Diabetes Medication:
Initiation and Intensification
Gregory A. Nichols, PhD
Annual Collaborative Diabetes Education Conference
for Health Professionals
January 21, 2012
Disclosures
• Employed by Kaiser Permanente Center for Health Research, Portland,
Oregon
• Government Research Funding:
– National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK)
– National Heart, Lung and Blood Institute (NHLBI)
– Agency for Healthcare Research and Quality (AHRQ)
• Industry Funding:
– GlaxoSmithKline
–
–
–
–
–
Merck & Co.
Novartis Pharmaceuticals
Tethys Bioscience
Takeda Pharmaceuticals America
Novo Nordisk
– AstraZeneca
– Amgen
The Need for Diabetes
Pharmacotherapy
• Diabetes is a metabolic condition
characterized by hyperglycemia
– Insulin Resistance
– Insufficient insulin production
• Progressive, typically requiring ongoing
therapy intensification
General Benefits of Metformin
• Reduces hepatic glucose production in the
presence of insulin
•
•
•
•
At least weight neutral
May be cardioprotective
May reduce cancer risk
Definitely prevents/delays diabetes in some
at-risk individuals
Metformin Initiation at
Diabetes Diagnosis
• Recommended by EASD/ADA
• Does early vs. late metformin initiation and
more intensive dosing:
– Increase the likelihood of successful metformin
therapy?
– Prolong its success?
Study Site and Sample Selection
• Kaiser Permanente Northwest
• All diabetes patients who initiated metformin
monotherapy as first-ever anti-hyperglycemic
drug, 2004-2006
• Members for > 1 year pre- and 6 months postmetformin initiation
• HbA1c measured pre- and post-metformin
initiation
Study Sample
n = 3,116
Study Sample
n = 3,116
Primary Failure or
Non-Adherence
n = 518 (16.6%)
Continued
Metformin
n = 2,598 (83.4%)
Study Sample
n = 3,116
Primary Failure or
Non-Adherence
n = 518 (16.6%)
No Refills, n=210
< 90 Days Supply, n=289
Added 2nd Agent, n=19
Continued
Metformin
n = 2,598 (83.4%)
Study Sample
n = 3,116
Primary Failure or
Non-Adherence
n = 518 (16.6%)
No Refills, n=210
< 90 Days Supply, n=289
Added 2nd Agent, n=19
Continued
Metformin
n = 2,598 (83.4%)
A1C Measured 6 Months
Post-Metformin
n = 2,508
Study Sample
n = 3,116
Primary Failure or
Non-Adherence
n = 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
and Did Not Achieve A1C < 7%
Did Not
Achieve < 7%
Achieved
A1C < 7% P value
Age at Metformin Initiation
55.2
58.6
<0.001
Duration of Diabetes (years)
2.4
2.0
<0.001
52.6%
48.4%
0.059
36.7
35.6
0.002
% Men
Body Mass Index
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
Characteristics of Patients Who Did
and Did Not Achieve A1C < 7%
Did Not
Achieve < 7%
A1C at Initiation
Achieved
A1C < 7% P value
8.9%
8.1%
<0.001
9.2
6.3
<0.001
Dose When A1C < 7%
(or last dose)
1,745
1,283
<0.001
Medicine Possession Ratio
64.2%
88.0%
<0.001
Months to 7% or Lowest A1C
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
Factors Associated with Probability
of Attaining A1C < 7%
Odds Ratio
95% CI
P value
Age at Initiation (per year)
1.02
1.01 – 1.03
<0.001
BMI (per kg/m2)
0.98
0.97 – 0.99
0.010
Initial Dose > 1000mg
1.71
1.33 – 2.20
0.004
MPR > 80%
4.59
3.60 – 5.85
<0.001
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
A1C at Metformin Initiation and
Probability of Attaining A1C < 7%*
A1C at Initiation
Odds Ratio
95% CI
P value
< 7.0% (n=522)
6.81
4.56 – 10.2
<0.001
7 – 7.9% (n=840)
1.67
1.27 – 2.19
<0.001
8 – 8.9% (n=455)
ref
--
--
> 9.0% (n=691)
0.67
0.50 – 0.88
0.005
*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
A1C at Metformin Initiation
100%
90%
80%
70%
Best HbA1c
60%
> 9%
8-8.9%
7-7.9%
6-6.9
< 6%
50%
40%
30%
20%
10%
0%
< 7% (n=522)
7 - 7.9% (n=840)
8 - 8.9% (n=455)
A1C at Metformin Initiation
> 9% (n=691)
Diabetes Duration and Probability of
Attaining A1C < 7%*
Duration of Diabetes
Odds Ratio
95% CI
P value
0–3 Months (n=935)
2.85
2.04 – 3.98
<0.001
4–11 Months (n=262)
1.73
1.13 – 2.64
0.011
12–23 Months (n=335)
ref
--
--
24–35 Months (n=281)
1.10
0.74 – 1.63
0.630
> 36 Months (n=695)
0.82
0.60 – 1.14
0.234
*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
Duration at Metformin Initiation
100%
90%
80%
70%
Best HbA1c
> 9%
8-8.9%
7-7.9%
6-6.9
< 6%
60%
50%
40%
30%
20%
10%
0%
0-3 Months
(n=935)
4-11 Months
(n=262)
12-23 Months
(n=335)
24-35 Months
(n=281)
Duration of Diabetes at Metformin Initiation
Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135
36+ Months
(n=695)
Study Sample
n = 3,116
Primary Failure or
Non-Adherence
n = 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 Failure
• Added/switched to another antihyperglycemic agent
• Subsequent HbA1c > 7.5%
• Composite of the above
Study Sample
n = 3,116
Primary Failure or
Non-Adherence
n = 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 Failure
n = 748 (41.6%)
Continued Success
N = 1,051 (58.4%)
Sample Characteristics
Failed
Metformin
Did Not Fail
P value
748
(41.6%)
1,051
(58.4%)
--
57.7
59.2
0.008
50.0%
47.3%
0.257
Duration of Diabetes at
Metformin Initiation, Months
26.5
21.4
<0.001
HbA1c at Metformin Initiation
8.2%
7.9%
<0.001
Months to Failure or End of
Follow-up
16.9
27.6
<0.001
N
(%)
Age in Years
% Men
Adapted from Brown et al. Diabetes Care 2010;33:501-506
Probability of Secondary Failure
Odds
Ratio
95% CI
p value
0.98
0.97 - 0.99
<0.001
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
< 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
Age at metformin initiation (per year)
Duration of Diabetes at Metformin Initiation:
HbA1c prior to metformin:
Adapted from Brown et al. Diabetes Care 2010;33:501-506
Secondary Failure of Metformin by
HbA1c at Initiation
1
Proportion Not Experiencing Secondary Failure
0.9
< 7%
12.3% /year
(10.5-14.4)
0.8
0.7
7-7.9%
17.8% /year
(15.7-20.1)
0.6
0.5
8-8.9%
19.2% /year
(16.2-22.8)
< 7%
7-7.9%
8-8.9%
> 9%
0.4
0.3
>= 9.0%
19.4% /year
(16.8-22.4)
0.2
0.1
0
0
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
Months on Metformin
Adapted from Brown et al. Diabetes Care 2010;33:501-506
36
38
40
42
44
46
48
50
52
54
58
Secondary Failure of Metformin by
Diabetes Duration at Initiation
Proportion Not Experiencing Secondary Failure
1
0.9
0-3 Months
12.2% /year
(10.5-14.4)
0.8
4-11 Months
17.8% /year
(15.7-20.1)
0.7
12-23 Months
21.4% /year
(17.8-25.8)
0.6
0.5
24-35 Months
18.4% /year
(14.7-22.9)
0.4
0-3 Months
4-11 Months
12-23 Months
24-35 Months
> 36 Months
0.3
0.2
>=36 Months
21.9% /year
(19.1-25.1)
0.1
Months on Metformin
Adapted from Brown et al. Diabetes Care 2010;33:501-506
58
54
52
50
48
46
44
42
40
38
36
34
32
30
28
26
24
22
20
18
16
14
12
10
8
6
4
0
0
Summary
• In KPNW clinical practice, 72% of drug
naïve patients attained the goal of A1C<7%
• After attaining goal, metformin
monotherapy secondary failure rates are
high
• But…
Summary
• Initiation at diagnosis greatly improves
chances of achieving A1C < 7%
• Patients who initiate metformin at diagnosis
and attain A1C < 7% remain in good
glycemic control for longer periods than
those who delay initiation
• Achieving good control with metformin is
possible even in patients with relatively high
pre-therapy A1C
Conclusions
• The EASD/ADA recommends initiating
metformin when diabetes is diagnosed
• The KPNW experience confirms the
wisdom of that recommendation
• Simultaneous lifestyle changes should also
be initiated at diagnosis, but exercise may
reduce metformin effectiveness
Sulphonylureas
• Been around since 1954
• Enhance beta cell production by allowing
release of insulin at lower glucose levels
• May cause weight gain
• More likely to cause hypoglycemia
• Have been associated with cardiovascular
disease
Study Site and Sample Selection
• Kaiser Permanente Northwest
• Diabetes patients who initiated SU (glyburide)
monotherapy as first-ever anti-hyperglycemic
drug
• Members for > 1 year pre- and post-SU initiation
• Therapeutic success defined as achievement of
A1C < 8%
• Failure defined as subsequent A1C > 8%
Characteristics Associated with
Initial Success of SUs
Achieved
A1C < 8%
Did Not
Achieve 8%
P value
4,091 (89.9%)
462 (11.1%)
--
Age
60.3
55.4
<0.001
A1C prior to SU
9.2%
10.4%
<0.001
1 Year Weight Change
with SU (kg)
-0.02
1.01
<0.001
Initial Dose (mg)
3.7
4.6
<0.001
Last Dose (mg)
5.0
7.8
<0.001
N (%)
Adapted from Nichols et al. Endocr Pract 2007;13:37-44
Characteristics Associated with
Secondary Failure of SUs
Subsequent
A1C >= 8%
A1C Never
>= 8%
P value
1,769 (43.2%)
2,322 (56.8%)
--
Age
58.9
61.6
<0.001
A1C prior to SU
9.6%
8.9%
<0.001
Diabetes Duration at
SU Initiation (months)
11.6
14.8
0.011
Months of follow-up
24.8
39.1
<0.001
56.6%
21.5%
<0.001
N (%)
Dose > 10mg
Adapted from Nichols et al. Endocr Pract 2007;13:37-44
A1C Prior to Initiation and
Secondary Failure of SUs
Hazard Ratio
95% CI
P value
< 7.0%
1.00
--
--
7.0 – 7.9%
1.25
0.93 – 1.67
0.135
8.0 – 8.9%
1.50
1.13 – 1.99
0.005
> 9.0%
1.81
1.37 – 2.38
<0.001
Adapted from Nichols et al. Endocr Pract 2007;13:37-44
Time to A1C > 8% by A1C
Achievement with SUs
Adapted from Nichols et al. Endocr Pract 2007;13:37-44
Summary and Conclusions (SUs)
• Patients are highly responsive to SU’s
• Initiation of SU’s at lower A1C levels
increases likelihood and durability of
response
• SU’s fail faster when A1C reductions are
smaller
Metformin/Sulphonylurea
Combination Therapy
• Typically initiated by adding one agent to
the other—rarely initiated simultaneously
• Despite different mechanisms of action,
glycemic benefits aren’t additive
• Durability of 2nd agent less than when
initiated as 1st agent
• Some evidence that the combination raises
CVD risk
Study Site and Sample Selection
• Kaiser Permanente Northwest
• Diabetes patients who initiated SU/metformin
combination therapy (SU/MET)
• Members for > 6 months pre- and post-SU/MET
initiation
• Therapeutic success defined as achievement of
A1C < 8%
• Time to insulin initiation when A1C > 8%
Patient Characteristics by Whether
A1C < 8% was Attained or
Maintained with SU/MET
Maintained
< 8%
Attained, Did
not Maintain
< 8%
Never
Attained < 8%
944 (24.3%)
2,241 (57.6%)
706 (18.1%)
Age at SU/MET Initiation
61.9
59.2
53.8
Last SU Dose
11.3
13.8
14.4
Last Metformin Dose
1,675
1,913
1,865
SU MPR
0.79
0.82
0.81
Metformin MPR
0.78
0.75
0.70
N (%)
Adapted from Nichols et al. J Gen Intern Med 2007;22:453-458
Glycemic History by Whether
A1C < 8% was Attained or
Maintained with SU/MET
Maintained
< 8%
Attained, Did
not Maintain
< 8%
Never
Attained < 8%
A1C Prior to SU/Met
8.9%
9.1%
10.3%
Best A1C on SU/Met
6.3%
6.7%
9.2%
Mean A1C on SU/Met
7.2%
8.1%
10.0%
Months on SU/Met
54.9
62.1
30.1
Months A1C < 8%
44.6
17.1
0
Glycemic Burden
11.1
31.8
63.9
Adapted from Nichols et al. J Gen Intern Med 2007;22:453-458
Time to Insulin Addition on SU/MET
Nichols et al. J Gen Intern Med 2007;22:453-458
Summary and Conclusions
(SU/MET)
• SU/MET works for most patients, but not
for long
• Most patients on SU/MET delay adding
insulin for WAY too long, incurring
tremendous glycemic burden
Insulin
•
•
•
•
•
•
A question of when (not if)
Can theoretically lower any level of A1C
Causes weight gain
Hypoglycemia
Has been associated with heart failure
“Psychological Insulin Resistance”
Study Site and Sample Selection
• Kaiser Permanente Northwest
• Diabetes patients who newly initiated insulin
therapy
• Members for > 1 year pre- and 270 days post
insulin initiation
• Early response defined as achievement of A1C <
7% at first measurement within 90-270 days
Characteristics Associated with Early
Glycemic Response to Insulin
Achieved
A1C < 7%
Did Not
Achieve <7%
P value
464 (40.7%)
675 (59.3%)
--
Mean Age
66.1
62.6
<0.001
Duration of Diabetes
8.5
9.0
0.050
Long-Acting Insulin Only
24.1%
39.6%
<0.001
Short-Acting Insulin Only
19.2%
5.6%
<0.001
Long- and Short-Acting Insulin
56.7%
54.8%
0.043
Concomitant Oral Agents
67.2%
73.0%
0.035
N (%)
Adapted from Nichols et al. Diabetes Care (submitted)
Characteristics Associated with Early
Glycemic Response to with Insulin
Achieved
A1C < 7%
Did Not
Achieve <7%
P value
A1C Prior to Insulin
8.2%
9.2%
<0.001
1st A1C 90 Days Post-Insulin
6.3%
8.0%
<0.001
Change in A1C
1.9%
1.2%
<0.001
Units per Day
47.4
53.2
<0.001
Adapted from Nichols et al. Diabetes Care (submitted)
Probability of Early
Glycemic Response to Insulin
Odds Ratio
95% CI
P value
Long-Acting Insulin Only
1.00
--
--
Short-Acting Insulin Only
3.13
1.96-5.01
<0.001
Long- and Short-Acting Insulin
2.04
1.53-2.74
<0.001
Pre-Insulin A1C
0.74
0.68-0.80
<0.001
Diabetes Duration
0.96
0.94-0.99
0.007
Units per Day
0.99
0.98-1.00
0.024
Concomitant Oral Agents
0.84
0.63-1.11
0.208
Adapted from Nichols et al. Diabetes Care (submitted)
Study Site and Sample Selection
• Kaiser Permanente Northwest
• Diabetes patients who newly initiated insulin
therapy (n=2,417)
• Members for > 1 year pre- and up to 7 years post
insulin initiation
• Glycemic response, usage and weight changes
analyzed each quarter (90 days) post-insulin
Glycemic Response to Insulin
Over Time
Nichols et al. Curr Med Res Opin 2010;26:9-15
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Units per Day
110
100
90
90.0%
80
85.0%
70
80.0%
60
Units/Day
% Purchasing Insulin
50
40
Nichols et al. Curr Med Res Opin 2010;26:9-15
75.0%
70.0%
Percent with Insulin Dispenses
Insulin Usage Over Time
100.0%
95.0%
Change in Weight with Insulin
18
60.0%
16
12
40.0%
10
8
30.0%
6
20.0%
4
Mean Change in Pounds
Proportion Gaining > 5% of Initial Weight
2
10.0%
0
-2
0.0%
Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr Qtr
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Nichols et al. Curr Med Res Opin 2010;26:9-15
Percent Gaining 5% of Initial Body Weight
Change from Baseline Body Weight in Pounds
50.0%
14
Summary and Conclusions (Insulin)
• Initiation of insulin at lower levels of A1C
increases glycemic response
• Ongoing dosage increases will probably be
necessary to maintain glycemic control
• Weight gain occurs rapidly but levels off
Other Anti-Hyperglycemics
•
•
•
•
•
•
Meglitinides (Starlix, Prandin)
Thiazolidinediones (Actos, Avandia)
Αlpha-glucosidase Inhibitors (Precose, Glyset)
DPP-4 Inhibitors (Januvia, Onglyza)
Pramlintide (Symlin)
Incretin mimetics (Byetta)
Summary and Conclusions
• Early initiation of pharmacotherapy
improves response to and durability of the
therapy
• This pattern continues as therapy escalates
to oral combination and then insulin
• Adherence also plays a role
• Does minimizing cumulative glycemic
burden reduce risk of complications?