Addressing Pathophysiology in the in Treatment of Type 2 Diabetes: Newer Agents
ObjectivesIslet-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
Reaven GM. Physiol Rev. 1995;75:473-486Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.
Insulin resistance- lipotoxicity
-cell dysfunction/Failure; dec. mass
± Environment ± Environment
IFG IGT
GenesGenes
Type 2 diabetes
Glucose
Toxicity
Glucose
Toxicity
hepatic
peripheral Abn. Firstphase
1st & 2nd
DM will NOT occur if B-cells not genetically predisposed
AACE/ACE: Recommendations Based on A1C at Diagnosis
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
A1C 6.5%-7.5% A1C 7.6%-9.0% A1C > 9.0%If undertreatment
If drugnaive
Insulin plusother
agent(s)*Insulin plus
other agent(s)*
Symptom
s
No
sym
ptom
s
Lifestyle Modifications
*Pramlintide can be used with prandial insulin, but insulin secretagogues should be discontinued with multidose insulin
Monotherapy
Dual therapy
Triple therapy
Dual therapy
Triple therapy
Triple therapy
AACE: American Association of Clinical EndocrinologistsAACE: American Association of Clinical Endocrinologists
Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes,Treating Defronzo’s Octet: WITHOUT HYPOGLCEMIA:
Match Patient Characteristics to Drug Characteristics
5.Gut CHOAbsorption:
Incretin,Pramlintide,Glucosidase inh.
Peripheralglucose uptake
--
-
1.Pancreatic insulin
Secretion:Incretin,
2.Pancreatic glucagon
Secretion- Incretin
HYPERGLYCEMIA
6.Fat- TZD, metformin
7.Brain-TZD,INCRETIN,bromocriptine
8.Kidney-
SGLT2
3.Muscle- TZD, Incretin
4.Liver Hepatic glucose production:Metformin, incretin, colesevelam
De
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
Restoration of morning peak in dopaminergic activity (via D2 receptor-mediated activity)
Decreased postprandial glucose levelsReduction in insulin resistance
Day-long reduction in plasma glucose, TGs and FFAs
Sympathetic toneHPA axis tone Hepatic gluconeogenesis FFA and TG Insulin resistance Inflammation/hypercoagulation
Low dopaminergic tone in hypothalamus in early morning in diabetes
Sympathetic toneHPA axis tone Hepatic gluconeogenesis FFA and TG Insulin resistance Inflammation/hypercoagulation
Impaired glucose metabolism, hyperglycemia and insulin resistance
Adverse cardiovascular pathology
9Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010Cincotta. 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
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
Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010
TolerabilityPlacebo 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.
*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
HR 0.58; 95% CI, 0.35-0.96
RRR=42%
KM Curve – Fast-Acting Bromocriptine Safety Trial Cumulative Percent Composite CVD Endpoint
Gaziano M. Diabetes Care 2010, March 23 online
Bromocriptine