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DiabetesDiabetes Medication: Medication: Initiation and IntensificationInitiation and Intensification
Gregory A. Nichols, PhDGregory A. Nichols, PhD
Annual Collaborative Diabetes Education Conference Annual Collaborative Diabetes Education Conference
for Health Professionalsfor Health Professionals
January 21, 2012January 21, 2012
DisclosuresDisclosures• Employed by Kaiser Permanente Center for Health Research, Portland, Employed by Kaiser Permanente Center for Health Research, Portland,
OregonOregon
• Government Research Funding:Government Research Funding:– National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK)National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK)
– National Heart, Lung and Blood Institute (NHLBI)National Heart, Lung and Blood Institute (NHLBI)
– Agency for Healthcare Research and Quality (AHRQ)Agency for Healthcare Research and Quality (AHRQ)
• Industry Funding:Industry Funding:
– GlaxoSmithKlineGlaxoSmithKline
– Merck & Co.Merck & Co.
– Novartis PharmaceuticalsNovartis Pharmaceuticals
– Tethys BioscienceTethys Bioscience
– Takeda Pharmaceuticals AmericaTakeda Pharmaceuticals America
– Novo NordiskNovo Nordisk
– AstraZenecaAstraZeneca
– AmgenAmgen
The Need for Diabetes The Need for Diabetes PharmacotherapyPharmacotherapy
• Diabetes is a metabolic condition Diabetes is a metabolic condition characterized by hyperglycemiacharacterized by hyperglycemia
– Insulin ResistanceInsulin Resistance
– Insufficient insulin productionInsufficient insulin production
• Progressive, typically requiring ongoing Progressive, typically requiring ongoing therapy intensificationtherapy intensification
General Benefits of MetforminGeneral Benefits of Metformin
• Reduces hepatic glucose production in the Reduces hepatic glucose production in the presence of insulinpresence of insulin
• At least weight neutralAt least weight neutral
• May be cardioprotectiveMay be cardioprotective
• May reduce cancer riskMay reduce cancer risk
• Definitely prevents/delays diabetes in some Definitely prevents/delays diabetes in some at-risk individualsat-risk individuals
Metformin Initiation at Metformin Initiation at Diabetes DiagnosisDiabetes Diagnosis
• Recommended by EASD/ADARecommended by EASD/ADA
• Does early vs. late metformin initiation and Does early vs. late metformin initiation and more intensive dosing:more intensive dosing:
– Increase the likelihood of successful metformin Increase the likelihood of successful metformin therapy?therapy?
– Prolong its success?Prolong its success?
Study Site and Sample SelectionStudy Site and Sample Selection
• Kaiser Permanente NorthwestKaiser Permanente Northwest
• All All diabetesdiabetes patients who initiated metformin patients who initiated metformin monotherapy as first-ever anti-hyperglycemic monotherapy as first-ever anti-hyperglycemic drug, 2004-2006drug, 2004-2006
• Members for > 1 year pre- and 6 months post-Members for > 1 year pre- and 6 months post-metformin initiation metformin initiation
• HbA1c measured pre- and post-metformin HbA1c measured pre- and post-metformin initiation initiation
Study Samplen = 3,116
Study Samplen = 3,116
Primary Failure or Non-Adherencen = 518 (16.6%)
Continued Metformin
n = 2,598 (83.4%)
Study Samplen = 3,116
Primary Failure or Non-Adherencen = 518 (16.6%)
Continued Metformin
n = 2,598 (83.4%)
No Refills, n=210
< 90 Days Supply, n=289
Added 2nd Agent, n=19
Study Samplen = 3,116
Primary Failure or Non-Adherencen = 518 (16.6%)
Continued Metformin
n = 2,598 (83.4%)
No Refills, n=210
< 90 Days Supply, n=289
Added 2nd Agent, n=19
A1C Measured 6 Months Post-Metformin
n = 2,508
Study Samplen = 3,116
Primary Failure or Non-Adherencen = 518 (16.6%)
Continued Metformin
n = 2,598 (83.4%)
No Refills, n=210
< 90 Days Supply, n=289
Added 2nd Agent, n=19
A1C Measured 6 Months Post-Metformin
n = 2,508
Never Achieved <7%n = 709 (28.3%)
Achieved < 7%n = 1,799 (71.7%)
Characteristics of Patients Who Did Characteristics of Patients Who Did and Did Not Achieve A1C < 7%and Did Not Achieve A1C < 7%
Did Not Did Not Achieve < 7%Achieve < 7%
Achieved Achieved A1C < 7%A1C < 7%
P valueP value
Age at Metformin InitiationAge at Metformin Initiation 55.255.2 58.658.6 <0.001<0.001
Duration of Diabetes (years)Duration of Diabetes (years) 2.42.4 2.02.0 <0.001<0.001
% Men% Men 52.6%52.6% 48.4%48.4% 0.0590.059
Body Mass IndexBody Mass Index 36.736.7 35.635.6 0.0020.002
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
Characteristics of Patients Who Did Characteristics of Patients Who Did and Did Not Achieve A1C < 7%and Did Not Achieve A1C < 7%
Did Not Did Not Achieve < 7%Achieve < 7%
Achieved Achieved A1C < 7%A1C < 7%
P valueP value
A1C at InitiationA1C at Initiation 8.9%8.9% 8.1%8.1% <0.001<0.001
Months to 7% or Lowest A1CMonths to 7% or Lowest A1C 9.29.2 6.36.3 <0.001<0.001
Dose When A1C < 7% Dose When A1C < 7% (or last dose)(or last dose)
1,7451,745 1,2831,283 <0.001<0.001
Medicine Possession RatioMedicine Possession Ratio 64.2%64.2% 88.0%88.0% <0.001<0.001
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
Factors Associated with Probability Factors Associated with Probability of Attaining A1C < 7%of Attaining A1C < 7%
Odds RatioOdds Ratio 95% CI95% CI P valueP value
Age at Initiation (per year)Age at Initiation (per year) 1.021.02 1.01 – 1.031.01 – 1.03 <0.001<0.001
BMI (per kg/mBMI (per kg/m22)) 0.980.98 0.97 – 0.990.97 – 0.99 0.0100.010
Initial Dose > 1000mgInitial Dose > 1000mg 1.711.71 1.33 – 2.201.33 – 2.20 0.0040.004
MPR MPR >> 80% 80% 4.594.59 3.60 – 5.853.60 – 5.85 <0.001<0.001
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
A1C at Metformin Initiation and A1C at Metformin Initiation and Probability of Attaining A1C < 7%*Probability of Attaining A1C < 7%*
A1C at InitiationA1C at Initiation Odds RatioOdds Ratio 95% CI95% CI P valueP value
< 7.0% (n=522)< 7.0% (n=522) 6.816.81 4.56 – 10.24.56 – 10.2 <0.001<0.001
7 – 7.9% (n=840)7 – 7.9% (n=840) 1.671.67 1.27 – 2.191.27 – 2.19 <0.001<0.001
8 – 8.9% (n=455)8 – 8.9% (n=455) refref ---- ----
> 9.0% (n=691)> 9.0% (n=691) 0.670.67 0.50 – 0.880.50 – 0.88 0.0050.005
*Controlling for age, BMI, Initial Dose, MPR, and duration of diabetes at initiation
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
Best A1C Achieved by Best A1C Achieved by A1C at Metformin InitiationA1C at Metformin Initiation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
< 7% (n=522) 7 - 7.9% (n=840) 8 - 8.9% (n=455) > 9% (n=691)
A1C at Metformin Initiation
> 9%8-8.9%7-7.9%6-6.9< 6%
Best HbA1c
Diabetes Duration and Probability of Diabetes Duration and Probability of Attaining A1C < 7%*Attaining A1C < 7%*
Duration of DiabetesDuration of Diabetes Odds RatioOdds Ratio 95% CI95% CI P valueP value
0–3 Months (n=935)0–3 Months (n=935) 2.852.85 2.04 – 3.982.04 – 3.98 <0.001<0.001
4–11 Months (n=262)4–11 Months (n=262) 1.731.73 1.13 – 2.641.13 – 2.64 0.0110.011
12–23 Months (n=335)12–23 Months (n=335) refref ---- ----
24–35 Months (n=281)24–35 Months (n=281) 1.101.10 0.74 – 1.630.74 – 1.63 0.6300.630
>> 36 Months (n=695) 36 Months (n=695) 0.820.82 0.60 – 1.140.60 – 1.14 0.2340.234
*Controlling for age, BMI, Initial Dose, MPR, and A1C at initiation
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
Best A1C Achieved by Diabetes Best A1C Achieved by Diabetes Duration at Metformin InitiationDuration at Metformin Initiation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0-3 Months(n=935)
4-11 Months(n=262)
12-23 Months(n=335)
24-35 Months(n=281)
36+ Months(n=695)
Duration of Diabetes at Metformin Initiation
> 9%8-8.9%7-7.9%6-6.9< 6%
Best HbA1c
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
Study Samplen = 3,116
Primary Failure or Non-Adherencen = 518 (16.6%)
Continued Metformin
n = 2,598 (83.4%)
No Refills, n=210
< 90 Days Supply, n=289
Added 2nd Agent, n=19
A1C Measured 6 Months Post-Metformin
n = 2,508
Never Achieved <7%n = 709 (28.3%)
Achieved < 7%n = 1,799 (71.7%)
Definitions of Secondary FailureDefinitions of Secondary Failure
• Added/switched to another anti-Added/switched to another anti-hyperglycemic agenthyperglycemic agent
• Subsequent HbA1c Subsequent HbA1c >> 7.5% 7.5%
• Composite of the aboveComposite of the above
Study Samplen = 3,116
Primary Failure or Non-Adherencen = 518 (16.6%)
Continued Metformin
n = 2,598 (83.4%)
No Refills, n=210
< 90 Days Supply, n=289
Added 2nd Agent, n=19
A1C Measured 6 Months Post-Metformin
n = 2,508
Never Achieved <7%n = 709 (28.3%)
Achieved < 7%n = 1,799 (71.7%)
Secondary Failuren = 748 (41.6%)
Continued SuccessN = 1,051 (58.4%)
Sample CharacteristicsSample Characteristics
Failed Failed MetforminMetformin Did Not FailDid Not Fail P valueP value
N N
(%)(%)
748 748
(41.6%)(41.6%)
1,051 1,051
(58.4%)(58.4%) ----
Age in YearsAge in Years 57.757.7 59.259.2 0.0080.008
% Men% Men 50.0%50.0% 47.3%47.3% 0.2570.257
Duration of Diabetes at Duration of Diabetes at Metformin Initiation, MonthsMetformin Initiation, Months
26.526.5 21.421.4 <0.001<0.001
HbA1c at Metformin InitiationHbA1c at Metformin Initiation 8.2%8.2% 7.9%7.9% <0.001<0.001
Months to Failure or End of Months to Failure or End of Follow-upFollow-up
16.916.9 27.627.6 <0.001<0.001
Adapted from Brown et al. Diabetes Care 2010;33:501-506
Probability of Secondary FailureProbability of Secondary Failure
Odds Ratio 95% CI p value
Age at metformin initiation (per year) 0.98 0.97 - 0.99 <0.001
Duration of Diabetes at Metformin Initiation:
0 - 3 Months (reference) 1.00 -- --
4 - 11 Months 1.56 1.12 - 2.18 0.008
12 - 23 Months 2.09 1.53 - 2.87 <0.001
24 - 35 Months 1.59 1.13 - 2.24 0.007
> 36 Months 2.20 1.68 - 2.87 <0.001
HbA1c prior to metformin:
< 7% (reference) 1.00 -- --
7 - 7.9% 1.53 1.19 - 1.98 0.001
8 - 8.9% 1.73 1.27 - 2.35 <0.001
> 9.0% 2.04 1.54 - 2.72 <0.001
Adapted from Brown et al. Diabetes Care 2010;33:501-506
Secondary Failure of Metformin by Secondary Failure of Metformin by HbA1c at InitiationHbA1c at Initiation
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Months on Metformin
Pro
po
rtio
n N
ot
Exp
eri
en
cin
g S
eco
nd
ary
Fail
ure
< 7%
7-7.9%8-8.9%
> 9%
< 7%12.3%/year(10.5-14.4)
7-7.9%17.8%/year(15.7-20.1)
8-8.9%19.2%/year(16.2-22.8)
>= 9.0%19.4%/year(16.8-22.4)
Adapted from Brown et al. Diabetes Care 2010;33:501-506
Secondary Failure of Metformin by Secondary Failure of Metformin by Diabetes Duration at InitiationDiabetes Duration at Initiation
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Months on Metformin
Pro
po
rtio
n N
ot
Ex
pe
rie
nc
ing
Se
co
nd
ary
Fa
ilu
re
0-3 Months4-11 Months12-23 Months24-35 Months> 36 Months
0-3 Months12.2%/year(10.5-14.4)
4-11 Months17.8%/year(15.7-20.1)12-23 Months
21.4%/year(17.8-25.8)
24-35 Months18.4%/year(14.7-22.9)
>=36 Months21.9%/year(19.1-25.1)
Adapted from Brown et al. Diabetes Care 2010;33:501-506
SummarySummary
• In KPNW clinical practice, 72% of drug In KPNW clinical practice, 72% of drug naïve patients attained the goal of A1C<7% naïve patients attained the goal of A1C<7%
• After attaining goal, metformin After attaining goal, metformin monotherapy secondary failure rates are monotherapy secondary failure rates are highhigh
• But…But…
SummarySummary
• Initiation at diagnosis greatly improves Initiation at diagnosis greatly improves chances of achieving A1C < 7%chances of achieving A1C < 7%
• Patients who initiate metformin at diagnosis Patients who initiate metformin at diagnosis and attain A1C < 7% remain in good and attain A1C < 7% remain in good glycemic control for longer periods than glycemic control for longer periods than those who delay initiationthose who delay initiation
• Achieving good control with metformin is Achieving good control with metformin is possible even in patients with relatively high possible even in patients with relatively high pre-therapy A1Cpre-therapy A1C
ConclusionsConclusions
• The EASD/ADA recommends initiating The EASD/ADA recommends initiating metformin when diabetes is diagnosed metformin when diabetes is diagnosed
• The KPNW experience confirms the The KPNW experience confirms the wisdom of that recommendationwisdom of that recommendation
• Simultaneous lifestyle changes should also Simultaneous lifestyle changes should also be initiated at diagnosis, but exercise may be initiated at diagnosis, but exercise may reduce metformin effectivenessreduce metformin effectiveness
SulphonylureasSulphonylureas
• Been around since 1954Been around since 1954
• Enhance beta cell production by allowing Enhance beta cell production by allowing release of insulin at lower glucose levelsrelease of insulin at lower glucose levels
• May cause weight gainMay cause weight gain
• More likely to cause hypoglycemiaMore likely to cause hypoglycemia
• Have been associated with cardiovascular Have been associated with cardiovascular diseasedisease
Study Site and Sample SelectionStudy Site and Sample Selection
• Kaiser Permanente NorthwestKaiser Permanente Northwest
• Diabetes patients who initiated SU (glyburide) Diabetes patients who initiated SU (glyburide) monotherapy as first-ever anti-hyperglycemic monotherapy as first-ever anti-hyperglycemic drugdrug
• Members for > 1 year pre- and post-SU initiation Members for > 1 year pre- and post-SU initiation
• Therapeutic success defined as achievement of Therapeutic success defined as achievement of A1C < 8%A1C < 8%
• Failure defined as subsequent A1C Failure defined as subsequent A1C >> 8% 8%
Characteristics Associated with Characteristics Associated with Initial Success of SUsInitial Success of SUs
Achieved Achieved
A1C < 8%A1C < 8%
Did Not Did Not
Achieve 8%Achieve 8% P valueP value
N (%)N (%) 4,091 (89.9%)4,091 (89.9%) 462 (11.1%)462 (11.1%) ----
AgeAge 60.360.3 55.455.4 <0.001<0.001
A1C prior to SUA1C prior to SU 9.2%9.2% 10.4%10.4% <0.001<0.001
1 Year Weight Change 1 Year Weight Change with SU (kg)with SU (kg)
-0.02-0.02 1.011.01 <0.001<0.001
Initial Dose (mg)Initial Dose (mg) 3.73.7 4.64.6 <0.001<0.001
Last Dose (mg)Last Dose (mg) 5.05.0 7.87.8 <0.001<0.001
Adapted from Nichols et al. Endocr Pract 2007;13:37-44
Characteristics Associated with Characteristics Associated with Secondary Failure of SUsSecondary Failure of SUs
Subsequent Subsequent
A1C >= 8%A1C >= 8%
A1C Never A1C Never
>= 8%>= 8% P valueP value
N (%)N (%) 1,769 (43.2%)1,769 (43.2%) 2,322 (56.8%)2,322 (56.8%) ----
AgeAge 58.958.9 61.661.6 <0.001<0.001
A1C prior to SUA1C prior to SU 9.6%9.6% 8.9%8.9% <0.001<0.001
Diabetes Duration at Diabetes Duration at SU Initiation (months)SU Initiation (months)
11.611.6 14.814.8 0.0110.011
Months of follow-upMonths of follow-up 24.824.8 39.139.1 <0.001<0.001
Dose Dose >> 10mg 10mg 56.6%56.6% 21.5%21.5% <0.001<0.001
Adapted from Nichols et al. Endocr Pract 2007;13:37-44
A1C Prior to Initiation and A1C Prior to Initiation and Secondary Failure of SUsSecondary Failure of SUs
Hazard RatioHazard Ratio 95% CI95% CI P valueP value
< 7.0%< 7.0% 1.001.00 ---- ----
7.0 – 7.9%7.0 – 7.9% 1.251.25 0.93 – 1.670.93 – 1.67 0.1350.135
8.0 – 8.9%8.0 – 8.9% 1.501.50 1.13 – 1.991.13 – 1.99 0.0050.005
>> 9.0% 9.0% 1.811.81 1.37 – 2.381.37 – 2.38 <0.001<0.001
Adapted from Nichols et al. Endocr Pract 2007;13:37-44
Time to A1C > 8% by A1C Time to A1C > 8% by A1C Achievement with SUsAchievement with SUs
Adapted from Nichols et al. Endocr Pract 2007;13:37-44
Summary and Conclusions (SUs)Summary and Conclusions (SUs)
• Patients are highly responsive to SU’sPatients are highly responsive to SU’s
• Initiation of SU’s at lower A1C levels Initiation of SU’s at lower A1C levels increases likelihood and durability of increases likelihood and durability of responseresponse
• SU’s fail faster when A1C reductions are SU’s fail faster when A1C reductions are smallersmaller
Metformin/Sulphonylurea Metformin/Sulphonylurea Combination TherapyCombination Therapy
• Typically initiated by adding one agent to Typically initiated by adding one agent to the other—rarely initiated simultaneouslythe other—rarely initiated simultaneously
• Despite different mechanisms of action, Despite different mechanisms of action, glycemic benefits aren’t additiveglycemic benefits aren’t additive
• Durability of 2Durability of 2ndnd agent less than when agent less than when initiated as 1initiated as 1stst agent agent
• Some evidence that the combination raises Some evidence that the combination raises CVD riskCVD risk
Study Site and Sample SelectionStudy Site and Sample Selection
• Kaiser Permanente NorthwestKaiser Permanente Northwest
• Diabetes patients who initiated SU/metformin Diabetes patients who initiated SU/metformin combination therapy (SU/MET)combination therapy (SU/MET)
• Members for > 6 months pre- and post-SU/MET Members for > 6 months pre- and post-SU/MET initiation initiation
• Therapeutic success defined as achievement of Therapeutic success defined as achievement of A1C < 8%A1C < 8%
• Time to insulin initiation when A1C Time to insulin initiation when A1C >> 8% 8%
Patient Characteristics by Whether Patient Characteristics by Whether A1C < 8% was Attained or A1C < 8% was Attained or Maintained with SU/METMaintained with SU/MET
Maintained Maintained < 8%< 8%
Attained, Did Attained, Did not Maintain not Maintain
< 8%< 8%Never Never
Attained < 8%Attained < 8%
N (%)N (%) 944 (24.3%)944 (24.3%) 2,241 (57.6%)2,241 (57.6%) 706 (18.1%)706 (18.1%)
Age at SU/MET InitiationAge at SU/MET Initiation 61.961.9 59.259.2 53.853.8
Last SU DoseLast SU Dose 11.311.3 13.813.8 14.414.4
Last Metformin DoseLast Metformin Dose 1,6751,675 1,9131,913 1,8651,865
SU MPRSU MPR 0.790.79 0.820.82 0.810.81
Metformin MPRMetformin MPR 0.780.78 0.750.75 0.700.70Adapted from Nichols et al. J Gen Intern Med 2007;22:453-458
Glycemic History by Whether Glycemic History by Whether A1C < 8% was Attained or A1C < 8% was Attained or Maintained with SU/METMaintained with SU/MET
Maintained Maintained < 8%< 8%
Attained, Did Attained, Did not Maintain not Maintain
< 8%< 8%Never Never
Attained < 8%Attained < 8%
A1C Prior to SU/MetA1C Prior to SU/Met 8.9%8.9% 9.1%9.1% 10.3%10.3%
Best A1C on SU/MetBest A1C on SU/Met 6.3%6.3% 6.7%6.7% 9.2%9.2%
Mean A1C on SU/MetMean A1C on SU/Met 7.2%7.2% 8.1%8.1% 10.0%10.0%
Months on SU/MetMonths on SU/Met 54.954.9 62.162.1 30.130.1
Months A1C < 8%Months A1C < 8% 44.644.6 17.117.1 00
Glycemic BurdenGlycemic Burden 11.111.1 31.831.8 63.963.9Adapted from Nichols et al. J Gen Intern Med 2007;22:453-458
Time to Insulin Addition on SU/METTime to Insulin Addition on SU/MET
Nichols et al. J Gen Intern Med 2007;22:453-458
Summary and Conclusions Summary and Conclusions (SU/MET)(SU/MET)
• SU/MET works for most patients, but not SU/MET works for most patients, but not for longfor long
• Most patients on SU/MET delay adding Most patients on SU/MET delay adding insulin for WAY too long, incurring insulin for WAY too long, incurring tremendous glycemic burdentremendous glycemic burden
InsulinInsulin
• A question of when (not if) A question of when (not if)
• Can theoretically lower any level of A1CCan theoretically lower any level of A1C
• Causes weight gainCauses weight gain
• HypoglycemiaHypoglycemia
• Has been associated with heart failureHas been associated with heart failure
• ““Psychological Insulin Resistance”Psychological Insulin Resistance”
Study Site and Sample SelectionStudy Site and Sample Selection
• Kaiser Permanente NorthwestKaiser Permanente Northwest
• Diabetes patients who newly initiated insulin Diabetes patients who newly initiated insulin therapytherapy
• Members for > 1 year pre- and 270 days post Members for > 1 year pre- and 270 days post insulin initiation insulin initiation
• Early response defined as achievement of A1C < Early response defined as achievement of A1C < 7% at first measurement within 90-270 days7% at first measurement within 90-270 days
Characteristics Associated with Early Characteristics Associated with Early Glycemic Response to InsulinGlycemic Response to Insulin
Achieved Achieved A1C < 7%A1C < 7%
Did Not Did Not Achieve <7%Achieve <7%
P P
valuevalue
N (%)N (%) 464 (40.7%)464 (40.7%) 675 (59.3%)675 (59.3%) ----
Mean AgeMean Age 66.166.1 62.662.6 <0.001<0.001
Duration of DiabetesDuration of Diabetes 8.58.5 9.09.0 0.0500.050
Long-Acting Insulin OnlyLong-Acting Insulin Only 24.1%24.1% 39.6%39.6% <0.001<0.001
Short-Acting Insulin OnlyShort-Acting Insulin Only 19.2%19.2% 5.6%5.6% <0.001<0.001
Long- and Short-Acting InsulinLong- and Short-Acting Insulin 56.7%56.7% 54.8%54.8% 0.0430.043
Concomitant Oral AgentsConcomitant Oral Agents 67.2%67.2% 73.0%73.0% 0.0350.035
Adapted from Nichols et al. Diabetes Care (submitted)
Characteristics Associated with Early Characteristics Associated with Early Glycemic Response to with InsulinGlycemic Response to with Insulin
Achieved Achieved A1C < 7%A1C < 7%
Did Not Did Not Achieve <7%Achieve <7%
P P
valuevalue
A1C Prior to InsulinA1C Prior to Insulin 8.2%8.2% 9.2%9.2% <0.001<0.001
11stst A1C 90 Days Post-Insulin A1C 90 Days Post-Insulin 6.3%6.3% 8.0%8.0% <0.001<0.001
Change in A1CChange in A1C 1.9%1.9% 1.2%1.2% <0.001<0.001
Units per DayUnits per Day 47.447.4 53.253.2 <0.001<0.001
Adapted from Nichols et al. Diabetes Care (submitted)
Probability of Early Probability of Early Glycemic Response to InsulinGlycemic Response to Insulin
Odds RatioOdds Ratio 95% CI95% CI P valueP value
Long-Acting Insulin OnlyLong-Acting Insulin Only 1.001.00 ---- ----
Short-Acting Insulin OnlyShort-Acting Insulin Only 3.133.13 1.96-5.011.96-5.01 <0.001<0.001
Long- and Short-Acting InsulinLong- and Short-Acting Insulin 2.042.04 1.53-2.741.53-2.74 <0.001<0.001
Pre-Insulin A1CPre-Insulin A1C 0.740.74 0.68-0.800.68-0.80 <0.001<0.001
Diabetes DurationDiabetes Duration 0.960.96 0.94-0.990.94-0.99 0.0070.007
Units per DayUnits per Day 0.990.99 0.98-1.000.98-1.00 0.0240.024
Concomitant Oral AgentsConcomitant Oral Agents 0.840.84 0.63-1.110.63-1.11 0.2080.208
Adapted from Nichols et al. Diabetes Care (submitted)
Study Site and Sample SelectionStudy Site and Sample Selection
• Kaiser Permanente NorthwestKaiser Permanente Northwest
• Diabetes patients who newly initiated insulin Diabetes patients who newly initiated insulin therapy (n=2,417)therapy (n=2,417)
• Members for > 1 year pre- and up to 7 years post Members for > 1 year pre- and up to 7 years post insulin initiation insulin initiation
• Glycemic response, usage and weight changes Glycemic response, usage and weight changes analyzed each quarter (90 days) post-insulinanalyzed each quarter (90 days) post-insulin
Glycemic Response to Insulin Glycemic Response to Insulin Over TimeOver Time
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
5.0%
6.0%
7.0%
8.0%
9.0%
10.0%
HbA1c < 7.0%
HbA1c 7-7.9%
HbA1c 8-8.9%
HbA1c > 9.0%
Nichols et al. Curr Med Res Opin 2010;26:9-15
Insulin Usage Over TimeInsulin Usage Over Time
40
50
60
70
80
90
100
110
Un
its p
er D
ay
70.0%
75.0%
80.0%
85.0%
90.0%
95.0%
100.0%
Percen
t w
ith
In
su
lin
Dis
pen
ses
Units/Day
% Purchasing Insulin
Nichols et al. Curr Med Res Opin 2010;26:9-15
Change in Weight with InsulinChange in Weight with Insulin
-2
0
2
4
6
8
10
12
14
16
18
Qtr1
Qtr2
Qtr3
Qtr4
Qtr5
Qtr6
Qtr7
Qtr8
Qtr9
Qtr10
Qtr11
Qtr12
Qtr13
Qtr14
Qtr15
Qtr16
Qtr17
Qtr18
Qtr19
Qtr20
Qtr21
Qtr22
Qtr23
Qtr24
Qtr25
Qtr26
Qtr27
Qtr28
Ch
an
ge f
rom
Baseli
ne B
od
y W
eig
ht
in P
ou
nd
s
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Perc
en
t G
ain
ing
5%
of
Init
ial
Bo
dy W
eig
ht
Mean Change in Pounds
Proportion Gaining > 5% of Initial Weight
Nichols et al. Curr Med Res Opin 2010;26:9-15
Summary and Conclusions (Insulin)Summary and Conclusions (Insulin)
• Initiation of insulin at lower levels of A1C Initiation of insulin at lower levels of A1C increases glycemic responseincreases glycemic response
• Ongoing dosage increases will probably be Ongoing dosage increases will probably be necessary to maintain glycemic controlnecessary to maintain glycemic control
• Weight gain occurs rapidly but levels offWeight gain occurs rapidly but levels off
Other Anti-HyperglycemicsOther Anti-Hyperglycemics
• Meglitinides (Starlix, Prandin)Meglitinides (Starlix, Prandin)
• Thiazolidinediones (Actos, Avandia)Thiazolidinediones (Actos, Avandia)
• ΑΑlpha-glucosidase Inhibitors (Precose, Glyset)lpha-glucosidase Inhibitors (Precose, Glyset)
• DPP-4 Inhibitors (Januvia, Onglyza)DPP-4 Inhibitors (Januvia, Onglyza)
• Pramlintide (Symlin)Pramlintide (Symlin)
• Incretin mimetics (Byetta)Incretin mimetics (Byetta)
Summary and ConclusionsSummary and Conclusions
• Early initiation of pharmacotherapy Early initiation of pharmacotherapy improves response to and durability of the improves response to and durability of the therapytherapy
• This pattern continues as therapy escalates This pattern continues as therapy escalates to oral combination and then insulinto oral combination and then insulin
• Adherence also plays a roleAdherence also plays a role
• Does minimizing cumulative glycemic Does minimizing cumulative glycemic burden reduce risk of complications?burden reduce risk of complications?