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

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

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

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