Pathophysiology in the
Treatment of Type 2
Diabetes
Newer Agents
Part 1 of 5
Addressing Pathophysiology in the in
Treatment of Type 2 Diabetes: Newer Agents
Objectives
Islet-Cell Defects:Incretins, &Amylin
• State the modes of action and clinical potential of amylin agonists,
and incretin-based therapies,
Hepatic and Peripheral Insulin Resistance
• State the modes of action and clinical potential of other more
recently introduced agents in the management of patients with type
2 diabetes: bromocryptine and colsevalam
Differentiate New andTraditional Treatment Strategies
Re: A1c lowering potential, route of administration, effects on weight
and/or CV risk factors, and whether or not they can be used as part
of mono- or combination therapy strategies
.
Type 2 Diabetes: Two Principal
Defects; Overview
Genes
Genes
Insulin resistancelipotoxicity
peripheral
±Environment
hepatic
b-cell dysfunction/
Failure; dec. mass
Abn. First
phase
±Environment
1st & 2nd
IFG
Glucose
Toxicity
Type 2 diabetes
IGT
Glucose
Toxicity
DM will NOT occur if B-cells not genetically predisposed
Reaven GM. Physiol Rev. 1995;75:473-486
Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;
Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.
AACE/ACE: Recommendations
Based on A1C at Diagnosis
Lifestyle Modifications
A1C 6.5%-7.5%
A1C 7.6%-9.0%
If under
treatment
Monotherapy
Dual therapy
Insulin plus
other
agent(s)*
Dual therapy
Triple therapy
A1C > 9.0%
Triple therapy
If drug
naive
Insulin plus
other
agent(s)*
Triple therapy
*Pramlintide can be used with prandial insulin, but insulin secretagogues should be discontinued
with multidose insulin
AACE: American Association of Clinical Endocrinologists
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes,
Treating Defronzo’s Octet: WITHOUT HYPOGLCEMIA:
Match Patient Characteristics to Drug Characteristics
1.Pancreatic
insulin
Secretion:
Incretin,
5.Gut CHO
Absorption:
8.Kidney
-
-
Incretin,
Pramlintide,
Glucosidase inh.
7.BrainTZD,INCRETIN,
bromocriptine
2.Pancreatic
glucagon
Secretion- Incretin
SGLT2
De
HYPERGLYCEMIA
-
-
3.MuscleTZD, Incretin
4.Liver
Hepatic glucose
production:
Metformin, incretin, colesevelam
Peripheral
glucose
uptake
6.Fat- TZD, metformin
Other Therapies:
Likely Effects on Hepatic and
Peripheral Insulin Resistance
Bromocriptine
IR begets IR: hyperinsulinemia in hypothalamus reduces nutrient sensing via increased NE/5HT,
overcoming nml spring rise in dopa/decreasing dopa in spring
Bromocryptine QR:
Proposed mechanism of action
Morning administration
(within 2 hours
of waking) of AGENTCorrects
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
9 Frontiers in Animal Diabetes Research Series.
Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome.
Taylor and Francis, Eds Hansen, B Shafrir, E London, pp 271-312, 2002
Bromocriptine-QR (quick release)
• The dopamine receptor agonist is indicated as an adjunct
to diet and exercise to improve glycemic control in adults
with diabetes.
• The specific mechanism by which bromocriptine mesylate
improves glycemic control is not known.
• Patients with type 2 diabetes should take bromocriptine
mesylate within two hours of waking in the morning. An
initial daily dose of 0.8 mg should be titrated weekly until a
maximum tolerated dose of 1.6 mg to 4.8 mg is achieved.
• Possible decreased risk for CV events with bromocriptine.
Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010
Bromocriptine In Treatment of Type 2 Diabetes
H Pijl, S Ohashi, M Matsuda,Y Miyazaki,
•
A Mahankali, V Kumar, R Pipek, P Iozzo,
•
J L Lancaster, A H Cincotta and R A DeFronzo
•
Diabetes Care 23:1154–1161, 2000
Bromocriptine-QR
Tolerability
Placebo
Bromocriptine-QR
Severe adverse events
14%
17%
Nausea
7%
22%
Orthostatic hypotension
0.8%
2.2%
Somnolence
1.3%
4.3%
Psychosis - may exacerbate psychotic disorders or reduce effectiveness of drugs that treat
psychosis; not reported with QR formulation to date
Safety
Cardiovascular
•Event rate lower in Bromocriptine-QR than placebo [1.8%
vs. 3.2%] in 1-year safety study.
Fibrosis
•Associated with ergot-derived dopamine receptor
agonists, maybe less in Bromocriptine-QR.
Drug interactions
(Caution combining)
•Other ergot-related drugs
•Dopamine receptor agonists or antagonists
•Strong inhibitors/agnoists/substrates of CYP3A4.
Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010
KM Curve – Fast-Acting Bromocriptine Safety Trial
Cumulative Percent Composite CVD Endpoint
HR 0.58; 95% CI, 0.35-0.96
RRR=42%
Bromocriptine
*MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc.
KM Curve: the separation in favor of Bromocriptine begins 3 months and persists through the end of the study
Gaziano M. Diabetes Care 2010, March 23 online