Diabetes Mellitus 101 for
Cardiologists (and Alike): 2015
An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes
in Cardiometabolic Patients:
Looking at Diabetes Medications with a Cardiologists Eye
Part 6
Stan Schwartz MD,FACP
Affiliate, Main Line Health System
Emeritus, Clinical Associate Professor of Medicine,
U of Pa.
6105472000
Central mechanisms
Satiety- appetite suppression
Biologic clock
Implications for Therapy
 Understand and Treat Central Mechanisms IR
 Understand and Treat Peripheral IR- fat, liver, muscle
 Understand and Treat Inflammation
 Understand and Treat Biome
Then Learned we have same solution Diurnally- Increased IR at Night
Daytime
Nightime
AM in diurnal Variation of IR
PM in diurnal Variation of IR
ADAPTIVE IR
MAL-ADAPTIVE IR
hyperinsulinemia
Bromocryptine QR:
Proposed mechanism of action
Morning administration
(within 2 hours
of waking) of AGENT
Corrects
Low dopaminergic tone in
hypothalamus in early morning in
diabetes
Sympathetic tone
HPA axis tone
 Hepatic gluconeogenesis
 FFA and TG
 Insulin resistance
 Inflammation/hypercoagulation
Impaired glucose metabolism, hyperglycemia and
insulin resistance
Adverse cardiovascular pathology
Restoration of morning peak in
dopaminergic activity (via D2
receptor-mediated activity)
Sympathetic tone
HPA axis tone
 Hepatic gluconeogenesis
 FFA and TG
 Insulin resistance
 Inflammation/hypercoagulation
Decreased postprandial glucose levels
Reduction in insulin resistance
Day-long reduction in plasma glucose, TGs and FFAs
Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010
Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal Diabetes Research Series. Taylor and Francis, Eds Hansen
B Shafrir, E London, pp 271-312, 2002
7
Bromocriptine-QR (Cycloset)
Dosing: Start with 0.8 mg (one tablet) within two hours of awakening in the AM.
Increase weekly as tolerated to target dose of 1.6 to 4.8 mg upon awakening
Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010
KM Curve – Fast-Acting Bromocryptine Safety Trial
Cumulative Percent Composite CVD Endpoint
HR 0.58; 95% CI, 0.35-0.96
RRR=42%
*MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc.
KM Curve: the separation in favor of Cycloset begins 3 months and persists through the end of the study
Gaziano M. Diabetes Care 2010, March 23 online
Impact of Bromocriptine-QR on CV Events
Bromocriptine-QR
(N=2054),
n (%)*
Placebo (N=1016),
n(%)*
Hazard Ratio
(95% CI)
CV death-inclusive composite
cardiovascular end point
39 (1.9)
33 (3.2)
0.61 (0.38 to 0.97)
Myocardial infarction
Stroke
Hospitalization for angina
7 (0.3)
5 (0.2)
9 (0.4)
9 (0.9)
6 (0.6)
9 (0.9)
0.41 (0.15 to 1.11)
0.44 (0.13 to 1.43)
0.52 (0.21 to 1.30)
Hospitalization for heart failure
9 (0.4)
6 (0.6)
0.77 (0.27 to 2.16)
Coronary revascularization
CV death
Coronary revascularization
following a primary end point
(ie, CABG after MI)
11 (0.5)
4 (0.2)
8 (0.8)
2 (0.2)
0.72 (0.29 to 1.80)
0.48 (0.07 to 3.43)
9 (0.4)
11 (1.1)
0.43 (0.18 to 1.03)
14 (0.7)
15 (1.5)
0.48 (0.23 to 1.00)
MACE composite—myocardial
infarction, stroke, CV death
CI, confidence interval; CV, cadiovascular; CABG, coronary artery bypass graft; MACE, major cardiovascular adverse event; MI, myocardial infarction. *Percentage of events per
total number per group: 2054 bromocriptine-QR, 1016 placebo.
Gaziano J M, Cincotta AH, Vinik A, Blonde L, Bohannon N, Scranton R. J Am Heart Assoc 2012;1:e002279
Cardiac Autonomic Imbalance and Inflammation in
the Progression of Diabetes
Adipose
Tissue
Lieb DC , Vinik, Parson et al. Exp Diab Res 2012
Autonomic Dysfunction and Sudden Death in
Diabetes
Stress
Sympathetic Overactivity
Activation of Central SNS
Renal Angiotensin
Hypertension
Enhanced SN responsiveness
Cardiac SNS
Oxidative/Nitrosative
Stress
Myocyte apoptosis
Vinik et al Endocrine Today2008
Nephropathy
LV Dysfunction/Sudden Death
Causes of Death in Diabetic
Autonomic Neuropathy
Sudden unexplained
Cardiac arrhythmia
Silent myocardial infarction

More likely to die of heart attack

Greater incidence of cardiac failure
Aspiration pneumonia
Ulcers, amputations, gangrene
Chronic renal failure