Diabetes Mellitus type IIDiabetes Mellitus type IIOptimizing Glucose ControlOptimizing Glucose Control

Andrea ShaylorLock Haven University PA

ProgramFebruary 26, 2009

FACTS

Diabetes affects an estimated 24.1 million people -> an increase of more than 3 million in ~2 yrs

6.2 million remain undiagnosed/untreated

Another 57 million with prediabetes/ impaired FPG

Pathophysiology

Genetics + EnvironmentObesity!

defects in glucose uptake ↓ concentration of insulin receptors↓ glycolytic enzymes glucokinase and hexokinase

Pathophysiology

*Beta-cell dysfunction and loss vs. insulin resistance*

Chronic exposure to high glucose causes: -glucose-induced toxicity, resulting in irreversible beta-cell damage -generation of reactive oxygen species causing oxidative stress which affects the mRNA for insulin gene expression, resulting in less insulin production

UKPDS: only 50% of pancreatic islet function remains at time of diagnosis

pg46

Beta-cell function declines as diabetes progresses

Lebovitz HE. Diabetes Rev. 1999;7:139-153.2004 Roper Survey of the U.S. Diabetes Market, courtesy GfK Market Measures.

Beta

-cell

fun

cti

on

(%

)

Beta-cell decline exceeds 50% by time of diagnosis

4 4 12 8 0 8 12

0

50

100

75

25 Type 2 Diabetes

IGT

Years from diagnosis

Postprandial

Hyperglycemia

Diagnosis

I nsulininitiation

Beta-cell function decline over time

This information is general diabetes information and not intended to suggest that NovoLog® Mix 70/30 can help reduce micro- and macrovascular complications of diabetes.

Diagnosis

ADA offers 3 criteria:

1)* FPG > 126mg/dL on 2 random occasions2) symptoms of hyperglycemia and a random plasma glucose >200mg/dL3) 2-hour plasma glucose level >200mg/dL after a 75-gram oral glucose tolerance test

Current Management

Lifestyle modification with diet and exercise ↓

FPG goal not met: monotherapy with metformin or sulfonylurea

↓Combination of above, or another oral agent

↓Addition of 3rd agent, various combinations, or new agent

ie incretin mimetic/Byetta or DPP-4 inhibitor/Januvia ↓

When all else fails: Insulin

Target for treatment Glycosylated hemoglobin A1C, average blood glucose

over past 3 mos, shows better correlation to micro and macrovascular complications than glycemic values

ADA and ACC recommendation: HgbA1C <6.5-7% UKPDS: for every 1% reduction in A1C:

- 21% reduction in death related to diabetes-14% reduction in risk for MI, 12% for stroke-32% reduction in risk for retinopathy-24-27% reduction in risk for nephropathy-30% reduction in risk for neuropathy

Intensive glycemic control associated with a 57% reduction in major CVD outcomes

Suboptimal Control Causes irreversible micro and macrovascular

complications, m & m Despite this, 60% of pts do not meet goals Prospective study of 7000 pts: Avg pt remained at A1C

>8% for 5 yrs and >7% for 10 yrs At time of all OA failure, many pts have had diabetes for

10-15 yrs, and long term complications have already developed

Meneghini, L. (2007). Why and How to Use Insulin Therapy Earlier in the Management of Type 2 Diabetes. Southern Medical Association, 100: 164-173.

PICO Question:

In the adult population with DM type II, should insulin be initiated earlier, after failure of just one oral agent, as measured by HbA1C, versus the further addition/combo of OAs, for better glycemic control thereby preventing or delaying the associated DM complications?

Retrospective cohort study involving 2501 patients with DM type II above OGLA failure threshold

Found that 24% of patients had insulin delayed for at least 1.8 yrs, and 50% delayed for 5 yrs with polytherapy, even in the presence of diabetes-related complications

A1C levels were closer to 9% before intervention was triggered

Rubino, A., McQuay, L., Gought, C., et al. (2007). Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with Type 2 Diabetes. Diabetic Medicine, 24: 1412-1418.

Evidence for Use Although oral agents succeed at lowering glucose, there

is still a continued loss of B-cell function with time. Sulfonylureas have been to shown to possibly increase

the risk of B-cell apoptosis. TZDs associated with adverse effects However, insulin is proven to prevent glucotoxicity and

lipotoxicity, in addition to preserving B-cell functioning

Tibaldi, J. (2008). Preserving Insulin Secretion in type 2 Diabetes Mellitus. Expert Review of Endocrinology & Metabolism : Medscape, 3(2): 147-159.

OAD Reduction in A1C

Actos or Avandia .1-.9

Prandin 1.1

Metformin 1.4

Sulfonylureas 1-2

Insulin ~2+

Vinik, Aaron. (2007). Advancing Therapy in Type 2 DM with Early, Comprehensive Progression from OA to Insulin Therapy. Clinical Therapeutics, 29: 1236-1253.

A1C levels before and after insulin

Window of Opportunity When blood glucose levels are normalized and

maintained early, the glucotoxicity and oxidative stress causing B-cell deterioration and apoptosis can be reversed:

Clinical trials of short periods of intensive insulin therapy administered early have resulted in temporary remission due to restored B-cell functioning

However, when same intensive insulin therapy used in pts with avg of 7.6 yrs of DM, insulin response was much less

Tibaldi, J. (2008). Preserving Insulin Secretion in type 2 Diabetes Mellitus. Expert Review of Endocrinology & Metabolism : Medscape, 3(2): 147-159.

ADA/ACE Goals & Algorithm

FPG<100mg/dL and 2hr PPG <140mg/dL If HbA1C remains >7% following lifestyle

changes + metformin after 3 mos-> consider insulin Metformin when combined with insulin has

weight-ameliorating effects

Vinik, Aaron. (2007). Advancing Therapy in Type 2 DM with Early, Comprehensive Progression from OA to Insulin Therapy. Clinical Therapeutics, 29: 1236-1253.

Regimen?

Elevated FPG-- basal Elevated PPG-- basal/bolus or *premixed

PP glycemic control accounts for 50% of overall glycemic control

INITIATE treat-to-target trial: Metformin+ premix BIAsp30: 66% reached <7% Metformin + basal glargine: 40% reached <7%

1-2-3 Trial: Failure on OA, with BIAsp30 added: 41% reached <7%, 21% reached <6.5% in 16 wks

Fleury-Milfort, Evelyne. (2007). Practical Strategies to improve treatment of type 2 diabetes. Journal of the American Academy of Nurse Practitioners, 20: 295-304.

55% of practitioners delay until absolutely necessary due to:~Fear of hypoglycemia & weight gain~More complicated and time consuming

PIR: DAWN study:5000 DM pts, 3000 HCPs- >1/2 pts not using insulin worry about the time to start & >1/2 view the start as personal failureLigthelm, R., Davidson, J. (2008). Initiating insulin in primary care- The role of modern premixed

formulations. Primary Care Diabetes 2: 9-16. Study published in Diabetes Educator found 50-77% of

pts admitted to feelings of failure vs 35% with fear of injectionsLarkin, M., Capasso, V., Chen, C., et al. (2008). Measuring Psychological Insulin Resistance. The Diabetes Educator, 34: 511-517.

Long term benefits outweigh Newer insulin analogues are safer,

simpler, better approximated to physiologic/endogenous insulin secretion, minimal weight gain

Smaller, more user-friendly needles Diabetes Education!

Ultimate Goal for Outcome

Reducing glucose toxicity Minimizing complications Preventing m & m by improving CV profile Limiting healthcare costs Improving QOL

References Brunton, S., Tenzer-Iglesias, P., Unger, J. (2008). Initiating and intensifying therapy in

type 2 Diabetes. The Journal of Family Practice, 57, S17-26. Fleury-Milfort, Evelyne. (2007). Practical Strategies to improve treatment of type 2

diabetes. Journal of the American Academy of Nurse Practitioners, 20: 295-304. Larkin, M., Capasso, V., Chen, C., et al. (2008). Measuring Psychological Insulin

Resistance. The Diabetes Educator, 34: 511-517. Ligthelm, R., Davidson, J. (2008). Initiating insulin in primary care- The role of modern

premixed formulations. Primary Care Diabetes 2: 9-16. Meneghini, L. (2007). Why and How to Use Insulin Therapy Earlier in the

Management of Type 2 Diabetes. Southern Medical Association, 100: 164-173. Rubino, A., McQuay, L., Gought, C., et al. (2007). Delayed initiation of subcutaneous

insulin therapy after failure of oral glucose-lowering agents in patients with Type 2 Diabetes. Diabetic Medicine, 24: 1412-1418.

Skyler, J., Bergenstal, R., Bonow, R., et al. (2008). Intensive Glycemic Control and the Prevention of Cardiovascular Events. Journal of the American College of Cardiology, 53: 298-304.

Tibaldi, J. (2008). Preserving Insulin Secretion in type 2 Diabetes Mellitus. Expert Review of Endocrinology & Metabolism : Medscape, 3(2): 147-159.Vinik, Aaron. (2007). Advancing Therapy in Type 2 DM with Early, Comprehensive Progression from OA to Insulin Therapy. Clinical Therapeutics, 29: 1236-1253.