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Type 2 Diabetes Mellitus -
Role of InsulinGayotri Goswami, MD, FACE
Assistant Clinical Professor of MedicineDivision of Endocrinology &
Metabolism
November 9, 2009
Stages of Type 2 Diabetes Related to Beta-Cell
Function
Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).
212 210 6 0 6 10 14
BetaCellFunction
(%)
0
50
100
75
25
Type2Phase1IGT
YearsfromDiagnosis
Type2Phase2
Type2Phase3
Postprandial
Hyperglycemia
Contributions of FPG and PPG to Overall Glycemia in T2DM
PPG+FPG=A1C(%)
01020304050607080
1 2 3 4 5
A1CQuintiles
Contribution(%)
PPG
FPG
FPG = fasting plasma glucose. PPG: Post prandial glucoseAdapted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.
<7.3 7.3- 8.4 8.5 - 9.2 9.3- 10.2 >10.2
7
Targets for Glycemic Control*Normal Goal
AmericanDiabetesAssociation1
A1C (%)Preprandial plasma glucose (mg/dL) Peak postprandial plasma glucose (mg/dL)
<6.0<110
<7.070-130<180
EuropeanDiabetesPolicyGroup2
A1C (%)Preprandial plasma glucose (mg/dL) Postprandial glucose (mg/dL)
<6.0<110
<6.5<110<135
AmericanAssociationofClinicalEndocrinologists3
A1C (%)Preprandial plasma glucose (mg/dL) Postprandial glucose (mg/dL)
<6.0<110
<6.5<110<140
*More stringent goal of <6.0% should be considered for individual patients. Generally, A1C goal for each patient is an A1C as close to normal as possible without significant hypoglycemia.A1C = glycosylated hemoglobin A1C.1. ADA. Diabetes Care. 2006;29(suppl 1):S4-S42. 2. European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730. 3. Feld S. Endocr Pract. 2002;8(suppl 1):40-82.
“Although insulin therapy has not traditionally been implemented early in the course of Type 2 diabetes, there is no reason why it should not be…”
Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.
Metabolic Management of type 2 DM
Nathan et al, A Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care,29:759-764,2006
Insulin
• Insulin is composed of 2 polypeptide chains the A and B linked together by disulphide bonds
• Among most species the A chain consists of 21 AA and the B of 30 AA
• Although the AA sequences differ in species there are certain segments of the molecule that are highly conserved
Insulin
• Most affective agent, when used in adequate doses to decrease any level of A1c to therapeutic goal
• Relatively large doses are used in Type 2 insulin resistant patients when compared to Type 1
• Has beneficial effects on TG and HDL but can cause weight gain
• Important side effect is hypoglycemia (can be reduced by education, peakless and short acting insulins)
Ideal insulin therapy
• One which replicates physiologic insulin secretion
• Maintains near-normal glycemia• Minimizes long term complications• Improves quality of life
Physiologic Blood Insulin Secretion Profile
PlasmaPlasmaInsulinInsulin((µU/mL)U/mL)
4:004:00
2525
5050
7575
8:008:00 12:0012:00 16:0016:00 20:0020:00 24:0024:00 4:004:00
Breakfast Lunch Dinner
Time
8:008:00
Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.
PlasmaInsulin(U/mL)
Time
4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00
Breakfast Lunch Dinner
Ideal Basal/Bolus Insulin – elementary principal
75
50
25
0
GlucoseBolusInsulinBaseInsulin
SkylerJ,Kelley’s Textbook of Internal Medicine2000.
HoursAfterGlucoseIngestion
PatientsWithType2DiabetesHealthySubjects
PlasmaInsulin
0
20
40
60
–1 0 1 2 3 4 5
90
180
270
360
–1 0 1 2 3 4 5
PlasmaGlucose
Mitrakou A, et al. Diabetes. 1990;39:1381–1390.
Loss of Early Insulin Release Leads to Postprandial
Hyperglycemia
(mU/L)(mg/dL)
Components of a daily regimen
• Basal:maintains interprandial and
overnight glycemic control
• Bolus /Nutritional/Prandial:controls the post meal glucose
surge
What are insulin analogs?
• An insulin analog is an altered form of insulin.
• Through genetic engineering of the underlying DNA,the amino acid sequence of insulin is changed to alter its absorption, distribution, metabolism and excretion.
INSULINS Peak (duration) hrs
• RAPID-ACTING INSULIN ANALOGS– Humalog (lispro) 1-2 (2-6)– Novolog (aspart) 1-2 (2-6)– Glulisine (epidra) 1-2 (2-6)
• SHORT-ACTING- Regular 2 - 4 (3-6)
• INTERMEDIATE-ACTING
– NPH (Neutral Protamine Hegedron)
6-12 (10-24) • LONG ACTING
– Lantus / glargine none (10-24)– Levemir / detemir -
Fixed dose insulin mixes
HUMULIN (NPH/REG)
–70/30
–50/50
HUMALOG (Prot-lispro/free lispro)
–75/25
NOVOLIN (NPH/REG)
–70/30
NOVOLOG MIX (Prot-aspart/aspart)
–70/30
Insulin delivery devices
LongActingAnalogs
Lantus (Glargine)- formulary
• Two positively charged arginine molecules are added to the C-terminus of the B-chain, asparagine at position 21 in the A-chain is replaced by glycine
Lantus
• Upon injection into the subcutaneous space(pH 7.4), the acidic (4.0) glargine solution is neutralized and it forms an amorphous suspension
• resulting in delayed absorption and an extended duration of action.
• Reduced incidence of hypoglycemia compared with NPH
Levemir (Detemir)
• To the Lysine AA at position B29 a fatty acid (myristic acid ) is bound.
• After it is absorbed it binds to albumin through the fatty acid at position B29 and the slowly dissociates from this complex.
.
NPH- formulary
• Neutral Protamine Hegedron: is a suspension of crystalline zinc insulin combined with a polypeptide protamine
• Intermediate acting and the most commonly used basal insulin
• Half life is 8 hours and reaches a peak concentration at 4-6 hrs
ShortActingAnalogs
Lispro (Humalog)- formulary
• Lysine and proline residues on the C-terminal end of the B-chain are reversed
Insulin Glulisine (Apidra)
•The AA asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid
Aspart (Novolog)
• The AA , B28, which is normally proline , is substituted with an aspartic acid residue
Human Insulin Time-Action Patterns
Time(hours) SCinjection
Normalinsulinsecretionatmealtime
Changeinseruminsulin
BaselineLevel
Theoreticalrepresentationofexpectedinsulinreleaseinnondiabeticsubjects
Human Insulin Time-Action Patterns
Time(hours) SCinjection
Normalinsulinsecretionatmealtime
Regularinsulin(human)
BaselineLevel
TheoreticalrepresentationofprofileassociatedwithRegularInsulin(human)
Changeinseruminsulin
Analog Insulin Time-Action Patterns
Time(hours) SCinjection
Normalinsulinsecretionatmealtime
BaselineLevel
Theoreticalrepresentationofexpectedinsulinreleaseinnondiabeticsubjects
Changeinseruminsulin
Analog Insulin Time-Action Patterns
Time(hours) SCinjection
Normalinsulinsecretionatmealtime
BaselineLevel
Theoreticalrepresentationofprofileassociatedwithrapid-actingInsulinAnalog
Changeinseruminsulin
Rapid-ActingInsulinAnalog
Analog Insulin Time-Action Patterns
Time(hours) SCinjection
Normalinsulinsecretionatmealtime
QD(basal)AnalogInsulin
BaselineLevel
TheoreticalrepresentationofprofileassociatedwithBasalAnalogInsulin
Changeinseruminsulin
Human Insulin Time-Action Patterns
Time(hours) SCinjection
Normalinsulinsecretionatmealtime
HumanPremix70/30(70%NPH&30%Regular)
BaselineLevel
TheoreticalrepresentationofprofileassociatedwithHumanPremix70/30
Changeinseruminsulin
Analog Insulin Time-Action Patterns
Time(hours) SCinjection
Normalinsulinsecretionatmealtime
BaselineLevel
TheoreticalrepresentationofprofileassociatedwithInsulinAnalogPremix
Changeinseruminsulin
InsulinAnalogPremix
Advantages of rapid acting insulin analogs
• Restores the early insulin peak in combination with meal ingestion
• Prevents the hyperinsulinemia resulting from the late absorption of regular insulin and thereby protects against hypoglycemia
OPTIONS………
• Once daily background or basal insulin if fasting BG is elevated but glucose values remain stable during the day
• A simple and practical approach is to implement once daily basal insulin and continue OAD therapy, titrating according to FBG *
•INSIGHT(Implementing New Strategies with Insulin Glargine for HyperglycemicTreatment – Gerstein et al 2006.Diab.Med.23:736-742
OPTIONS………
• Once daily or twice daily pre-mixed insulin analogue, orally administered drugs may or may not be continued
• Basal bolus therapy…..first initiate basal along with 1 bolus injection before the largest meal and eventually at each meal if needed
OAD and Insulin
• Proven to be effective in a review of 20 RCT
• Provides comparable glycemic control to insulin monotherapy
• Reduction in total daily insulin requirements
• Reduces weight gain and helps glycemic control by peripheral insulin sensitization and inhibiting hepatic gluconeogenesis
Dosing
• Glargine is effectively administered either in the morning or evening, provided the timing of injection is consistent each day
• Detemir is administered both once and twice daily
• NPH is usually administered twice daily, in the morning and at bedtime
Dosing
• Short acting analogs are given 5-15 minutes before a meal while Apidra or Glulysine can be given upti 20 minutes after start of a meal
• RI is given atleast 20-30 minutes before a meal
• A short acting analog can be started as 10% of the TDD (basal insulin can then be decreased by 10%) and can be added to the heaviest meal
What doses to start with……..
• With HbA1c <8%, begin 0.1U/Kg body weight
• HbA1c 8-10%, start 0.2U/kg body weight• HbA1c >10%, start 0.3U/Kg body weight• 10 units /day• With pre-mixes can divide the total dose
by 2 if used twice a day• With insulin glargine, adjust dose every 3-
7 days until target fasting dose is reached
Bergenstal Endocrine Practice,Jan 2006
Titration
• Forced weekly titration (physician led)Treat to Target Trial (Glargine/NPH) & (Detemir
BID/NPH)• Patient- led titration (usually every 2-3
days according to BG goal)AT.LANTUS trialPREDICTIVE trial
Titration
• For titrating prandial insulin pre-meal BG and 2 hour post meal BG is needed and doses are adjusted according to the goals
Glycemic Control
LANTUSVsNPH+Oralagents(TreattoTargetTrial)
Riddleetal.DiabetesCare;2003:3080-3086
Large multicenter trial, patients had A1cBetween 8-10%, 24 weeks duration with eitherLantus/NPH + 2 oral agents to bring FBG to<100mg/dL
Adverse effects
4T Study (Three year efficacy of complex insulin
regimens )• 3 year open label, multicenter trial • 708 patients with A1c levels between 7-
10%• On Metformin and a SFU• Outcomes – A1c , hypoglycemia & weight
gain• Randomly assigned to 3 groups1. Biphasic aspart2. Aspart pre-meals TID3. Basal Detemir once daily (twice if needed)
Holman et al.NEJM.2009,361,18
Results
• Median A1c was similar in biphasic (7.1%)prandial (6.8%) and basal (6.95)
• Median rates of hypoglycemia per patient per year were lowest in the basal (1.7), biphasic (3.0), and prandial (5.7), p<0.001 for overall comparison
• Mean weight gain was higher in the prandial group(5.7kg±0.5) than either biphasic (6.4±0.5) or basal (3.6 ±0.5)
Adverse effects
• Detemir has been associated with less weight gain when compared with NPH at equivalent glycemic control
• Detemir also had significantly less weight gain when compared with glargine
(Detemir 3kg; glargine 3.9kg,P<0.012)
Raslova et al, 2004.Diabetes.Res.Clin.Pract 66:193-20Haak T et al.2005.Diabetes Obes metab.7:56-64Hermansen K et al 2006.Diabetes Care 29;1269-1274
Conclusions
• The insulin analogues offer improved pharmacokinetic and pharmacodynamic profiles compared to NPH and RI and therefore offer advantages with respect to safety,efficacy and variability
• These advantages may help Type 2 Diabetics overcome some of the barriers associated with insulin initiation, hypoglycemia and weight gain
Conclusions
• Lantus offers a consistent 24 hour profile and predictability and a lower risk of hypoglycemia when compared with NPH and therefore facilitates more aggressive titration
• Detemir is associated with equivalent glycemic control, less risk of hypoglycemia lower within-subject day-to-day control and less weight gain