Use of insulin in Type 2 Diabetes When oral Therapy Fails

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					Use of insulin in Type 2 Diabetes: When oral Therapy Fails
Nataša Janičić, MD, PhD

Assistant Professor Georgetown University Hospital

DM Trends Among Adults in the United States, 1991 and 2001
1991 2001

No Data

<4%

4%-6%

7%-8%

9%-10%

>10%

Adapted from Mokdad AH et al. JAMA. 2003;289:76-79.

Burden of Diabetes in the U.S.
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Affects more than 17 million persons Increases the risk of heart attack & stroke > 3fold

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Leading cause of new blindness, end stage renal disease, and amputation
17% of all deaths after age 25

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Costs $100 billion per year 15% of all hospital admissions

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Related to our society’s
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 Obesity  Age  Growth of ethnic populations with high prevalence  Physical activity

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Treatment Strategies for Diabetes: Are Patients Achieving Good Control?
Hypertension BP <140/90 mm Hg
Hyperlipidemia LDL-C <130 mg/dL Diabetes A1C <7.0

41%
59%

41% 59%
58%

42%

Controlled Uncontrolled
Harris MI et al. Diabetes Care. 2000;23:754

Criteria for Diagnosis of Diabetes1
Normoglycemia
• FPG <100 mg/dL


Prediabetes2 (IFG or IGT)
IFG: FPG 100 and <126 mg/dL IGT: 2-hr PG† 140 and <200 mg/dL • • • •

Diabetes*
FPG 126 mg/dL 2-hr PG† 200 mg/dL Symptoms of diabetes and casual PG concentration 200 mg/dL

• 2-hr PG† <140 mg/dL


1ADA.

Diabetes Care. 2002;25(suppl 1):S5 2ADA/NIDDKD. Diabetes Care. 2002;25:742

Natural History of Type 2 Diabetes
350 300 250 200 150 100 50

Glucose (mg/dL)

PPPG

Fasting glucose

Relative -Cell Function (%)

250 200 150 100 50 0

Insulin resistance -cell failure –10 –5 0
Insulin level

5 10 15 20 25 30 Diabetes (yr)

T2DM Is Characterized by Insulin Deficiency and Insulin Resistance
Inherited/Acquired Factors

Overweight, Inactivity (Inherited/Acquired)  FFA

Insulin Deficiency

Insulin Resistance

Glucolipotoxicity

 Glucose Uptake  Production of Glucose in the Liver

Hyperglycemia T2DM
FFA indicates free fatty acid.
Adapted from Yki-Järvinen H. In: Textbook of Diabetes 1. 3rd ed. Oxford, UK: Blackwell; 2003:22.122.19.

Diabetic Complications
Microvascular Complications
Diabetic Retinopathy

Macrovascular Complications
Stroke

Diabetic Nephropathy

Heart Disease

Diabetic Neuropathy
Peripheral Vascular Disease

Harris MI. Clin Invest Med 1995;18:231-239
Nelson RG et al. Adv Nephrol Necker Hosp 1995;24:145-156

World Health Organization, 2002;Fact Sheet N° 138

UKPDS: Lessons Learned
• Sulfonylureas, insulin, and metformin provide similar glucose lowering and efficacy – All reduce risk of complications
• Combination therapy (using agents with different actions) may be needed early in course of disease • Progressive loss of -cell function suggests that early, more aggressive insulin therapy may be necessary

Therapy for Type 2 Diabetes: Sites of Action Pancreas
Impaired insulin = Insulin deficiency secretion
Exogenous insulin Rx Sulfonylurea Meglitinide Acarbose Miglitol

Gut
Carbohydrate metabolism

Hyperglycemia

Liver
HGP
Metformin

Muscle
Glucose Insulin = resistance uptake
Rosiglitazone
Pioglitazone

Davis SN. Postgrad Med. 2000;16

Oral Meds for Type 2 DM
Drug
Sulfonylureas Metformin Acarbose TZD’s

Weight

Risk for Hypo

Yes No __ No No

A1c Change % 1.5

1.5 0.75 1-2

Oral Diabetic Agents


Metformin  GI side effects, Lactic Acidosis  Contraindicated in Renal Insufficiency (Cr > 1,5 mg/dl) Sulfonylureas  Hypoglycemia Glitazones  Action to slow  Can cause or exacerbate heart failure and pulmonary edema. Should be avoided in patients with left ventricular dysfunction.

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Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A consensus statement from the ADA and the European Association for the study of Diabetes. Nathan et al. Diabetes Care 29:1963-1972, 2006.

Insulin
The most powerful agent to control blood glucose

Barriers to Insulin Therapy
Practical Limitations of Conventional Tactics


Need to mix and inject insulins


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Complexity of starting insulin therapy
Limitations of various insulin preparations Physician and patient concerns about hypoglycemia

Physician and patient concerns about weight gain

Korytkowski M. Int J Obes Relat Metab Disord. 2002;26(suppl 3):S18

Transition from oral to insulin therapy
 

Continue one or two oral agents and start basal insulin Start 10 units of Lantus and increase every 3 days based on FBG Advantages: 1 injection with no mixing
Slow, safe, and simple titration

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Low dosage Limited weight gain Effective improvement in glycemic control

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The Treat-To-Target Trial
CONCLUSIONS




Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA1C in a majority of overweight patients with DM2 with HbA1C between 7.5 and 10% on oral agents alone. Glargine causes significantly less nocturnal hypoglycemia than NPH.

Diabetes Care26:3080-3086,2003.

New and Emerging Therapies
  
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Inhaled insulin (Exubera) Insulin Detemir (Levemir) Exenatide (Byetta) Pramlintide acetate (Symlin) Rimonabant- cannabinoid receptor (CB1) antagonist

Exenatide is synthetic Exendin-4 A Salivary Gland Hormone in the Gila Monster

Heloderma suspectum

Exenatide (GLP-1 Analogue) as alternative to Insulin Tx


Enhances glucose-dependent insulin secretion Suppresses postprandial glucagon secretion Delays gastric emptying



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Reduces food intake Reduces A1c ~ 0.8 point



Kendall et al Diab Care 28:1083-91, 2005 Defronzo et al Diab Care 28:1092-1100, 2005

Amylin


 

37–amino acid peptide cosecreted together with insulin from islet ß-cells Pramlintide (Symilin) - synthetic amylin analog

Pramlintide has been approved for treatment of type 1 and insulin-requiring type 2 diabetes Injection 15 min before meals Slows gastric emptying, suppresses plasma levels of glucagon, increases satiety, reduces appetite and blunts postprandial hyperglycemia

 

ABC’s of Diabetes Management
Glycemic control A1C Preprandial plasma glucose
Blood pressure Lipids

<7.0%* 90-130 mg/dl (5.0-7.2 mmol/l)
<130/80 mmHg

Postprandial plasma glucose <180 mg/dl (<10.0 mmol/l)

LDL-Cholesterol Triglycerides HDL
Antiplatelet therapy Smoking cessation
Diabetes Care 26:s35, 2003

<100 mg/dl (<2.6 mmol/l) <150 mg/dl (<1.7 mmol/l) >40 mg/dl (>1.1 mmol/l)

Summary: Be Aggressive


The majority of patients will require combination therapy to control the dual defect of insulin deficiency and insulin resistance Improved glycemic control can reduce microvascular and macrovascular outcomes A1C levels consistently >7% indicate patient may benefit from insulin therapy
Timely initiation of insulin optimizes blood glucose and improves prognosis

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Over time, most patients will need insulin to achieve and sustain glycemic targets

Borderline Diabetes

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Risk factors for type 2 diabetes · Age ≥45 years · Overweight (BMI ≥25 kg/m2*) · Family history of diabetes · Physical inactivity · Race/ethnicity · Previously identified IFG/IGT · History of GDM or delivery of baby >9 lbs · Hypertension (≥40/90 mmHg) · HDL-C ≤35 mg/dL and/or triglyceride level ≥250 mg/dL · Polycystic ovarian disease · History of vascular disease


				
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