Slide 1 - Mayo Clinic: Medical Education and Research
Transcript of 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
PJP043004
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
PJP043004
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
PJP043004
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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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
PJP043004
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)
- Incretins, DPP IV inhibitors
- Intermediate/long acting insulin/insulin analogs
• 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
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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.
PJP080304
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
• Height 160 cm (63 in)
• Weight 74 kg (165 lbs)
• Blood pressure 130/85
• Remainder of the examination -unremarkable
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Case Study 1Case 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?
• 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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Case Study 2Case 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
• 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
PJP031507
Case Study 2Case Study 2
• Height 175 cm (69 in)
• Weight 75 Kg (176 lbs)
• Blood pressure 124/82 mmHg
• Remainder of examination -unremarkable
• Height 175 cm (69 in)
• Weight 75 Kg (176 lbs)
• Blood pressure 124/82 mmHg
• Remainder of examination -unremarkable
PJP031507
Case Study 2Case 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?
• 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
PJP043004
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.
PJP080304
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
PJP031507
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
• 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
PJP031507
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.
PJP031507
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
PJP031507
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.
PJP043004
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.
PJP043004
Insulin Therapy In Type 2 Diabetes Mellitus
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
• 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
PJP043004
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
PJP031507
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
• 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
PJP043004
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
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