B ASAL I NSULIN AND
C ARDIOVASCULAR AND O THER
O UTCOMES IN D YSGLYCEMIA
T HE ORIGIN T RIAL
I NVESTIGATORS
NEJM J ULY 26, 2012: 367;4
Charles Wang
4 th Year PharmD Candidate
University of Georgia College of Pharmacy
8/27/2012

O VERVIEW
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ORIGIN Trial
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Outcome Reduction with Initial Glargine
Intervention
Tested if sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events.
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Funding
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Sanofi
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BioPharma Norge
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Study Dates
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September 2003 – December 2011

B ACKGROUND
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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:
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Cardiovascular disease
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Ischemic heart disease
Stroke
Peripheral vascular disease
Diabetic retinopathy, nephropathy, and neuropathy

B ACKGROUND
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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)
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15% reduction in myocardial infarction
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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

B ACKGROUND
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Insulin glargine
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Brand name: Lantus
Long acting basal insulin
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Consists of microcrystals that slowly release insulin
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Usually given once daily
“peakless” profile according to package insert
Formulated at an acidic pH of 4
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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
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Precipitates out of solution and reduces effectiveness

D ESIGN
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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
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Used 2-by-2 factorial design
Double-blinded
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Randomized
537 cardiology, diabetes, or other clinical sites
40 countries

D ESIGN
N-3 fatty-acid supplements
Placebo
Insulin Glargine Standard of Care
Insulin Glargine +
N-3 fatty-acid supplements
Insulin Glargine +
Placebo
Standard of Care +
N-3 fatty-acid supplements
Standard of Care +
Placebo

I NCLUSION C RITERIA
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Impaired Glucose Tolerance
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PPG ≥ 140 < 200 mg/dL
FPG < 126 mg/dL
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OR Impaired Fasting Glucose without DM
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FPG ≥ 110 and < 126
PPG must be <200 mg/dL
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OR early type 2 diabetes
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FPG ≥ 126 mg/dL or a PPG ≥ 200 or a previous diagnosis of DM and either:
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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%)

I NCLUSION C RITERIA
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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
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Prior MI
Prior Stroke
Prior coronary, carotid, or peripheral arterial revascularization
Angina with documented ischemic changes
Microalbuminuria or clinical albuminuria
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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

E XCLUSION C RITERIA
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Type 1 diabetes
Requiring insulin treatment
Known anti-GAD Ab positivity in the past
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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

M ETHODS
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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
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Targeting a FPG level of 95 mg/dL
Those without a diabetes diagnosis
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Reduced dose of insulin by 10 units per day and stopped any metformin by the last visit

M ETHODS
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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.

B ASELINE C HARACTERISTICS

B ASELINE C HARACTERISTICS

B ASELINE C HARACTERISTICS

B ASELINE C HARACTERISTICS

O UTCOMES
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Co-primary Outcomes
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Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
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A revascularization procedure (cardiac, carotid, or peripheral) or hospitalization for heart failure
Other outcomes
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Microvascular events
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Incident cases of diabetes in participants without baseline diabetes
All-cause mortality
New or recurrent cancers
Hypoglycemic episodes
Weight

R ESULTS

R ESULTS

R ESULTS

H AZARD R ATIO
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Used when presenting results with survival analysis data
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Should not be considered the same as relative risk ratio
A hazard is the rate at which events happen
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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.

R ESULTS
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Coprimary Outcomes
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No significant difference in either outcome
MI, Stroke, or death from CV causes
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HR: 1.02; 95%CI 0.94-1.11; P=0.63
Revascularization or Hospitalization for CHF
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HR: 1.04; 95%CI 0.97-1.11; P=0.27
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Other Outcomes
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All-outcome death
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HR: 0.98; 95%CI 0.9 to 1.08; P=0.7
Microvascular Events
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HR: 0.97; 95%CI 0.90 to 1.05; P 0.43

R ESULTS
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1,456 participants without diabetes at randomization, (737 assigned to Lantus and 719 assigned to standard care)
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Lantus Group were 28% less likely to develop diabetes
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OR:0.72; 95%CI, 0.58 to 0.91; P=0.006
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No significant difference of incidence of cancer
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HR: 1.00; 95%CI, 0.88 to 1.13; P=0.97
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Incidence of first episode of severe hypoglycemia
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1 per 100 person-years in Lantus
0.31 per 100 person years in standard care
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P=<0.001

R ESULTS
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Weight Changes
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+1.6 kg in Lantus Group
-0.5 kg in standard of care group

A UTHOR ’ S C ONCLUSION
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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
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Modest increase in weight

S TRENGTHS
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Very large sample size
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Long follow up duration and high rate of followup and treatment adherence
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6.2 year average follow up time
Well distributed baseline
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Large and diverse data collection

L IMITATIONS
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Only included relatively controlled diabetics
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Did not include patients currently on insulin
No standard, standard care, thus allowing each physician to determine course of care.
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Guideline-suggested degrees of glycemic control
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Did not test more intense versus less intense glucose control

D ISCUSSION
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Metformin was used in 47% of the insulinglargine group
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Cardioprotective effect of metformin might have mitigated cardiovascular harm of insulin.
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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.
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Most likely due to the masking of the hyperglycemia by residual Lantus.