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Use of insulin in Type 2 Diabetes: When oral Therapy Fails

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Title: Use of insulin in Type 2 Diabetes: When oral Therapy Fails


1
Use of insulin in Type 2 DiabetesWhen oral
Therapy Fails
  • Nataa Janicic, MD, PhD
  • Assistant Professor
  • Georgetown University Hospital

2
(No Transcript)
3
Burden of Diabetes in the U.S.
  • Affects more than 17 million persons
  • Increases the risk of heart attack stroke gt
    3-fold
  • Leading cause of new blindness, end stage renal
    disease, and amputation
  • 17 of all deaths after age 25
  • Costs 100 billion per year
  • 15 of all hospital admissions

4
  • Related to our societys
  • ? Obesity
  • ? Age
  • ? Growth of ethnic populations with high
    prevalence
  • ? Physical activity

5
Treatment Strategies for DiabetesAre Patients
Achieving Good Control?
Diabetes
Hypertension
Hyperlipidemia
BP lt140/90 mm Hg
LDL-C lt130 mg/dL
A1C lt7.0
41
41
42
58
59
59
Controlled
Uncontrolled
Harris MI et al. Diabetes Care. 200023754
6
Criteria for Diagnosis of Diabetes1
Prediabetes2 (IFG or IGT)
Normoglycemia
Diabetes
  • IFG FPG ?100 and
  • lt126 mg/dL
  • IGT 2-hr PG ?140
  • and lt200 mg/dL
  • FPG ?126 mg/dL
  • 2-hr PG ?200 mg/dL
  • Symptoms of
  • diabetes and casual
  • PG concentration ?200 mg/dL
  • FPG lt100 mg/dL
  • 2-hr PG lt140 mg/dL

1ADA. Diabetes Care. 200225(suppl
1)S52ADA/NIDDKD. Diabetes Care. 200225742
7
Natural History of Type 2 Diabetes
350
300
PPPG
250
Glucose(mg/dL)
Fasting glucose
200
150
100
50
250
Insulin resistance
200
Relative ?-Cell Function ()
150
100
Insulin level
50
?-cell failure
0
15
20
25
30
10
0
5
10
5
Diabetes (yr)
8
T2DM Is Characterized by Insulin Deficiency and
Insulin Resistance
Overweight, Inactivity (Inherited/Acquired)
Inherited/Acquired Factors
Insulin Deficiency
Insulin Resistance
? FFA
Gluco-lipotoxicity
? GlucoseUptake
? 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 200322.1?22.19.
9
Diabetic Complications
Macrovascular Complications
Microvascular Complications
Diabetic Retinopathy
Stroke
Diabetic Nephropathy
Heart Disease
Diabetic Neuropathy
Peripheral Vascular Disease
Harris MI. Clin Invest Med 199518231-239 Nelson
RG et al. Adv Nephrol Necker Hosp
199524145-156 World Health Organization,
2002Fact Sheet N 138
10
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

11
Therapy for Type 2 Diabetes Sites of Action
Pancreas
Gut
Impaired insulin secretion
Insulin deficiency
Carbohydrate metabolism

Acarbose
Exogenous insulin Rx
Miglitol
Sulfonylurea
Meglitinide
Hyperglycemia
Liver
Muscle
Glucose uptake
Insulin resistance

HGP
Rosiglitazone
Metformin
Pioglitazone
Davis SN. Postgrad Med. 200016
12
Oral Meds for Type 2 DM
13
Oral Diabetic Agents
  • Metformin
  • GI side effects, Lactic Acidosis
  • Contraindicated in Renal Insufficiency (Cr gt 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.

14
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
291963-1972, 2006.
15
Insulin
  • The
  • most powerful agent
  • to control blood glucose

16
Barriers to Insulin Therapy
Practical Limitations of Conventional Tactics
  • Need to mix and inject insulins
  • 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.
200226(suppl 3)S18
17
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
  • Low dosage
  • Limited weight gain
  • Effective improvement in glycemic control

18
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 Care263080-3086,2003.
19
New and Emerging Therapies
  • Inhaled insulin (Exubera)
  • Insulin Detemir (Levemir)
  • Exenatide (Byetta)
  • Pramlintide acetate (Symlin)
  • Rimonabant- cannabinoid receptor (CB1) antagonist

20
Exenatide is synthetic Exendin-4A Salivary Gland
Hormonein the Gila Monster
Heloderma suspectum
21
Exenatide (GLP-1 Analogue) as alternative to
Insulin Tx
  • Enhances glucose-dependent insulin secretion
  • Suppresses postprandial glucagon secretion
  • Delays gastric emptying
  • Reduces food intake
  • Reduces A1c 0.8 point

Kendall et al Diab Care 281083-91, 2005
Defronzo et al Diab Care 281092-1100, 2005
22
Amylin
  • 37amino 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

23
ABCs of Diabetes Management
Diabetes Care 26s35, 2003
24
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 gt7 indicate patient may
    benefit from insulin therapy
  • Timely initiation of insulin optimizes blood
    glucose and improves prognosis
  • Over time, most patients will need insulin to
    achieve and sustain glycemic targets

25
Borderline Diabetes
26
  • 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 gt9 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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