Slide 1 - Mayo Clinic: Medical Education and Research

PJP043004

Earlier Initiation of Insulin Treatment in

Type 2 Diabetes Mellitus

Earlier Initiation of Insulin Treatment in

Type 2 Diabetes Mellitus

P. J. Palumbo, MD, MACP, MACE Professor of Medicine

Mayo Clinic College of Medicine Mayo Clinic, Scottsdale, Arizona

P. J. Palumbo, MD, MACP, MACE Professor of Medicine

Mayo Clinic College of Medicine Mayo Clinic, Scottsdale, Arizona

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DISCLOSUREDISCLOSURE

Relevant Financial Relationship(s) None

Off Label UsageNone

Relevant Financial Relationship(s) None

Off Label UsageNone

Educational Objectives 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

• 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

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Characteristics of Type 2 Diabetes: OverviewCharacteristics 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

• 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 require

insulin

Over time, manypatients require

insulin

Different agents maybe needed to treat

both aspects

Different agents maybe needed to treat

both aspects

Multipleinterventions

may be required

Multipleinterventions

may be required

Type 2 Diabetes: Pathogenesis in a Nutshell

Type 2 Diabetes: Pathogenesis in a Nutshell (cont.)

Potential Causes for Falling Insulin Secretion: Glucolipotoxicity

Potential Causes for Falling Insulin Secretion: Glucolipotoxicity (cont.)

Increased Insulin Secretion Following Elimination of Glucotoxicity

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Matching Pharmacology to Pathophysiology

Matching Pharmacology to Pathophysiology

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Plasma Glucose

PostprandialGlucagonPostprandialGlucagon

Tissues

Liver

GastricEmptyingGastricEmptying

InsulinInsulinPancreas

Rate ofglucose

appearance

Rate ofglucose

appearance

Rate ofglucose

disappearance

Rate ofglucose

disappearance

AmylinAmylin

FoodIntake**FoodIntake**

Satiety *Satiety *

Stomach

Brain

GLP-1GLP-1

GutGut

Multi-Hormonal Regulation of Glucose Homeostasis

Multi-Hormonal Regulation of Glucose Homeostasis

** Reported in rodents* Inferred from animal studies

GlucoseDisposalGlucoseDisposal

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Timeline for Utilization of TherapiesTimeline for Utilization of Therapies

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Antihyperglycemic Agents forType 2 Diabetes

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

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

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Therapeutic Options for Managing Type 2 DM

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)


- Intermediate/long acting insulin/insulin analogs

• Postprandial and HbA1c

- Regular insulin/insulin analogs

- Alpha-glucosidase inhibitors (AGI)

- Meglitinides

- Amylin


• Fasting and HbA1c

- Sulfonylureas (SU)

- Biguanides

- Thiazolidinediones (TZD)


- Intermediate/long acting insulin/insulin analogs

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Treatment Strategies for Post-Prandial Hyperglycemia

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)

• 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)

ADA Algorithm for Management ADA Algorithm for Management of Type 2 DMof Type 2 DM

Tier 1 : Well-validated core therapiesTier 1 : Well-validated core therapies

Step 1: Initial therapyStep 1: Initial therapy

Lifestyle+metforminLifestyle+metformin

Step 2: Additional therapyStep 2: Additional therapy

InsulinInsulin

SulfonylureaSulfonylurea

ADA Algorithm for Management ADA Algorithm for Management of Type 2 DMof Type 2 DM

Tier 2: Step 2Tier 2: Step 2 Less well-validated therapiesLess well-validated therapies ThiazolidenedionesThiazolidenediones GLP-1 agonistGLP-1 agonist Other therapy:Other therapy: Alpha-glucosidase inhibitorAlpha-glucosidase inhibitor GlinideGlinide PramlinitidePramlinitide DPP-4 inhibitorDPP-4 inhibitor

ADA Algorithm for managementADA Algorithm for managementof Type 2 DMof Type 2 DM

Tier 2: Step 3Tier 2: Step 3

Intensive insulin therapyIntensive insulin therapy

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A1C Targets Suggested

by Different Organizations A1C Targets Suggested

by Different Organizations

• AACE target: A1C <6.5%

• EASD target: A1C <6.5%

• ADA target: A1C <7% (general) A1C <6%* (individual

patient)

• AACE target: A1C <6.5%

• EASD target: A1C <6.5%

• ADA target: A1C <7% (general) A1C <6%* (individual

patient)

Optimal target: A1C <6% (normal range)

*As close to normal (<6%) without significant hypoglycemia.

ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes.

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No A1c Threshold in Type 2 Diabetes

Ad

just

ed I

nci

den

ce p

er 1

000

Per

son

Yea

rs (

%)

Stratton IM, et al. BMJ. 2000;321:405-412.

Epidemiologic Data From the UKPDS

Updated Mean A1c (%)

40

60

80

20

0

5 6 7 8 9 10 11

Myocardial Infarction

Microvascular End Points

ADA Goal

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Case Study 1Case 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

• 45 year old woman

• Presents with fatigue

• No prior medical problems

• Family history of DM


• Weight 74 kg (165 lbs)

• Blood pressure 130/85

• Remainder of the examination -unremarkable

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• 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?

• 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?

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• 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

• 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

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• Weight 75 Kg (176 lbs)

• Blood pressure 124/82 mmHg

• Remainder of examination -unremarkable


• Weight 75 Kg (176 lbs)

• Blood pressure 124/82 mmHg

• Remainder of examination -unremarkable

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• 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?

• 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?

A1C reduction with glucose-lowering medications

Nathan DM. N Engl J Med. 2007;356:437-40.

Oral agents A1C (%)*

Sulfonylureas 1.5

Biguanides (metformin) 1.5

Glinides 1.0–1.5

Thiazolidinediones 0.8–1.0

DPP-IV inhibitors 0.5–0.9

α-Glucosidase inhibitors 0.5–0.8

Parenteral/inhaled agents

Insulin ≥2.5

Inhaled insulin 1.5

GLP analogues 0.6

Amylin analogues 0.6

*MonotherapyDPP = dipeptidyl peptidase; GLP = glucagon-like peptide

Oral diabetes agents

Drug class Agent(s) Mechanism(s) of action

α-Glucosidase inhibitors

Acarbose, miglitol Delay carbohydrate absorption

Biguanides Metformin Hepatic glucose production Insulin sensitivity in liver + muscle

Sulfonylureas Glimepiride, glipizide, glyburide

Insulin secretion from pancreatic cells

Meglitinides Nateglinide, repaglinide

Insulin secretion from pancreatic cells

Thiazolidinediones Pioglitazone, rosiglitazone

Insulin sensitivity in fat cells + muscle

DPP-IV inhibitors Sitagliptin, vildagliptin (Phase III)

GLP-1 degradation; Glucose-dependent insulin secretion

Trujillo J. Formulary. 2006.Luna B, Feinglos MN. Am Fam Physician. 2001.

Smyth S, Heron A. Nat Med. 2006.

Incretin agents in glucose control

DPP-IV inhibitors Incretin mimetics

• Significant A1C

• Weight neutral

• Oral administration

• Almost no GI side effects

• Very low rate of hypoglycemia

• Multiple targets (GLP-1 and GIP)

• Significant A1C

• Weight loss

• Injection

• Higher rate of GI side effects

• Low rate of hypoglycemia

• Single target (GLP-1)

Trujillo J. Formulary. 2006;41:130-41.GIP = gastric inhibitory peptide

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Efficacy of Oral AntihyperglycemicsDeclines With Time

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

• 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. 1995;44:1249-1258; Turner RC et al. JAMA. 1999;281:2005-2012

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ADOPT: Cumulative Incidence of Monotherapy Failure (FPG >180 mg/dL)

ADOPT: Cumulative Incidence of Monotherapy Failure (FPG >180 mg/dL)

10781076

958

10781076

958

120712051114

120712051114

139313971337

139313971337

957950781

957950781

844818617

844818617

324311218

324311218

Patients at Risk

RosiglitazoneMetforminGlyburide

Patients at Risk

RosiglitazoneMetforminGlyburide

Time (years)Time (years)00 11 22 33 44 55

Pe

rce

nt

(%)

Pe

rce

nt

(%)

00

1010

2020

3030

4040

GlyburideGlyburide

MetforminMetformin

RosiglitazoneRosiglitazone

Rosiglitazone vs Metformin32% risk reduction, P<.001

Rosiglitazone vs Glyburide63% risk reduction, P<.001

Rosiglitazone vs Metformin32% risk reduction, P<.001

Rosiglitazone vs Glyburide63% risk reduction, P<.001

Kahn SE, et al. N Engl J Med. 2006;355:2427-2443.

UKPDS 33: Glycemic control declines over time

UKPDS Group. Lancet. 1998;352:837-53.

9

8

7

60

Years from randomization

Diet (conventional treatment) Sulfonylurea or insulin (intensive treatment)

6.2% (upper limit of normal)

0 3 6 9 12 15

ADA target

A1C, median

(%)

N = 3867 with newly diagnosed T2DM

Glycemic control deteriorates with standard therapies

Cook MN et al. Diabetes Care. 2005;28:995-1000.

N = 2220 with T2DM treated with SU + MET

≥109.0-9.98.0-8.94.0-7.9

~85% of patients had A1C ≥8% after 4 years

Patients with

A1C ≥8%(%)

SU = sulfonylurea, MET = metformin

Pre-SU A1C levels (%)100

80

60

40

20

00 1 2 3 4

Time from sulfonylurea initiation (years)

Need for insulin increases over time

Wright A et al. Diabetes Care. 2002;25:330-6.

Chlorpropamide

UKPDS 57: N = 826 with newly diagnosed T2DM

60

40

20

0

Patientsrequiring additional

insulin (%)

1 2 3 4 5 6

Glipizide

Years from randomization

~53% of patients required additional insulin therapy by year 6

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

Insulin Therapy for Type 2 Diabetes Mellitus

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Indications for Insulin Therapy in Patients With Type 2 DiabetesIndications for Insulin Therapy in Patients With Type 2 Diabetes

• Hyperglycemia despite optimal oral therapy (A1C >8%)• 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)

• Hyperglycemia despite optimal oral therapy (A1C >8%)• 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. 2003;26(suppl 1):S121-S125.DeWitt DE, Hirsch IB. JAMA. 2003;289:2254-2264.

American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S121-S125.DeWitt DE, Hirsch IB. JAMA. 2003;289:2254-2264.

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Initiated Treatment by Glycemic Level in Type 2 Diabetes

Initiated Treatment by Glycemic Level in Type 2 Diabetes

Market Measures, Inc. The Management of Diabetes, Study XIII. Sept 1997.

*Significantly higher than endocrinologists

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Early Insulin Treatment inType 2 DM

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







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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

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 0.0001CSII = continuous subcutaneous insulin infusionFPG = fasting blood glucose2 hr ppBG = 2 hour postprandial blood glucoseFPI = fasting plasma insulin2 hr pp insulin = 2 hour postprandial insulin

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 0.0001CSII = continuous subcutaneous insulin infusionFPG = fasting blood glucose2 hr ppBG = 2 hour postprandial blood glucoseFPI = fasting plasma insulin2 hr pp insulin = 2 hour postprandial insulin

Ilkava, et al. Diabetes Care 1997; 20:1353-1356.

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Malmberg K. BMJ. 1997;314:1512-1515

Intensive Insulin Therapy After MIReduces Mortality: DIGAMI Study

Intensive Insulin Therapy After MIReduces Mortality: DIGAMI Study

All SubjectsAll Subjects

N=620N=620

28% Risk Reduction28% Risk Reduction P=0.011 P=0.011

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0.7

0.6

0.5

0.4

0.3

0.2

0.1

000 11 22 33 44 55

Low-Risk and Not Previously on InsulinLow-Risk and Not Previously on Insulin

N=272N=272

51% Risk Reduction51% Risk Reduction P=0.004 P=0.004

00 11

YearsYears22 33 44 55

Mor

talit

y ra

teM

orta

lity

rate

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

YearsYears

Standard treatmentStandard treatment

IV insulin 24 hours, then 4 injections daily IV insulin 24 hours, then 4 injections daily

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63% of Patients with Diabetes Not at ADA A1c Goal <7%

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. 2004;291:335-342.

Only 7% of adults with diabetes in NHANES 1999-2000 attained:

• A1c level <7%

• Blood pressure <130/80 mm Hg

• Total cholesterol <200 mg/dL

Only 7% of adults with diabetes in NHANES 1999-2000 attained:

• A1c level <7%

• Blood pressure <130/80 mm Hg

• Total cholesterol <200 mg/dL

0

20

40

60

80

100

>10%

>9%

>8%

7-8%

<7%

0

20

40

60

80

100

>10%

>9%

>8%

7-8%

<7%

% o

f Sub

ject

sn

= 40

4%

of S

ubje

cts

n =

404

37.2%>8%

37.2%>8%

63%7%63%7%

7.8%

25.8%

37.0%

17.0%

A1cA1c12.4%

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

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

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. 2007;99(suppl):15B-26.Stotland NL. Insulin. 2006;1:38-45.

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Insulin Delivery SystemsInsulin Delivery Systems

DeWitt DE, Hirsch IB. JAMA. 2003;289:2254-2264.

American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S121-S125.

DeWitt DE, Hirsch IB. JAMA. 2003;289:2254-2264.

American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S121-S125.

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• 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

• 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

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Mimicking Nature with Insulin Therapy: Basal/Bolus Insulin Concept

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

• 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

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Basal-Bolus Insulin Treatmentwith Insulin Analogues

Basal-Bolus Insulin Treatmentwith Insulin Analogues

B=breakfast; L=lunch; D=dinner

06000600 08000800 1800180012001200 24002400 06000600

Time of dayTime of day

2020

4040

6060

8080

100100 B B LL DD GlargineGlargine

Lispro, glulisine, or aspartLispro, glulisine, or aspart

Normal patternNormal pattern

U/mLU/mL

Basal and bolus insulin pharmacodynamics

Formulation Coverage Duration (hr) Dosing

Glargine Basal 24 Once daily

Detemir Basal 14 Once or twice daily

NPH Basal 13 Twice daily

Lispro Prandial 3–4 ≤15 min premeal to immediately postmeal

Aspart Prandial 3–4 ≤15 min premeal to immediately postmeal

Glulisine Prandial 3–4 ≤15 min premeal to ≤20 min postmeal

RHI Prandial 6–8 30 min premeal

Flood TM. J Fam Practice. 2007;56(suppl):S1-12.RHI = regular human insulin

Bas

alB

olu

s

Treat-to-Target: Nocturnal hypoglycemia vs glycemic control

Riddle MC et al. Diabetes Care. 2003;26:3080―6.

Insulin glargine (n = 367)

NPH (n =

389) P

A1C ≤7% (%) 58 57

Without nocturnal hypoglycemia (%) 33 27 <0.05

FPG ≤100 mg/dL (%) 36 34

Without nocturnal hypoglycemia (%) 22 16 <0.03

Dose, mean (units/day) 47.2 41.8 <0.005

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UKPDS 10-Year Follow-up5-Year Post-Trial (1997-2002) N=3277

UKPDS 10-Year Follow-up5-Year Post-Trial (1997-2002) N=3277

• 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-INS=Sulfonylurea-Insulin **P valueN Eng J Med 2008; 359:1577-1589

• 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-INS=Sulfonylurea-Insulin **P valueN Eng J Med 2008; 359:1577-1589

Summary: Earlier Initiation of Insulin Treatment in Type 2 DM







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Selected ReferencesSelected References

• Palumbo PJ. Glycemic Control, Mealtime Glucose Excursions and Diabetic Complications in Type 2 Diabetes Mellitus. Mayo Clin Proc 2001; 76:609-618.

• 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; 331:257-263

• 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 Diabetes—How Many, How Fast…How Good? N Eng J Med 2007; 356:437-440

• Palumbo PJ. Glycemic Control, Mealtime Glucose Excursions and Diabetic Complications in Type 2 Diabetes Mellitus. Mayo Clin Proc 2001; 76:609-618.

• 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; 331:257-263

• 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 Diabetes—How Many, How Fast…How Good? N Eng J Med 2007; 356:437-440

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Slide 1 - Mayo Clinic: Medical Education and Research