The Ominous Octet: How Pathophysiology and Therapy Merge

Lou Haenel, IV, DO,FACE, FAOI
Endocrinology
Roper St Francis
Charleston, SC
THE OMINOUS OCTET: HOW
PATHOPHYSIOLOGY AND THERAPY
MERGE
Sulfonylureas
 Glipizide
 Glyburide
 Glimeperide
Metformin
 Gold Standard
 Improves Insulin Resistance
 Decreases Hepatic Glucose Production
 Just missed ss of macrovascular rr in UKPDS
 First line pharmacotherapy in all algorithms
 MOA – Activation of AMP activated protein
kinase
 Influence on gut microbiome ??
Glucagon Like Peptide 1 Agonists
Dipeptidyl peptidase 4 Inhibitor
INCRETIN THERAPY
Byetta (exenatide)
Bydureon (exenatide)
Victoza (liraglutide)
Trulicity (dulaglutide)
Tanzeum (albiglutide)
GLP1 AGONISTS
GLP-1 secreted upon
the ingestion of food
Januvia (sitagliptin) - Janumet
Onglyza (saxagliptin) - Kombiglyze
Tradjenta (linagliptin).Jentadueto
Nesina (alogliptin) – Kazano
(alogliptin+pioglitazone) - Oseni
DPP 4 INHIBITORS
Symlin
Pramlintide
AMYLIN
Amylin: The Second -Cell
Hormone
• Important regulator of glucose influx into bloodstream
• First reported in 1987
• 37-amino acid neuroendocrine hormone
• Colocated and cosecreted with insulin from pancreatic -
cells
• Not synonymous with “amyloid deposits”
Amylin
Insulin
Unger. Williams Textbook of Endocrinology. 1992.
Amylin Helps Regulate
Postprandial Glycemia via
Multiple Mechanisms
Brain
_ Food Intake
Nutrient
Delivery
Liver
Plasma Glucose
_
Glucagon
Amylin
Insulin
Pancreas
Model derived from animal studies
Muscle
and
Fat
_
Neurotransmitter Modification
CYCLOSET
22
23
CYCLOSET ®: Proposed
mechanism of action

Diabetes patients may have low morning levels of hyothalamic dopamine, which is thought
to lead to hyperglycemia and dyslipidemia

CYCLOSET resets aberrant low morning hypothalamic dopaminergic activity, which may
reset neuroendocrine metabolic control
Decreased
lipolysis in
adipose tissue
Decreased
postprandial
hepatic glucose
output
Decreased insulin
resistance
Meier, Diabetes Reviews 1996; 4 (4): 476-487
24
Cycloset:A unique formulation
of bromocriptine
CYCLOSET®
4.8 mg tablets

Traditional formulations of bromocriptine
were not designed to provide the same
pharmacokinetic/pharmacodynamic profile
as CYCLOSET at equivalent dosing

CYCLOSET is a novel quick-release
formulation of bromocriptine that increases
CNS dopaminergic activity

CYCLOSET has no AB-rated equivalent
Novartis Parlodel®
5 mg tablets
Mylan bromocriptine
5 mg tablets
*AB is the FDA therapeutic equivalence rating that indicates
bioequivalence has been studied and demonstrated
Data on file, Santarus, Inc
25
CYCLOSET ® : Summary of efficacy
 Following once-daily, early morning administration of CYCLOSET:

CYCLOSET controlled glucose throughout the day, reducing
postprandial glucose without increasing insulin levels
 CYCLOSET reduced HbA1c by 0.6%–0.9% vs. placebo when added to other oral
antidiabetics
 CYCLOSET adds consistent glycemic control, with 35% to 40% of patients failing
other oral antidiabetics reaching HbA1c goal in 24 weeks
26
CYCLOSET® CV Safety Trial
Cumulative % experiencing
Composite CVD Endpoint
In a 3070-patient, 52 week safety study, CYCLOSET use was not associated with
an increased risk for adverse CV events
42% relative risk reduction for composite CVD endpoint vs. placebo was
observed
1.5% of patients on CYCLOSET vs. 3% on placebo experienced any composite
CVD endpoint*
5.0
HR 0.58 (95% CI, 0.35 – 0.96)
4.0
RRR=42%
Placebo
3.0
CYCLOSET
2.0
1.0
0.0
0
1
2
3
4
5
6
7
Months
8
9
*MI, stroke, hospitalization for unstable angina,
hospitalization for CHF, or coronary revascularization
10
11
12
13
p<0.05
n =3070
Prescribing Information, CYCLOSET
Gaziano et al, Diabetes Care 2010;33:1503-1508
27
CYCLOSET
Summary
®
Safety trial:
 Demonstrated cardiovascular safety
 In a 3070-patient, 52 week safety study, CYCLOSET use was not
associated with an increased risk for adverse CV events
 42% relative risk reduction for composite CVD endpoint vs. placebo
was observed; Hazard ratio=0.58 (95% CI, 0.35-0.96)
 1.5% of patients on CYCLOSET vs. 3% on placebo experienced any
composite CVD endpoint
 Demonstrated overall safety
 Rate of SAEs vs. placebo 8.5% vs. 9.6%, respectively
 No significant weight gain or severe hypoglycemia compared with
placebo observed in clinical trials
28
Invokana (canagliflozin) - Invokamet
Farxiga (dapagliflozin) - Xigduo
Jardiance (empagliflozin)
SGLT 2 INHIBITORS