin
 Consists of microcrystals that slowly release insulin

Usually given once daily
 “peakless” profile according to package insert


Formulated at an acidic pH of 4
Water soluble at that pH
 Physiologic pH (~7.4) causes the insulin to come out of
solution that forms hexamers
 Hexamers slows dissociation into insulin monomers which
is the physiologically active unit of insulin.
 Do not mix Lantus with any other insulin
 Precipitates out of solution and reduces effectiveness

DESIGN
Trial tested the effects of titrated basal insulin
glargine versus standard of care and of n-3 fatty
acid supplements versus placebo on
cardiovascular outcomes
 Study Design






Used 2-by-2 factorial design
Double-blinded
Randomized
537 cardiology, diabetes, or other clinical sites
40 countries
DESIGN
Insulin Glargine
Standard of Care
N-3 fatty-acid
supplements
Insulin Glargine +
N-3 fatty-acid
supplements
Standard of Care +
N-3 fatty-acid
supplements
Placebo
Insulin Glargine +
Placebo
Standard of Care +
Placebo
INCLUSION CRITERIA

Impaired Glucose Tolerance
PPG ≥ 140 < 200 mg/dL
 FPG < 126 mg/dL


OR Impaired Fasting Glucose without DM
FPG ≥ 110 and < 126
 PPG must be <200 mg/dL


OR early type 2 diabetes

FPG ≥ 126 mg/dL or a PPG ≥ 200 or a previous
diagnosis of DM and either:
No pharmacologic treatment for at least 10 weeks prior to
screening or
 An A1c of < 150% of the upper limit for the laboratory (<9%
if 6%)

INCLUSION CRITERIA



OR taking one oral antidiabetic drugs for at least 10
weeks at the time of screening and <8.5% A1c
Men or women ≥ 50 years old
Must be at risk for cardiovascular disease





Prior MI
Prior Stroke
Prior coronary, carotid, or peripheral arterial
revascularization
Angina with documented ischemic changes
Microalbuminuria or clinical albuminuria

A:C ratio > 30 mg/mg
LV hypertrophy
 At least 50% stenosis on angiography of a coronary,
carotid, or lower extremity artery
 Ankle/brachial index <0.9

EXCLUSION CRITERIA



Type 1 diabetes
Requiring insulin treatment
Known anti-GAD Ab positivity in the past








Autoimmune antibodies differentiates between types of
diabetes
HgA1c >150% of upper limit (≥9%)
CABG within 4 years of screening
SrCr > 2.0 mg/dL
ALT or AST > 2.5 times upper limit of normal
Chronic or recurrent treatment of systemic
corticosteroids or niacin treatment
Heart Failure of NYHA Class III or IV
Prior heart transplant or awaiting heart transplant
METHODS
12,537 participants
 2-by-2 factorial design
 Follow up for 7 years
 6,264 in the Insulin Glargine Group
 6,273 in the Standard Care Group
 In the insulin group, participants added an
evening injection to their control regimen and
increased the dose at least once weekly



Targeting a FPG level of 95 mg/dL
Those without a diabetes diagnosis

Reduced dose of insulin by 10 units per day and
stopped any metformin by the last visit
METHODS
Those in the Standard Care arms were treated on
the basis of the investigator’s best judgment and
local guidelines
 Also, those that did not have a diabetes diagnosis
and were not using glucose lowering drugs were
scheduled for a Glucose Tolerance Test and
retested if it did not establish a diagnosis of
diabetes.

BASELINE CHARACTERISTICS
BASELINE CHARACTERISTICS
BASELINE CHARACTERISTICS
BASELINE CHARACTERISTICS
OUTCOMES

Co-primary Outcomes



Death from cardiovascular causes, nonfatal
myocardial infarction, or nonfatal stroke
A revascularization procedure (cardiac, carotid, or
peripheral) or hospitalization for heart failure
Other outcomes






Microvascular events
Incident cases of diabetes in participants without
baseline diabetes
All-cause mortality
New or recurrent cancers
Hypoglycemic episodes
Weight
RESULTS
RESULTS
RESULTS
HAZARD RATIO

Used when presenting results with survival analysis
data


Should not be considered the same as relative risk ratio
A hazard is the rate at which events happen





Probability=length of time x hazard
The hazard ratio is an expression of the hazard or chance
of events occurring in the treatment arm as a ratio of the
hazard of the events occurring in the control arm
Assume proportional hazard
Risk does not depend on time
A hazard ration of 2 means that the treatment will cause
the patient to progress more quickly, that a person that
has not progressed has twice the chance of having
progressed to a certain point when compared to someone in
the control group.
RESULTS

Coprimary Outcomes
No significant difference in either outcome
 MI, Stroke, or death from CV causes



Revascularization or Hospitalization for CHF


HR: 1.02; 95%CI 0.94-1.11; P=0.63
HR: 1.04; 95%CI 0.97-1.11; P=0.27
Other Outcomes

All-outcome death


HR: 0.98; 95%CI 0.9 to 1.08; P=0.7
Microvascular Events

HR: 0.97; 95%CI 0.90 to 1.05; P 0.43
RESULTS

1,456 participants without diabetes at
randomization, (737 assigned to Lantus and 719
assigned to standard care)
Lantus Group were 28% less likely to develop
diabetes
 OR:0.72; 95%CI, 0.58 to 0.91; P=0.006


No significant difference of incidence of cancer


HR: 1.00; 95%CI, 0.88 to 1.13; P=0.97
Incidence of first episode of severe hypoglycemia
1 per 100 person-years in Lantus
 0.31 per 100 person years in standard care
 P=<0.001

RESULTS

Weight Changes
+1.6 kg in Lantus Group
 -0.5 kg in standard of care group

AUTHOR’S CONCLUSION
When used to target normal fasting plasma
glucose levels for more than 6 years, insulin
glargine had a neutral effect on cardiovascular
outcomes and cancers
 Reduced new-onset diabetes
 Increased hypoglycemia events
 Modest increase in weight

STRENGTHS
Very large sample size
 Long follow up duration and high rate of followup and treatment adherence


6.2 year average follow up time
Well distributed baseline
 Large and diverse data collection

LIMITATIONS
Only included relatively controlled diabetics
 Did not include patients currently on insulin
 No standard, standard care, thus allowing each
physician to determine course of care.



Guideline-suggested degrees of glycemic control
Did not test more intense versus less intense
glucose control
DISCUSSION

Metformin was used in 47% of the insulinglargine group
Cardioprotective effect of metformin might have
mitigated cardiovascular harm of insulin.
 60% of standard care was also on [


Patients that were not diagnosed with diabetes
had a reduced incidence of developing diabetes in
the Lantus group.

Most likely due to the masking of the hyperglycemia
by residual Lantus.

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