Exendin - A New Incretin?

ADA June 2012 Conference

Alpha cells and the origin of glucagon-like sequences and their receptors

David M. Irwin, Department of Laboratory Medicine and Pathobiology, University of Toronto

Summary of presentation:

Incretin Hormones – 2 known human incretin hormones

-          Glucagon-like peptide 1 (GLP-1)

-          Glucose-dependent insulinotropic peptide (GIP)

Other incretins = Exendin

-          Long acting GLP-1 analogue

o   Acts through the GLP-1 receptor

o   Have increased circulating half-life

o   Synthetic version marketed

-          From the venom of a lizard (Gila monster)

-          No known orthologs in vertebrates, not a product of the proglucagon gene

-          Anole Lizard Exendin – sequence of peptides are not similar to GLP-1 or GIP (human genome)

-          Other animals had similar exendin to lizard (chicken, turkey, duck, zebra finch, xenopus)

-          Exendin 1, 2, 3,and 4 sequences – exendin 3 and 4 are GLP-1 like in their sequence and function; exendin 1 and 2 similar to the are GIP-like in sequence and function

-          Expression of the exendin gene in the chicken and xenopus brain – who knows what it is duing there?

-          No exendin gene in human genome!

-          Exendin genes are found in birds, reptiles and frogs

-          No obvious candidate receptor for exendin; glucagon, GLP1, GLP2, and GIP act through related receptors

-          There are novel group of receptors present in fish, reptiles, birds that are NOT present in mammals – why do mammals not have this gene?

-          GLP1 receptors not found in fish

-          GCGR – duplicated in fish (glucagon receptors)

-          GLP2R – single copy in all species

-          GIPR – no intact gene found in birds

-          GRLR – not found in mammals (glucagon-receptor-like-receptors

Conclusion

o   Genomic data useful for identifying new genes

o   Continues to yield surprises

o   Hormone and receptor families are larger and more complex

-          Open questions

o   What does exendin do in other vertebrates?

o   Is GRLR the receptor for exendin?

o   Why do humans (all mammals) not have Exendin/GRLR?

o   What ligand/receptor has replace the function of Exendin/GRLR in mammals?

ADA 2012 Part 1

Omega-3 Fatty Acids & CV outcomes in patients with dysglycemia

Clinical Question
In patients at high risk for cardiovascular events and have impaired fasting glucose, impaired glucose tolerance, or diabetes, what are the benefits (death from cardiovascular causes) and risks (adverse effects) of 1-g n-3 fatty acids (containing at least 900mg of ethyl esters) compared to placebo at 6.2 years of therapy?

Answer
Efficacy Outcomes
In 12,536 patients (n=6281 in n-3 fatty acid group and n=6255 in placebo group), there was no statistical difference in the primary outcome of death from cardiovascular causes after a median follow-up of 6.2 years.  All secondary outcomes (mycoardial infarction, stroke, death from cardiovascular causes, death from any cause/arrhythmia, hospitalization for heart failure, revascularization procedure, angina, limb or digit amputation for ischemia, and hospitalization for any cardiovascular cause) were all non-significant.  By the end of the trial, patients in the group receiving n-3 fatty acids had a mean reduction in the triglyceride level of 0.16mmol/L as compared to placebo (p<0.001).  No significant between-group differences in the levels of other lipid fractions, plasma glucose levels, glycated hemoglobin levels, blood pressure, or heart rate.

Adverse Effects
The most commonly reported reasons for permanently stopping a study drug was abdominal discomfort (n=32 (0.51%) in the n-3 fatty acid group and 18 (0.29%) in the placebo group), lower gastrointestinal symptoms (n=14 in n-3 fatty acid group and 24 in the placebo group).  Bleeding was reported in 57 (0.91%) patients receiving n-3 fatty acids, as compared with 65 (1.04%) patients in the placebo group, with intracranial bleeding reported in 42 patients, and 51 patients, respectively.



Reference:  The ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012.published on June 11, 2012.

Opioid Conversion

Update on OxyContin & OxyNEO

Effective March 1, 2012 Purdue Pharma is withdrawing its current formulation of oxycodone  controlled release tablet, OxyContin, and introducing OxyNEO.  OxyNEO is a long-acting
formulation of oxycodone, intended for twice-daily dosing, similar to OxyContin.  OxyNeo has a harder coating, making it more difficult to crush.  Additionally, it turns into a gel-like substance when added to water.  These properties are intended to reduce tampering with the medication.


What is the Ontario Drug Benefit (ODB) funding status of OxyContin and OxyNEO?


Effective February 29, 2012, the ministry will remove OxyContin from the Ontario Drug Benefit Formulary/Comparative Drug Index (“ODB Formulary”). OxyNEO will be funded through the Exceptional Access Program (EAP) and through the Facilitated Access to Palliative Care Drugs mechanism. There will also be a one-year transition period for patients currently receiving OxyContin. Details are provided below.
 
Existing ODB recipients of OxyContin:
ODB recipients who have had a claim submitted to the ODB program for OxyContin between September 1, 2011 and February 28, 2012, will receive automatic coverage for OxyContin for one (1) month. All coverage for OxyContin will cease on April 2, 2012. In addition, these patients will receive automatic coverage for OxyNEO (10mg, 15mg, 20mg, 30mg, 40mg and 80mg) for a period of one year (February 29, 2012 to February 28, 2013). If coverage for OxyNEO is required beyond February 28, 2013, an EAP approval will be required.

Prescribers are asked to note that the current turnaround time for EAP requests is approximately three months. For patients for whom OxyNEO continues to be an appropriate therapy, it is recommended that prescribers submit EAP requests to the ministry at least three months in advance of February 28, 2013. The ministry will send out reminder notices throughout the year.





What is the Exceptional Access Program?


The Exceptional Access Program (EAP) facilitates patient access in exceptional circumstances to drugs not listed on the Formulary or where Formulary drugs were ineffective, not tolerated, or where no listed alternative was available. To apply through the EAP, a physician must submit a request documenting complete and relevant medical information to the ministry, and provide the clinical rationale for requesting the unlisted drug and reasons why covered benefits are not suitable. All requests are reviewed according to the guidelines recommended by the CED and approved by the Executive Officer, and include a thorough assessment of the patient’s specific case and clinical circumstances, as provide by the physician, as well as the available scientific evidence. For more information about the EAP, please visit the ministry website at:
www.health.gov.on.ca/english/providers/program/drugs/eap_mn.html

This posting contains pieces of information directly taken from the Ontario Public Drug Program announcement on 2/17/12.  Complete information can be obtained by clicking here.

American Diabetes Association - 2012 Recommendations

In the Diabetes Care, January supplement, ADA has published 2012 recommendations.  The following posts are some of highlights of the recommendations and comparison against the CDA 2008 recommendations:

Criteria for testing diabetes in asymptomatic adult individuals (ADA recommendations)

1.       Testing should be considered in all adults who are overweight (BMI ≥ 25kg/m²) and who have one or more additional risk factors:

·         Physical inactivity

·         First-degree relative with diabetes

·         High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)

·         Women who delivered a baby weighing > 9 lb or who were diagnosed with GDM

·         Hypertension (BP≥140/90 mmHg or on therapy for hypertension

·         HDL < 0.90 mmol/L and/or TG > 2.82 mmol/L

·         Women with PCOS

·         A1C ≥ 7.5%, IGT, or IFG on previous testing

·         Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)

·         History of CVD

2.       In the absence of the above criteria, testing for diabetes should begin at age 45 years

3.     If results are normal, testing should be repeated at least at 3-year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status.

NOTE: CDA guidelines recommend screening for diabetes every 3 years in individuals ≥ 40 years of age.  More frequent and/or earlier testing should be considered in people with additional risk factors for diabetes (same risk factors as ADA, but also includes schizophrenia and other risk factors in appendix 1, S194 of 2008 recommendations.)

Bottomline:  ADA recommendations are more strict with screening for diabetes

Diagnosis of Diabetes

Did you know that A1C > or = 6.5% using a standardized, validated assay, in the absence of conditions that affect the accuracy of the A1C can be used to diagnose diabetes?

There is a position states by the Canadian Diabetes Association that was posted in July 2011 - http://www.diabetes.ca/documents/for-professionals/CJD--July_2011--Position_Statement.pdf

For factors that can affect A1C include erythropoiesis, altered hemoglobin, alcoholism, chronic renal failure, erythrocyte destruction, assays, etc.  See website above for more detailed information.