BASAL INSULIN AND CARDIOVASCULAR AND OTHER OUTCOMES IN DYSGLYCEMIATHE ORIGIN TRIAL INVESTIGATORSNEJM JULY 26, 2012: 367;4Charles Wang

4th Year PharmD Candidate

University of Georgia College of Pharmacy

8/27/2012

OVERVIEW

ORIGIN Trial Outcome Reduction with Initial Glargine

InterventionTested 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 new-

onset 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

HR: 1.02; 95%CI 0.94-1.11; P=0.63 Revascularization or Hospitalization for CHF

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

follow-up 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 insulin-glargine 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.