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Earlier Initiation of Insulin Treatment in Type 2 Diabetes Mellitus

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Review management of Type 2 DM and goals of therapy. Review evidence of beneficial effect of early ... DeWitt DE, Hirsch IB. JAMA. 2003;289:2254-2264. ... – PowerPoint PPT presentation

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Title: Earlier Initiation of Insulin Treatment in Type 2 Diabetes Mellitus


1
Earlier Initiation of Insulin Treatment inType
2 Diabetes Mellitus
  • P. J. Palumbo, MD, MACP, MACE Professor of
    MedicineMayo Clinic College of Medicine Mayo
    Clinic, Scottsdale, Arizona

2
DISCLOSURE
  • Relevant Financial Relationship(s)
  • None
  • Off Label Usage
  • None

3
Educational Objectives
  • Review management of Type 2 DM and goals of
    therapy
  • Review evidence of beneficial effect of early
    initiation of insulin treatment in Type 2 DM

4
Characteristics of Type 2 Diabetes Overview
  • Absolute or relative insulin deficiency
  • Impaired beta cell function
  • Insulin resistance
  • Twin components
  • Fasting hyperglycemia
  • Postprandial hyperglycemia
  • Associated disturbances
  • Hypertension
  • Fasting and postprandial dyslipdemia
  • Atherothrombotic changes

Over time, manypatients requireinsulin
Different agents maybe needed to treatboth
aspects
Multipleinterventionsmay be required
5
Type 2 Diabetes Pathogenesis in a Nutshell
6
Type 2 Diabetes Pathogenesis in a Nutshell
(cont.)
7
Potential Causes for Falling Insulin Secretion
Glucolipotoxicity
8
Potential Causes for Falling Insulin Secretion
Glucolipotoxicity (cont.)
9
Increased Insulin Secretion Following Elimination
of Glucotoxicity
10
Matching Pharmacology to Pathophysiology
11
Multi-Hormonal Regulation of Glucose Homeostasis
Brain
Liver
Stomach
Rate ofglucoseappearance
PostprandialGlucagon
Gastric Emptying
Plasma Glucose
Amylin
Rate ofglucosedisappearance
Pancreas
GlucoseDisposal
Gut
Insulin
Tissues
GLP-1
Inferred from animal studies
Reported in rodents
12
Timeline for Utilization of Therapies
13
Antihyperglycemic Agents forType 2 Diabetes
  • Class Available Agents
  • ?-Glucosidase inhibitor Acarbose, miglitol
  • Thiazolidinedione Pioglitazone,
    rosiglitazone
  • Biguanide Metformin
  • Meglitinide Repaglinide, nateglinide
  • Sulfonylurea Glimepiride, glipizide,
  • Amylin Pramlintide
  • Incretins Exenatide
  • DPP-4 inhibitors Sitagliptin, Vildagliptin
  • Insulin Many preparations

14
Therapeutic Options for Managing Type 2 DM
  • Postprandial and HbA1c
  • Regular insulin/insulin analogs
  • Alpha-glucosidase inhibitors (AGI)
  • Meglitinides
  • Amylin
  • Incretins, DPP IV inhibitors
  • Fasting and HbA1c
  • Sulfonylureas (SU)
  • Biguanides
  • Thiazolidinediones (TZD)
  • Incretins, DPP IV inhibitors
  • Intermediate/long acting insulin/insulin analogs

15
Treatment Strategies for Post-Prandial
Hyperglycemia
  • Rapid-acting insulin secretogogue with meals
  • Combination rapid-acting insulin
    secretogogue/sulfonylurea with biguanide or
    thiazolidinedione (fixed combinations)
  • Combination daytime oral agent with evening
  • insulin or with inhaled insulin with meals
  • Incretin therapy/DPP-4 inhibitor
  • Amylin/insulin therapy
  • Basal/bolus insulin therapy
  • Continuous subcutaneous insulin therapy (pump
    therapy)

16
ADA Algorithm for Management of Type 2 DM
  • Tier 1 Well-validated core therapies
  • Step 1 Initial therapy
  • Lifestylemetformin
  • Step 2 Additional therapy
  • Insulin
  • Sulfonylurea

17
ADA Algorithm for Management of Type 2 DM
  • Tier 2 Step 2
  • Less well-validated therapies
  • Thiazolidenediones
  • GLP-1 agonist
  • Other therapy
  • Alpha-glucosidase
    inhibitor
  • Glinide
  • Pramlinitide
  • DPP-4 inhibitor

18
ADA Algorithm for managementof Type 2 DM
  • Tier 2 Step 3
  • Intensive insulin therapy

19
A1C Targets Suggested by Different Organizations

Optimal target A1C lt6 (normal range)
  • AACE target A1C lt6.5
  • EASD target A1C lt6.5
  • ADA target A1C lt7 (general) A1C lt6
    (individual patient)

As close to normal (lt6) without significant
hypoglycemia. ADA American Diabetes
Association EASD European Association for the
Study of Diabetes.
20
No A1c Threshold in Type 2 Diabetes
80
Epidemiologic Data From the UKPDS
Myocardial Infarction
Microvascular End Points
60
Adjusted Incidence per 1000Person Years ()
40
20
0
5
6
7
8
9
10
11
Updated Mean A1c ()
Stratton IM, et al. BMJ. 2000321405-412.
21
Case Study 1
  • 45 year old woman
  • Presents with fatigue
  • No prior medical problems
  • Family history of DM
  • Height 160 cm (63 in)
  • Weight 74 kg (165 lbs)
  • Blood pressure 130/85
  • Remainder of the examination -unremarkable

22
Case Study 1
  • Laboratory studies
  • FPG 135, 142 mg/dL
  • HBA1C 7.3
  • Total Cholesterol 200 mg/dL
  • Total Triglycerides 250 mg/dL
  • HDL-Cholesterol 30 mg/dL
  • LDL-Cholesterol 120 mg/dL
  • Initial treatment?

23
Case Study 2
  • 45 year old man
  • Referred for diabetes management
  • Known type 2 DM for past 5 years
  • Treatment
  • Metaglip 5/500mg twice daily
  • Rosiglitazone 4 mg twice daily

24
Case Study 2
  • Height 175 cm (69 in)
  • Weight 75 Kg (176 lbs)
  • Blood pressure 124/82 mmHg
  • Remainder of examination -unremarkable

25
Case Study 2
  • Laboratory studies
  • FPG 185 mg/dL
  • HBA1C 7.5
  • Total Cholesterol 212 mg/dL
  • Total Triglycerides 185 mg/dL
  • HDL-Cholesterol 40 mg/dL
  • LDL-Cholesterol 135 mg/dL
  • Modification of treatment?

26
A1C reduction with glucose-lowering medications
Monotherapy DPP dipeptidyl peptidase GLP
glucagon-like peptide
Nathan DM. N Engl J Med. 2007356437-40.
27
Oral diabetes agents
Trujillo J. Formulary. 2006. Luna B, Feinglos MN.
Am Fam Physician. 2001. Smyth S, Heron A. Nat
Med. 2006.
28
Incretin agents in glucose control
GIP gastric inhibitory peptide
Trujillo J. Formulary. 200641130-41.
29
Efficacy of Oral AntihyperglycemicsDeclines With
Time
  • A1C rises at 0.2 to 0.3 yearly on stable
    therapy
  • This rate is the same as for diet alone,
    sulfonylureas, and metformin
  • ?-Cell function declines at the same rate with
    all these treatments
  • Recent studies suggest longer preservation of
    beta cell function with thiazolidinediones
    (Tripod/Pipod)
  • Combination treatments are routinely needed

UKPDS Group. Diabetes. 1995441249-1258 Turner
RC et al. JAMA. 19992812005-2012
30
ADOPT Cumulative Incidence of Monotherapy
Failure (FPG gt180 mg/dL)
Kahn SE, et al. N Engl J Med. 20063552427-2443.
31
UKPDS 33 Glycemic control declines over time
N 3867 with newly diagnosed T2DM
9 8 7 6 0
A1C, median ()
ADA target
6.2 (upper limit of normal)
0 3 6
9 12 15
Years from randomization
Diet (conventional treatment)
Sulfonylurea or insulin (intensive treatment)
UKPDS Group. Lancet. 1998352837-53.
32
Glycemic control deteriorates with standard
therapies
N 2220 with T2DM treated with SU MET
Pre-SU A1C levels ()
100
10 9.0-9.9 8.0-8.9 4.0-7.9
80
Patients withA1C 8 ()
60
  • 85 of patients had A1C 8 after 4 years

40
20
0
0
1
2
3
4
Time from sulfonylurea initiation (years)
SU sulfonylurea, MET metformin
Cook MN et al. Diabetes Care. 200528995-1000.
33
Need for insulin increases over time
UKPDS 57 N 826 with newly diagnosed T2DM
60
40
Patients requiring additional insulin ()
20
0
1
2
3
4
5
6
Years from randomization
Chlorpropamide
Glipizide
53 of patients required additional insulin
therapy by year 6
Wright A et al. Diabetes Care. 200225330-6.
34
Insulin Therapy In Type 2 Diabetes Mellitus
  • Non-obese patients may have islet cell/insulin
    antibodies
  • Non-obese patients more likely to require
    insulin
  • Start insulin therapy earlier in non-obese
    patients
  • Insulin therapy reduces glucose
    toxicity/lipotoxicity

35
Insulin Therapy for Type 2 Diabetes Mellitus
36
Indications for Insulin Therapy in Patients With
Type 2 Diabetes
  • Hyperglycemia despite optimal oral therapy (A1C
    gt8)
  • Decompensation
  • Injury, stress, illness
  • Severe hyperglycemia with ketonemia/ketonuria
  • Uncontrolled weight loss
  • Surgery
  • Gestational diabetes
  • Hypersensitivity to oral agents
  • Diabetes associated with certain
    conditions/syndromes (eg, pancreatic diabetes,
    drug- or chemical-induced diabetes,
    endocrinopathies, insulin-receptor disorders,
    some genetic syndromes)

American Diabetes Association. Diabetes Care.
200326(suppl 1)S121-S125. DeWitt DE, Hirsch IB.
JAMA. 20032892254-2264.
37
Initiated Treatment by Glycemic Level in Type 2
Diabetes
Market Measures, Inc. The Management of Diabetes,
Study XIII. Sept 1997.
38
Early Insulin Treatment inType 2 DM
  • Improves glycemic control and reduces
    glucotoxicity and lipotoxicity
  • May preserve ?-cell function/delay ?-cell failure
  • Restores near-normal insulin response to meals
  • Decreases insulin resistance
  • Maintains long term beneficial effect on
    decreasing comorbidities
  • Improves survivorship

39
Mean Glucose Hemoglobin A1C and Insulin Levels
After 2 Weeks of CSII in New Type 2 DM
(n-9)Follow up at 6 months on diet aloneMean
27/-1 17 (SE) months
  • Before After P value
  • FBG mmol/L 11.6 6.6 0.01
  • 2 hr PP BG mmol/L 16.7 7.4 0.001
  • FPI pmol/L 155 201 NS
  • 2 hr PP insulin pmol/L 252 453 NS
  • Hemoglobin A1C 11.2 6.1 0.0001
  • CSII continuous subcutaneous insulin infusion
  • FPG fasting blood glucose
  • 2 hr ppBG 2 hour postprandial blood glucose
  • FPI fasting plasma insulin
  • 2 hr pp insulin 2 hour postprandial insulin

Ilkava, et al. Diabetes Care 1997 201353-1356.
40
Intensive Insulin Therapy After MIReduces
Mortality DIGAMI Study
Malmberg K. BMJ. 19973141512-1515
41
63 of Patients with Diabetes Not at ADA A1c
Goal lt7
  • Only 7 of adults with diabetes in NHANES
    1999-2000 attained
  • A1c level lt7
  • Blood pressure lt130/80 mm Hg
  • Total cholesterol lt200 mg/dL

Adults aged 20-74 years with previously diagnosed
diabetes who participated in the interview and
examination components of the National Health
Examination Survey (NHANES), 1999-2000. Saydah SH
et al. JAMA. 2004291335-342.
42
SummaryInsulin Therapy
  • Replaces complete lack of insulin in type 1
    diabetes
  • Supplements progressive deficiency in type 2
    diabetes
  • Basal insulin added to oral agents can be used to
    start
  • Full replacement requires a basal-bolus regimen
  • Hypoglycemia and weight gain are the main medical
    risks
  • New insulin analogues and injection devices
    facilitate use

43
Is Insulin Atherogenic?
  • Endogenous hyperinsulinemia is a marker for
    insulin resistance
  • Exogenous insulin therapy has not been shown to
    be associated with cardiovascular events (unless
    related to suboptimal glycemic control)
  • University Group Diabetes Program (UDGP)
  • United Kingdom Prevention of Diabetes Study
    (UKPDS)
  • Diabetes Control and Complications Trial (EDIC)
  • Kumomoto Study
  • VADT
  • ACCORD

44
Barriers to Using Insulin
  • Patient resistance
  • Perceived significance of needing insulin
  • Fear of injections
  • Complexity of regimens
  • Pain, lipohypertrophy
  • Physician resistance
  • Perceived cardiovascular risks
  • Lack of time and resources to supervise treatment
  • Medical limitations of insulin treatment
  • Hypoglycemia
  • Weight gain

45
Dispelling misconceptions about insulin
  • Traditional thinking
  • Atherogenic
  • Fear of hypoglycemia
  • Fear of weight gain
  • Frequent injections
  • Newer concepts
  • Anti-atherogenic
  • Less nocturnal hypoglycemia with steady-state
    once-daily basal insulins
  • Weight neutral
  • Long-acting basal insulins require fewer
    injections

Dandona P et al. Am J Cardiol. 200799(suppl)15B-
26. Stotland NL. Insulin. 2006138-45.
46
Insulin Delivery Systems
  • DeWitt DE, Hirsch IB. JAMA. 20032892254-2264.
  • American Diabetes Association. Diabetes Care.
    200326(suppl 1)S121-S125.

47
Insulin Therapy In Type 2 Diabetes Mellitus
  • Carbohydrate counting
  • Establish insulin/carbohydrate ratio
  • 1 unit for 10-15 grams carbohydrate
  • Balanced calorie controlled diet
  • 50 carbohydrate (complex/fiber)
  • 30 fat (35 if monosaturated fat is increased)
  • 20 protein
  • Regular exercise

48
Mimicking Nature with Insulin Therapy
Basal/Bolus Insulin Concept
  • Basal insulin
  • Suppresses glucose production between meals and
    overnight
  • Nearly constant levels
  • 50 of daily needs
  • Bolus insulin (mealtime or Prandial)
  • Limits hyperglycemia after meals
  • Immediate rise and sharp peak at one hour
  • 10 to 20 of total daily insulin requirement at
    each meal
  • Ideally, for insulin replacement therapy, each
    component should come from a different insulin
    with a specific profile

49
Basal-Bolus Insulin Treatmentwith Insulin
Analogues
Bbreakfast Llunch Ddinner
50
Basal and bolus insulin pharmacodynamics
Basal
Bolus
RHI regular human insulin
Flood TM. J Fam Practice. 200756(suppl)S1-12.
51
Treat-to-Target Nocturnal hypoglycemia vs
glycemic control
Riddle MC et al. Diabetes Care. 2003263080?6.
52
UKPDS 10-Year Follow-up5-Year Post-Trial
(1997-2002) N3277
  • A1c differences lost after first year post-trial
  • SU-INS group risk reduction
  • Any diabetes-related end point 9 (.04)
    Microvascular disease 24 (.001)
    MI
    15
    (0.01) Death from any cause 13
    (0.007)
  • SU-INSSulfonylurea-Insulin P value
  • N Eng J Med 2008 3591577-1589

53
Summary Earlier Initiation of Insulin Treatment
in Type 2 DM
  • Improves glycemic control and reduces
    glucotoxicity and lipotoxicity
  • May preserve ?-cell function/delay ?-cell failure
  • Restores near-normal insulin response to meals
  • Decreases insulin resistance
  • Maintains long term beneficial effect on
    decreasing comorbidities
  • Improves survivorship

54
Selected References
  • Palumbo PJ. Glycemic Control, Mealtime Glucose
    Excursions and Diabetic Complications in Type 2
    Diabetes Mellitus. Mayo Clin Proc 2001
    76609-618.
  • Chan JL, Abrahamson MS. Pharmacological
    Management of Type 2 Diabetes Mellitus Rationale
    for Rational Use of Insulin. Mayo Clin Proc 2003
    78 459-467.
  • Zangeneh F, Kodva YC, Basu A. Insulin Senstizers.
    Mayo Clin Proc 2003 78 471-479.
  • Palumbo PJ. The Case for Insulin Treatment Early
    in Type 2 Diabetes. Cleveland Clinic J Med 2004
    71 385-405
  • Nelson SE, Palumbo PJ. Addition of Insulin to
    Oral Therapy in Patients with Type 2 Diabetes. Am
    J Med Sci 2006 331257-263
  • Hoogwerf BJ. Exenatide and Pramlintide New
    Glucose Lowering Agents for Treating Diabetes
    Mellitus. Cleveland Clinic J Med 2006 72
    477-484
  • Nathan D. Finding New Treatments for DiabetesHow
    Many, How FastHow Good? N Eng J Med 2007
    356437-440
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