1. Insulin 201:
Moving beyond basal insulin
in type 2 diabetes
Dr. Sara Stafford, MDCM FRCPC
Fraser Health Division of Endocrinology
2. Disclosure
• Honoraria for CME:
– Eli Lilly, Boehringer Ingelheim, Novo
Nordisk, Animas, Sanofi Aventis, Merck
• This program was developed by
– Dr. Alice YY Cheng
• This program was supported by an
unrestricted educational grant from
Sanofi Diabetes
3. Learning objectives
By the end of this program, you will be able to :
1. Name the 3 types of insulin, 3 insulin regimens and
pros/cons of each
2. Discuss the evidence comparing regimens
3. Identify the patient who needs to move beyond
basal insulin alone
4. Select the regimen best suited for a particular
patient
5. Pick a starting dose and titrate
4. In your practice, what is the most
common starting regimen for
your pts with T2DM?
11. Normal Insulin Secretion:
The Basal-Bolus Insulin Concept
Endogenous Insulin
Insulin effect
Bolus Insulin
Basal Insulin
B
L
D
HS
Time of administration
B = breakfast; L = lunch; D = dinner; HS = bedtime.
1. Leahy JL. In: Leahy JL, Cefalu WT (eds). Insulin Therapy. Marcel Dekker Inc., New York, 2002.
2. Bolli GB, et al. Diabetologia 1999; 42:1151-67.
13. Basal alone
Endogenous Insulin
Insulin effect
Bolus Insulin
Basal Insulin
B
L
D
Time of administration
B = breakfast; L = lunch; D = dinner; HS = bedtime.
HS
14. Basal-Bolus
Endogenous Insulin
Insulin effect
Bolus Insulin
Basal Insulin
B
L
D
HS
Time of administration
B = breakfast; L = lunch; D = dinner; HS = bedtime.
1. Leahy JL. In: Leahy JL, Cefalu WT (eds). Insulin Therapy. Marcel Dekker Inc., New York, 2002.
15. Basal Plus Bolus (main meal)
Endogenous Insulin
Insulin effect
Bolus Insulin
Basal Insulin
B
L
D
Time of administration
HS
19. Basal alone
•
•
•
•
•
PROS
One injection
One type of insulin
Convenient
Control fasting
One SMBG
CONS
• No targeted
postprandial control
• Need functioning
pancreas to provide
bolus insulin
28. A1C Comparison Between Analogue Premix BID vs
Basal-Bolus Therapy in Type 2 Diabetes
0.5
Mean ΔA1C From Baseline (%)
0
Liebl et al,
Hirao et al,
Miyashita et al,
Fritsche et al,
Masuda et al,
2009
2008
2008
2010
2008
-0.7 (28%)
–1.0
-1.2 (50%)*
–2.0
-1.3 (47%)
-1.6 (60%)
-1.9 (NR)
P=0.0052
-2.0 (NR)
P=0.0009
P=0.32
–3.0
-2.6(32%) -2.6 (33%)
P=NS
–4.0
–5.0
NovoMix 30 BID
Humalog Mix50 BID
(*Number in brackets indicates the
% achieving A1C <7%; NR=Not
reported)
-4.2 (NR)
Basal-Bolus
Liebl A et al. Diabetes Obes Metab 2009;11:45-52. Hirao K et al. Diabetes Res Clin Pract 2008;79:171-176. Miyashita
Y et al. Cardiovasc Diabetol 2008;7:16-24. Fritsche A et al. Diabetes Obes Metab 2010;12:115-123. Masuda H et al.
Diabetes Obes Metab 2008;10:1261-1265.
-4.4 (NR)
P=NS
29. A1C Comparison for Analogue Premix TID vs Basal-Bolus
Therapy in Type 2 Diabetes
0.5
Ligthelm et al, 2006
Rosenstock et al, 2008
Mean ΔA1C From Baseline (%)
0
–1.0
-1.3
–2.0
–3.0
-1.2
P=NS
Non-inferior
-1.9
NovoMix TID
-2.1
P= 0.021
Not Non-inferior
–4.0
–5.0
Ligthelm RJ et al. Exp Clin Endocrinol Diabetes 2006;114:511-519.
Rosenstock J et al. Diabetes Care 2008;31:20-25.
Humalog Mix50 TID
Basal-Bolus
32. 1-2-3 Study
Randomized patients (HbA1c>7% at
baseline) n= 343
80
11
60
29.7%
40
37%
20
0
Additional
patients who
achieved
HbA1c <7.0%
with 1 bolus
added
to basal
Patients who
achieved
HbA1c <7.0%
with basal
during run in
10
HbA1c (%)
Patients (%) with HbA1C <7.0%
Whole population n= 785
T2D pts failing OHAs
10.19
10.19
Glulisine 1x
9
Glulisine 3x
More hypo
8
7.44
7
-0.44%
7.40
7.29
6
Run in
Davidson et al ADA 09
Glulisine 2x
10.16
Baseline
Week 8
Week 16
Week 24
32
33. But we don’t treat people for
only 24-52 weeks!!
41. Transition to a Complex Insulin Regimen
From one year onwards, if HbA1c levels were >6.5%, sulfonylurea
therapy was stopped and a second type of insulin was added
First Phase
Add biphasic insulin*
twice a day
Add prandial insulin*
three times a day
R
Add prandial insulin
at midday
Add basal insulin
before bed
Add basal insulin*
once (or twice) daily
708 T2DM
on dual
oral agents
Second Phase
Add prandial insulin
three times a day
*
N Engl J Med 2009;361:1736-47
Intensify to a complex insulin regimen in
year one if unacceptable hyperglycaemia
42. Primary Outcome: HbA1c at 3 Years
Median±95% confidence interval
N Engl J Med 2009;361:1736-47
43. Increase in Body Weight Over 3 Years
N Engl J Med 2009;361:1736-47
44. Grade 2 or 3 Hypoglycemia Over 3 Years
All
patients
N Engl J Med 2009;361:1736-47
Patients with
HbA1c ≤6.5%
45. Complex Insulin Regimens
Proportion eligible for a second
type of insulin per protocol
N Engl J Med 2009;361:1736-47
Proportion taking
two types of insulin
46. Therefore …
•
•
•
Diabetes is PROGRESSIVE
The regimen must change over time
All roads lead to Basal Bolus concept
• If you’re not going to titrate – don’t start
47. When should we consider
moving from Basal Alone to
another regimen?
48. When to progress?
• Fasting glucose at target YET the A1C
remains above target
• Fasting glucose CLOSE to target BUT
the postprandial readings are very high
50. Basal insulin self-titration tool
10
• You will inject ______ units of insulin each night
• You will continue to increase by 1 unit every night until
4-7
your blood sugar level is _______ mmol/L before
breakfast
• Do not increase your insulin when your fasting blood
4-7
sugar is _______ mmol/L
51. Basal Bolus (MDI)
• 0.5 u/kg = TDI
• 50% bolus, 50% basal
• Add 10% of basal dose as bolus insulin
with each meal
• Add 5-10 units at each meal
52. Premixed
• 0.5 units / kg = TDI
• 2/3 in the AM + 1/3 in the PM
• 5-10 units BID
53. What about the orals?
• METFORMIN
• METFORMIN
• METFORMIN
•
•
•
•
Secretagogues only if basal alone
TZD – stop
DPP-4 – benefit but cost
GLP-1 receptor agonist – benefit (dose
& weight) but cost (off-label)
55. How to approach logbook?
1. Where are the lows / highs?
2. Why are there lows / highs?
3. Do I adjust / switch or add?
a) Titrate to avoid hypoglycemia first
b) Titrate to reduce hyperglycemia
56. Where are the lows / highs?
•
•
•
•
•
Look for pattern of timing
AC meals?
PC meals?
Bedtime?
Nocturnal?
57. Why are there lows / highs?
•
•
•
Too much / little food
Too much / little activity
Too much / little insulin activity
•
•
•
What did you EAT?
What did you DO?
What did you TAKE?
58. Patterns to look for …
Breakfast
Before
After
Lunch
Before
After
Supper
Before
After
Sunday
Monday
Tuesday
Wednesday
Thursday
If high fasting …
Too little insulin overnight OR
Nocturnal hypoglycemia
Bedtime
59. Patterns to look for …
Breakfast
Before
After
Lunch
Before
After
Supper
Before
After
Bedtime
Sunday
Monday
Tuesday
Wednesday
Thursday
Reflects the bolus insulin from the meal prior
60. Patterns to look for …
Breakfast
Before
After
Lunch
Before
After
Supper
Before
After
Bedtime
Sunday
Monday
Tuesday
Wednesday
Thursday
2h pc meal sugar reflects the bolus
insulin from the meal
61. If on premixed …
Breakfast
Before
After
Lunch
Before
After
Supper
Before
After
Bedtime
Sunday
Monday
Tuesday
Wednesday
Thursday
Reflects the bolus portion of the premixed
injection at breakfast / dinner
63. Adjust / Switch / Add?
• Based on the patterns and the reasons,
one can decide whether to
– Adjust existing doses
– Switch to different treatment
– Add a treatment
64. How much to titrate by?
2 units OR 10%
“Not an exact science … trial and error!”
65. Future considerations
Does early insulin replacement therapy
strategy with basal insulin…
• Reduce macrovascular events?
• Delay progression of microvascular complications?
• Prevent progression to diabetes in individuals with
IFG/IGT by restoring beta cell function?
68. ORIGIN: Research questions
In high-risk people with IFG, IGT or early
diabetes:
a) Does insulin replacement therapy targeting fasting
normoglycemia (≤ 5.3 mmol/L) with insulin glargine
reduce CV outcomes more than standard
approaches to dysglycemia?
b) Does adding omega-3 fatty acids reduce CV
death?
IFG: impaired fasting glucose
IGT: impaired glucose tolerance
CV: cardiovascular
The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.
The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203859.
69. ORIGIN: Trial Design
Omega-3 PUFA
Median 6.2 years
R
and
IFG or IGT or newly
detected or
early T2D
(on 0 or 1 oral agent)
N=12,537
Placebo*
Standard glycemic
care
N=6273
Participants with
high CV risk
Omega n=6319
R
Placebo n=6292
Titrated insulin
glargine to FPG
goal ≤ 5.3 mmol/L
N=6264
Omega-3 PUFA
Median 6.2 years
R
Placebo*
*Placebo of omega-3 PUFA
IFG: impaired fasting glucose; IGT: impaired glucose tolerance; T2D: type 2 diabetes; PUFA: polyunsaturated fatty acid
The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.
The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203859.
70. Baseline Characteristics (n=12,537)
Mean Age = 63.5 yrs; Females = 35%
Prior Diabetes (for ~ 5.4 y)
New Diabetes
IFG &/or IGT
N
10321
760
1452
%
82
6
12
Smoking
Hypertension
Any Albuminuria
Previous CVD
Median FPG
Median A1C
12
80
15
59
125 mg/dl
6.4%
6.9 mM
74. 1st Co-primary: MI, Stroke, or CV Death
0.5
Time to Adjudicated Primary Outcome 1 - CV Death MI Stroke
1
2
3
4
5
6
7
G
6264
6057
5850
5619
5379
5151
3611
766
SC 6273
6043
5847
5632
5415
5156
3639
800
0.3
0.2
Adj. HR 1.02 (0.94, 1.11)
Log Rank P = 0.63
Glargine
0.1
Standard Care
0.0
Proportion with events
0.4
# at Risk
0
1
2
3
4
Years of Follow-up
5
6
7
75. 2nd Co-Primary: MI, Stroke, CV Death,
Revascularization, Heart Failure
0.5
Time to Adjudicated Primary Outcome 2 - CV Death-MI-Stroke-HF Hosp-Revasc
1
2
3
4
5
6
7
G
6264
5827
5474
5153
4835
4523
3076
631
SC 6273
5833
5493
5186
4880
4555
3142
663
0.3
0.2
Adj. HR 1.04 (0.97, 1.11)
Log Rank P = 0.27
Glargine
0.1
Standard Care
0.0
Proportion with events
0.4
# at Risk
0
1
2
3
4
Years of Follow-up
5
6
7
76. All-cause Death
0.5
Time to Adjudicated All Death
1
2
3
4
5
6
7
G
6264
6150
6024
5857
5687
5508
3906
847
SC 6273
6159
6029
5878
5710
5501
3931
878
0.3
0.2
Adj. HR 0.98 (0.90, 1.08)
Log Rank P = 0.70
Glargine
0.1
Standard Care
0.0
Proportion with events
0.4
# at Risk
0
1
2
3
4
Years of Follow-up
5
6
7
77. Cancers Overall & by Type
(N=953) Glargine Standard
HR (95%CI)
P
N (%)
Rate
N (%)
Rate
Cancer Death 0.94 (0.77, 1.15) 0.52
Any Cancer
1.00 (0.88, 1.13) 0.97
189 (3.0) 0.51 201 (3.2) 0.54
Lung
Colon
Breast
Prostate
Melanoma
Other
Any Skin
80 (1.3)
0.22
66 (1.1)
0.18
76 (1.2)
0.21
70 (1.1)
0.19
28 (0.4)
0.08
28 (0.4)
0.08
88 (2.1)
0.36
89 (2.2)
0.38
15 (0.2)
0.04
17 (0.3)
0.05
1.21 (0.87, 1.67)
1.09 (0.79, 1.51)
1.01 (0.60, 1.71)
0.94 (0.70, 1.26)
0.88 (0.44, 1.75)
0.95 (0.80, 1.14)
1.02 (0.78, 1.33)
476 (7.6) 1.32 477 (7.6) 1.32
0.27
0.61
0.95
0.70
0.71
0.59
0.88
233 (3.7) 0.64 245 (3.9) 0.67
110 (1.8) 0.30 108 (1.7) 0.29
HR
Favors Insulin
Favors Standard
78. ORIGIN: Effect on new diabetes among 1456
participants with no diabetes at study entry
Insulin
glargine
N (%)
Standard
care
N (%)
OR (95% CI)
After 1st OGTT
After 2nd OGTT
Adjudicated +
uncertain diabetes
P
0.72 (0.58 0.91)
0.80 (0.64 1.00)
0.69 (0.56 0.86)
0.006
182 (24.7) 224 (31.2)
0.050
219 (29.7) 248 (34.5)
0.001
254 (34.5) 310 (43.1)
0.5
1
2
Favours Insulin
Favours Standard
Odds Ratio (OR)
•
•
•
1st OGTT: a median of 24 days after last visit
2nd OGTT: a median of 100 days after the last visit
“Uncertain diabetes”: cases of diabetes that could not be confirmed
by the predefined adjudication criteria
The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.
79. ORIGIN: Hypoglycemia & weight
Glargine
(N=6264)
% no./100py
Any non-severe
≥ 1 episode
Severe
≥ 1 episode
Participants with no
hypoglycemia
Standard
(N=6273)
% no./100py
57
17
25
5
<0.001
6*
1.0
2
0.3
<0.001
43
75
*One death due to hypoglycemia in the glargine
group
Glargine
Standard
Weight change since
1.6 kg (3.5 lbs)
randomized
-0.5 kg (1 lb)
P
<0.001
P
<0.001
The ORIGIN Trial Investigators. N Engl J Med 2012. DOI: 10.1056/NEJMoa1203858.
81. MI, stroke or CV death
0.30
Time to Adjudicated Primary Outcome 1 - CV Death MI Stroke
2
3
4
5
6
7
6044
5843
5630
5403
5154
3601
791
P
6051
5852
5616
5387
5140
3604
766
6255
0.15
0.20
0.25
1
n-3 6281
0.10
n-3 fatty acids
0.05
Placebo
HR 1.01; 95% CI, 0.93-1.10
0.0
Proportion with events
# at Risk
0
1
2
3
4
Years of Follow-up
5
6
7
82. Insulin - What can we tell our patients?
• Glargine insulin in type 2 diabetes (over 6 years):
– Achieves near-normal glycemic control
– Neutral effect on CV outcomes
– Does not increase cancer
– Increases the risk of hypoglycemia (modest)
– Increase weight (modest)
– Slows progression to diabetes BUT this must be
balanced against the increase hypoglycemia and weight
gain and in the context of other oral therapies that have
also shown a reduction in progression to diabetes
83. Omega 3 - What can we tell our patients?
• The use of omega-3 fatty acids has a neutral effect
on CV outcomes
• This is in keeping with findings from recent metaanalyses of omega-3 fatty acids in the modern era
of CV management 1,2
• One more large-scale ongoing trial – ASCEND3 – is
evaluating the use of 1 g of omega-3 fatty acids in
people with diabetes for primary prevention –
15,480 randomized – follow up to 2017
ASCEND: A Study of Cardiovascular Events iN Diabetes
1. Kwak SM, et al. Arch Intern Med 2012;172:686-94.
2. Chen Q, et al. Cardiovasc Drugs Ther 2011;25:259-65.
3. ASCEND: http://www.ctsu.ox.ac.uk/ascend Accessed June 21, 2012.
Notes de l'éditeur
This is a polling question to get the audience engaged. There is no discussion of the correct answer at this point.
Although there may be a number of different insulins to try to remember, it is much simpler to remember that there really are only 3 types of insulin: Basal, Bolus, Premixed.
Starting with the bolus insulins … the traditional insulin is shows as Human Regular. It was good for its time but to make a better time-action profile that would match the “boluses” of food better, the profile was made to have faster onset, faster peak and faster disappearance.
On the basal side, the traditional insulin is NPH which is a cloudy insulin requiring resuspension. To make a better basal, the profile was flattened and lengthened as with the 2 basal analogues.
The premixed insulins are mixtures of basal and bolus in a predetermined ratio.
In individuals with normal weight who do not have diabetes, two patterns of insulin output are seen: basal insulin, which is secreted at a fairly constant rate between meals and at night to maintain euglycemia, and during early morning hours; and bolus insulin, which is meal-related.1
The therapeutic challenge for patients with diabetes is to provide enough basal insulin to control between-meal hyperglycemia – which is due to hepatic glucose production – and enough bolus insulin to minimize hyperglycemia immediately after meals. The provision of adequate levels of basal and bolus insulin may reduce risk for hypoglycemia in individuals with erratic schedules or in those who have greater insulin requirements.1,2
References:
1. McCall AL. Insulin therapy and hypoglycemia. In: Leahy JL, Cefalu WT (eds). Insulin Therapy. Marcel Dekker Inc., New York, 2002.
2. Leahy JL. Intensive insulin therapy in type 1 diabetes mellitus. In: Leahy JL, Cefalu WT (eds). Insulin Therapy. Marcel Dekker Inc., New York, 2002.
In keeping with the Rules of 3s, there are 3 basic regimens
Basal insulin alone
Only providing “background insulin”
Rely on the pancreas to provide the “spikes” of insuin
As the name would suggest, this regimen consists of both basal and bolus insulins. The bolus insulins are given with “boluses” of food and the basal insulin is given as background.
A variation of basal-bolus is one bolus with the largest meal as opposed to a bolus with each meal. The basal remains the same.
The third regimen is premixed BID. Here you can see both traditional human 30/70 and the premixed analogues.
A variation on the premixed regimen is TID premixed.
Basal insulin performs better than human premixed insulin with respect to A1c reduction.
Diabetes Care. 2005 Feb;28(2):254-9.
Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes.
Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-Järvinen H.
OBJECTIVE:
To compare the efficacy and safety of adding once-daily basal insulin versus switching to twice-daily premixed insulin in type 2 diabetic patients insufficiently controlled by oral antidiabetic agents (OADs).
RESEARCH DESIGN AND METHODS:
In a 24-week, multinational, multicenter, open, parallel group clinical trial, 371 insulin-naive patients with poor glycemic control (fasting blood glucose [FBG] >/=120 mg/dl, HbA(1c) 7.5-10.5%) on OADs (sulfonylurea plus metformin) were randomized to once-daily morning insulin glargine plus glimepiride and metformin (glargine plus OAD) or to 30% regular/70% human NPH insulin (70/30) twice daily without OADs. Insulin dosage was titrated to target FBG </=100 mg/dl (both insulins) and predinner blood glucose </=100 mg/dl (70/30 only) using a weekly forced-titration algorithm.
RESULTS:
Mean HbA(1c) decrease from baseline was significantly more pronounced (-1.64 vs. -1.31%, P = 0.0003), and more patients reached HbA(1c) </=7.0% without confirmed nocturnal hypoglycemia (45.5 vs. 28.6%, P = 0.0013) with glargine plus OAD than with 70/30. Similarly, FBG decrease was greater with glargine plus OAD (adjusted mean difference -17 mg/dl [-0.9 mmol/l], P < 0.0001), and more patients reached target FBG </=100 mg/dl with glargine plus OAD than with 70/30 (31.6 vs. 15.0%, P = 0.0001). Glargine plus OAD patients had fewer confirmed hypoglycemic episodes than 70/30 patients (mean 4.07 vs. 9.87/patient-year, P < 0.0001).
CONCLUSIONS:
Initiating insulin treatment by adding basal insulin glargine once daily to glimepiride plus metformin treatment was safer and more effective than beginning twice-daily injections of 70/30 and discontinuing OADs in type 2 diabetic patients inadequately controlled with OADs.
When comparing Basal analogues to Premixed analogues, not surprisingly, the basal achieved better fasting control, but less postprandial control.
Ann Intern Med 2008 Oct 21;149(8):549-59. Epub 2008 Sep 15.
Systematic review: comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes.
Qayyum R, Bolen S, Maruthur N, FeldmanL, Wilson LM, Marinopoulos SS, Ranasinghe P, Amer M, Bass EB
Abstract
BACKGROUND:
Evidence comparing premixed insulin analogues (a mixture of rapid-acting and intermediate-acting insulin analogues) with other antidiabetic agents is urgently required to guide appropriate therapy.
PURPOSE:
To summarize the English-language literature on the effectiveness and safety of premixed insulin analogues compared with other antidiabetic agents in adults with type 2 diabetes.
DATA SOURCES:
The authors searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to February 2008 and sought unpublished data from the U.S. Food and Drug Administration, European Medicines Agency, and industry.
STUDY SELECTION:
Studies with control groups that compared premixed insulin analogues with another antidiabetic medication in adults with type 2 diabetes.
DATA EXTRACTION:
2 reviewers using standardized protocols performed serial abstraction.
DATA SYNTHESIS:
Evidence from clinical trials was inconclusive for clinical outcomes, such as mortality. Therefore, the review focused on intermediate outcomes. Premixed insulin analogues were similar to premixed human insulin in decreasing fasting glucose levels, hemoglobin A(1c) levels, and the incidence of hypoglycemia but were more effective in decreasing postprandial glucose levels (mean difference, -1.1 mmol/L; 95% CI, -1.4 to -0.7 mmol/L [-19.2 mg/dL; 95% CI, -25.9 to -12.5 mg/dL]). Compared with long-acting insulin analogues, premixed insulin analogues were superior in decreasing postprandial glucose levels (mean difference, -1.5 mmol/L; CI, -1.9 to -1.2 mmol/L [-27.9 mg/dL; CI, -34.3 to -21.5 mg/dL]) and hemoglobin A(1c) levels (mean difference, -0.39% [CI, -0.50% to -0.28%]) but were inferior in decreasing fasting glucose levels (mean difference, 0.7 mmol/L; CI, 0.3 to 1.0 mmol/L [12.0 mg/dL; CI, 6.0 to 18.1 mg/dL]) and were associated with a higher incidence of hypoglycemia. Compared with noninsulin antidiabetic agents, premixed insulin analogues were more effective in decreasing fasting glucose levels (mean difference, -1.1 mmol/L; CI, -1.7 to -0.6 mmol/L [-20.5 mg/dL; CI, -29.9 to -11.2 mg/dL]), postprandial glucose levels (mean difference, -2.1 mmol/L; CI, -3.4 to -0.8 mmol/L [-37.4 mg/dL; CI, -61.0 to -13.7 mg/dL]), and hemoglobin A(1c) levels (mean difference, -0.49% [CI, -0.86% to -0.12%]) but were associated with a higher incidence of hypoglycemia.
LIMITATIONS:
The literature search was restricted to studies published in English. Data on clinical outcomes were limited. The small number of studies for each comparison limited assessment of between-study heterogeneity.
CONCLUSION:
Premixed insulin analogues provide glycemic control similar to that of premixed human insulin and may provide tighter glycemic control than long-acting insulin analogues and noninsulin antidiabetic agents.
And not surprisingly, the premixed produced better A1c control (because of the added postprandial control) but had more hypoglycemia..
Currently, there is a common perception among clinicians that basal-bolus insulin regimens are associated with significantly better A1C lowering than analogue premix regimens. However, only two of the five major trials comparing basal-bolus insulin therapy to analogue premixes (shown here) support this perception.
Although cross-study comparisons cannot be made given the varying study designs, patient populations and titration regimens across trials, it is important to note that three of the five major clinical trials (Hirao et al., Miyashita et al., and Masuda et al.) found no statistically significant differences in A1C reductions between analogue premix insulin therapy and basal-bolus insulin regimens. These findings suggest that patients using analogue premixes twice-daily may achieve similar A1C lowering as patients using basal-bolus regimens.
A brief review of each of the five major trials cited in this slide is provided below:
Liebl et al: This was a 26-week, multicentre, randomized, treat-to-target trial that included 719 type 2 diabetic patients who were uncontrolled by oral antihyperglycemic agents, with or without basal insulin. Oral therapy was discontinued and subjects were randomized to receive basal-bolus therapy (insulin detemir once-daily and insulin aspart at mealtimes) or analogue premix therapy (NovoMix 30) twice-daily. Insulin was titrated to achieve fasting, pre-dinner and postprandial plasma glucose targets, as appropriate. In the overall population, A1C lowering was found to be superior with basal-bolus therapy versus analogue premix therapy. However, no significant difference in A1C lowering between regimens was found in insulin-naïve subjects.
Hirao et al: In this 6-month, open-label, randomized trial, insulin-naïve Japanese patients with type 2 diabetes (n=160) were randomized to twice-daily analogue premix therapy (NovoMix 30) or basal-bolus insulin therapy (insulin aspart tid with or without NPH insulin). At 6 months, similar mean reductions in A1C were noted in both treatment groups (-2.6%).
Miyashita et al: In this 6-month prospective randomized trial, 42 type 2 diabetic patients failing sulfonylurea therapy were randomly assigned to receive basal-bolus therapy (insulin aspart tid and basal insulin once-daily) or twice-daily analogue premix therapy (NovoMix 30). At the end of the study period, A1C was significantly reduced in both groups compared to baseline, with no significant difference between groups in percentage change in A1C.
Fritsche et al: In this 52-week, open-label, randomized, multicentre trial, 310 subjects with long-standing insulin-treated type 2 diabetes on premix insulin therapy (with or without metformin) were randomized to a basal-bolus regimen (insulin glargine once-daily and insulin glulisine at mealtimes) or analogue premix therapy (NovoMix 30) twice-daily. At 1 year, mean reductions in A1C were significantly greater in patients treated with the basal-bolus regimen versus analogue premix therapy. In addition, the number of patients who reached an A1C < 7.0% at endpoint was significantly higher with basal-bolus insulin compared to analogue premix insulin (p=0.0004).
Masuda et al: In this 12-week, randomized study, 28 patients with type 2 diabetes were randomized to receive basal-bolus therapy (NPH insulin at bedtime and preprandial insulin lispro) or analogue premix therapy (Humalog Mix50) twice-daily. At the end of the study period, mean A1C improved in both treatment arms, with no significant difference between groups in percentage change in A1C.
Note that the results of the Treating to Target in Type 2 Diabetes (4T) Study were not included on this slide because the design of this trial allowed for the addition of a rapid-acting analogue at lunchtime. Therefore, the 4-T Study cannot be considered a “pure” analogue premix versus basal-bolus insulin comparison (note that the results of the 4-T study are discussed later in this program).
References:
Liebl A, Prager R, Binz K, et al; PREFER Study Group. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab 2009;11:45-52.
Hirao K, Arai K, Yamauchi M, et al; Japan Diabetes Clinical Data Management Study Group. Six-month multicentric, open-label, randomized trial of twice-daily injections of biphasic insulin aspart 30 versus multiple daily injections of insulin aspart in Japanese type 2 diabetic patients (JDDM 11). Diabetes Res Clin Pract 2008;79:171-176.
Miyashita Y, Nishimura R, Nemoto M, et al. Prospective randomized study for optimal insulin therapy in type 2 diabetic patients with secondary failure. Cardiovasc Diabetol 2008;7:16-24.
Fritsche A, Larbig M, Owens D, et al; GINGER study group. Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes-results of the GINGER study. Diabetes Obes Metab 2010;12:115-123.
Masuda H, Sakamoto M, Irie J, et al. Comparison of twice-daily injections of biphasic insulin lispro and basal-bolus therapy: glycaemic control and quality-of-life of insulin-naïve type 2 diabetic patients. Diabetes Obes Metab 2008;10:1261-1265.
Two studies have compared analogue premix tid therapy to basal-bolus therapy in patients with type 2 diabetes (results are shown here).
In the 16-week, non-inferiority study by Ligthelm et al., 394 patients with type 2 diabetes on a once- or twice-daily insulin regimen were randomized to receive either analogue premix tid therapy or basal-bolus insulin therapy (NPH plus insulin aspart). Patients receiving analogue premix therapy were treated according to BMI:
For BMI ≤ 30 kg/m2: subjects received biphasic insulin aspart 70 (aspart 70%/aspart protamine crystals 30%; NovoMix 70) with breakfast and lunch and biphasic insulin aspart 30 (NovoMix 30) with dinner.
For BMI > 30 kg/m2: subjects received biphasic insulin aspart 50 (aspart 50%/aspart protamine crystals 50%; NovoMix 50) with breakfast and lunch and biphasic insulin aspart 30 (NovoMix 30) with dinner.
Note that NovoMix 70 and NovoMix 50 are not available in Canada.
A1C levels achieved with each treatment were compared using a predefined non-inferiority criterion of 0.4%. At the end of the 16-week study period, A1C reductions with analogue premix tid therapy were found to be non-inferior to those obtained with basal-bolus therapy. This finding suggests that an analogue premix tid regimen is a suitable alternative to an intensified basal-bolus insulin regimen in patients with inadequately controlled type 2 diabetes.
In the 24-week, non-inferiority study by Rosenstock et al., type 2 diabetic patients previously treated with insulin glargine (≥30 units/day) plus oral antihyperglycemic agents were randomized to receive analogue premix tid therapy (50% insulin lispro/50% insulin lispro protamine [Humalog Mix50] with meals) or basal-bolus insulin (insulin glargine at bedtime plus insulin lispro at mealtimes). At the end of the study period, both treatments were associated with significant A1C reductions (p<0.0001). However, the difference in A1C change from baseline to endpoint (basal-bolus therapy minus analogue premix tid therapy) was -0.22%, and non-inferiority was not demonstrated based on the prespecified non-inferiority margin of 0.3%.
It is important to note that the results of this non-inferiority study do not indicate that basal-bolus therapy is superior to analogue premix tid therapy. Non-inferiority studies are used to investigate whether a certain treatment is no worse than a reference (comparator) treatment. No claims of superiority can be made since non-inferiority studies are not designed a priori to examine which of the therapeutic interventions examined is superior.
References:
Ligthelm RJ, Mouritzen U, Lynggaard H, et al. Biphasic insulin aspart given thrice daily is as efficacious as a basal-bolus insulin regimen with four daily injections: a randomised open-label parallel group four months comparison in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 2006;114:511-519.
Rosenstock J, Ahmann AJ, Colon G, et al. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy. Diabetes Care 2008;31:20-25.
Endocr Pract. 2011 May-Jun;17(3):395-403.
A stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure.
Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander P.
Abstract
OBJECTIVE:
To determine whether 1 or 2 preprandial injections before the meals of greatest glycemic impact can be as effective as 3 preprandial injections in patients with type 2 diabetes mellitus and basal insulin treatment failure.
METHODS:
This was an open-label, parallel-group, 1:1:1 randomized study of adults with type 2 diabetes mellitus on oral antidiabetic drugs with glycated hemoglobin (A1C) levels of 8.0% or greater. After a 14-week run-in with insulin glargine, patients with an A1C level greater than 7.0% were randomly assigned to 1, 2, or 3 time(s) daily insulin glulisine for 24 weeks. Changes in A1C from randomization to study end; percentage of patients achieving an A1C level less than 7.0%; changes in A1C, fasting glucose concentrations, and weight at individual study points; and safety (adverse events and hypoglycemia) were assessed throughout the study.
RESULTS:
Three hundred forty-three of 631 patients (54%) completing the run-in phase with insulin glargine were randomly assigned to treatment arms. During the randomization phase, A1C reductions with insulin glulisine once or twice daily were noninferior to insulin glulisine 3 times daily (confidence intervals: -0.39 to 0.36 and -0.30 to 0.43; P>.5 for both). However, more patients met the target A1C with 3 preprandial injections (46 [46%]) than with 2 injections (34 [33%]) or 1 injection (30 [30%]). Severe hypoglycemia occurred in twice as many patients receiving 3 preprandial injections (16%) compared with those receiving 2 injections (8%) and 1 injection (7%), but these differences did not reach significance.
CONCLUSION:
This study provides evidence that initiation of prandial insulin in a simplified stepwise approach is an effective alternative to the current routine 3 preprandial injection basal-bolus approach.
Endocr Pract. 2011 May-Jun;17(3):395-403.
A stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure.
Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander P.
Abstract
OBJECTIVE:
To determine whether 1 or 2 preprandial injections before the meals of greatest glycemic impact can be as effective as 3 preprandial injections in patients with type 2 diabetes mellitus and basal insulin treatment failure.
METHODS:
This was an open-label, parallel-group, 1:1:1 randomized study of adults with type 2 diabetes mellitus on oral antidiabetic drugs with glycated hemoglobin (A1C) levels of 8.0% or greater. After a 14-week run-in with insulin glargine, patients with an A1C level greater than 7.0% were randomly assigned to 1, 2, or 3 time(s) daily insulin glulisine for 24 weeks. Changes in A1C from randomization to study end; percentage of patients achieving an A1C level less than 7.0%; changes in A1C, fasting glucose concentrations, and weight at individual study points; and safety (adverse events and hypoglycemia) were assessed throughout the study.
RESULTS:
Three hundred forty-three of 631 patients (54%) completing the run-in phase with insulin glargine were randomly assigned to treatment arms. During the randomization phase, A1C reductions with insulin glulisine once or twice daily were noninferior to insulin glulisine 3 times daily (confidence intervals: -0.39 to 0.36 and -0.30 to 0.43; P>.5 for both). However, more patients met the target A1C with 3 preprandial injections (46 [46%]) than with 2 injections (34 [33%]) or 1 injection (30 [30%]). Severe hypoglycemia occurred in twice as many patients receiving 3 preprandial injections (16%) compared with those receiving 2 injections (8%) and 1 injection (7%), but these differences did not reach significance.
CONCLUSION:
This study provides evidence that initiation of prandial insulin in a simplified stepwise approach is an effective alternative to the current routine 3 preprandial injection basal-bolus approach.
Diabetes Car.e 2009 Jun;32(6):1007-13. Epub 2009 Mar 31.
DURAbility of basal versus lispro mix 75/25 insulin efficacy (DURABLE) trial 24-week results: safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes.
Buse JB, Wolffenbuttel BH, Herman WH, Shemonsky NK, Jiang HH, Fahrbach JL, Scism-Bacon JL, Martin SA.
OBJECTIVE:
To compare the ability of two starter insulin regimens to achieve glycemic control in a large, ethnically diverse population with type 2 diabetes.
RESEARCH DESIGN AND METHODS:
During the initiation phase of the DURABLE trial, patients were randomized to a twice-daily lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% lispro) (n = 1,045) or daily glargine (GL) (n = 1,046) with continuation of prestudy oral antihyperglycemic drugs.
RESULTS:
Baseline A1C was similar (LM75/25: 9.1 +/- 1.3%; GL: 9.0 +/- 1.2%; P = 0.414). At 24 weeks, LM75/25 patients had lower A1C than GL patients (7.2 +/- 1.1 vs. 7.3 +/- 1.1%, P = 0.005), greater A1C reduction (-1.8 +/- 1.3 vs. -1.7 +/- 1.3%, P = 0.005), and higher percentage reaching A1C target <7.0% (47.5 vs. 40.3%, P < 0.001). LM75/25 was associated with higher insulin dose (0.47 +/- 0.23 vs. 0.40 +/- 0.23 units x kg(-1) x day(-1), P < 0.001) and more weight gain (3.6 +/- 4.0 vs. 2.5 +/- 4.0 kg, P < 0.0001). LM75/25 patients had a higher overall hypoglycemia rate than GL patients (28.0 +/- 41.6 vs. 23.1 +/- 40.7 episodes x pt(-1) x year(-1), P = 0.007) but lower nocturnal hypoglycemia rate (8.9 +/- 19.3 vs. 11.4 +/- 25.3 episodes x pt(-1) x year(-1), P = 0.009). Severe hypoglycemia rates were low in both groups (LM75/25: 0.10 +/- 1.6 vs. GL: 0.03 +/- 0.3 episodes x pt(-1) x year(-1), P = 0.167).
CONCLUSIONS:
Compared with GL, LM75/25 resulted in slightly lower A1C at 24 weeks and a moderately higher percentage reaching A1C target <7.0%. Patients receiving LM75/25 experienced more weight gain and higher rates of overall hypoglycemia but lower rates of nocturnal hypoglycemia. Durability of regimens will be evaluated in the following 2-year maintenance phase.
Diabetes Car.e 2009 Jun;32(6):1007-13. Epub 2009 Mar 31.
DURAbility of basal versus lispro mix 75/25 insulin efficacy (DURABLE) trial 24-week results: safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes.
Buse JB, Wolffenbuttel BH, Herman WH, Shemonsky NK, Jiang HH, Fahrbach JL, Scism-Bacon JL, Martin SA.
OBJECTIVE:
To compare the ability of two starter insulin regimens to achieve glycemic control in a large, ethnically diverse population with type 2 diabetes.
RESEARCH DESIGN AND METHODS:
During the initiation phase of the DURABLE trial, patients were randomized to a twice-daily lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% lispro) (n = 1,045) or daily glargine (GL) (n = 1,046) with continuation of prestudy oral antihyperglycemic drugs.
RESULTS:
Baseline A1C was similar (LM75/25: 9.1 +/- 1.3%; GL: 9.0 +/- 1.2%; P = 0.414). At 24 weeks, LM75/25 patients had lower A1C than GL patients (7.2 +/- 1.1 vs. 7.3 +/- 1.1%, P = 0.005), greater A1C reduction (-1.8 +/- 1.3 vs. -1.7 +/- 1.3%, P = 0.005), and higher percentage reaching A1C target <7.0% (47.5 vs. 40.3%, P < 0.001). LM75/25 was associated with higher insulin dose (0.47 +/- 0.23 vs. 0.40 +/- 0.23 units x kg(-1) x day(-1), P < 0.001) and more weight gain (3.6 +/- 4.0 vs. 2.5 +/- 4.0 kg, P < 0.0001). LM75/25 patients had a higher overall hypoglycemia rate than GL patients (28.0 +/- 41.6 vs. 23.1 +/- 40.7 episodes x pt(-1) x year(-1), P = 0.007) but lower nocturnal hypoglycemia rate (8.9 +/- 19.3 vs. 11.4 +/- 25.3 episodes x pt(-1) x year(-1), P = 0.009). Severe hypoglycemia rates were low in both groups (LM75/25: 0.10 +/- 1.6 vs. GL: 0.03 +/- 0.3 episodes x pt(-1) x year(-1), P = 0.167).
CONCLUSIONS:
Compared with GL, LM75/25 resulted in slightly lower A1C at 24 weeks and a moderately higher percentage reaching A1C target <7.0%. Patients receiving LM75/25 experienced more weight gain and higher rates of overall hypoglycemia but lower rates of nocturnal hypoglycemia. Durability of regimens will be evaluated in the following 2-year maintenance phase.
The premixed group have lower A1c (difference 0.1%) but more hypoglycemia over 24 weeks.
Diabetes Car.e 2009 Jun;32(6):1007-13. Epub 2009 Mar 31.
DURAbility of basal versus lispro mix 75/25 insulin efficacy (DURABLE) trial 24-week results: safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes.
Buse JB, Wolffenbuttel BH, Herman WH, Shemonsky NK, Jiang HH, Fahrbach JL, Scism-Bacon JL, Martin SA.
OBJECTIVE:
To compare the ability of two starter insulin regimens to achieve glycemic control in a large, ethnically diverse population with type 2 diabetes.
RESEARCH DESIGN AND METHODS:
During the initiation phase of the DURABLE trial, patients were randomized to a twice-daily lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% lispro) (n = 1,045) or daily glargine (GL) (n = 1,046) with continuation of prestudy oral antihyperglycemic drugs.
RESULTS:
Baseline A1C was similar (LM75/25: 9.1 +/- 1.3%; GL: 9.0 +/- 1.2%; P = 0.414). At 24 weeks, LM75/25 patients had lower A1C than GL patients (7.2 +/- 1.1 vs. 7.3 +/- 1.1%, P = 0.005), greater A1C reduction (-1.8 +/- 1.3 vs. -1.7 +/- 1.3%, P = 0.005), and higher percentage reaching A1C target <7.0% (47.5 vs. 40.3%, P < 0.001). LM75/25 was associated with higher insulin dose (0.47 +/- 0.23 vs. 0.40 +/- 0.23 units x kg(-1) x day(-1), P < 0.001) and more weight gain (3.6 +/- 4.0 vs. 2.5 +/- 4.0 kg, P < 0.0001). LM75/25 patients had a higher overall hypoglycemia rate than GL patients (28.0 +/- 41.6 vs. 23.1 +/- 40.7 episodes x pt(-1) x year(-1), P = 0.007) but lower nocturnal hypoglycemia rate (8.9 +/- 19.3 vs. 11.4 +/- 25.3 episodes x pt(-1) x year(-1), P = 0.009). Severe hypoglycemia rates were low in both groups (LM75/25: 0.10 +/- 1.6 vs. GL: 0.03 +/- 0.3 episodes x pt(-1) x year(-1), P = 0.167).
CONCLUSIONS:
Compared with GL, LM75/25 resulted in slightly lower A1C at 24 weeks and a moderately higher percentage reaching A1C target <7.0%. Patients receiving LM75/25 experienced more weight gain and higher rates of overall hypoglycemia but lower rates of nocturnal hypoglycemia. Durability of regimens will be evaluated in the following 2-year maintenance phase.
Diabetes Care. 2011 Feb;34(2):249-55.
The DURAbility of Basal versus Lispro mix 75/25 insulin Efficacy (DURABLE) trial: comparing the durability of lispro mix 75/25 and glargine.
Buse JB, Wolffenbuttel BH, Herman WH, Hippler S, Martin SA, Jiang HH, Shenouda SK, Fahrbach JL.
Abstract
OBJECTIVE:
This study compared the durability of glycemic control of twice-daily insulin lispro mix 75/25 (LM75/25: 75% insulin lispro protamine suspension/25% lispro) and once-daily insulin glargine, added to oral antihyperglycemic drugs in type 2 diabetes patients.
RESEARCH DESIGN AND METHODS:
During the initiation phase, patients were randomized to LM75/25 or glargine. After 6 months, patients with A1C ≤ 7.0% advanced to the maintenance phase for ≤ 24 months. The primary objective was the between-group comparison of duration of maintaining the A1C goal.
RESULTS:
Of 900 patients receiving LM75/25 and 918 patients receiving glargine who completed initiation, 473 and 419, respectively, had A1C ≤ 7.0% and continued into maintenance. Baseline characteristics except age were similar in this group. Median time of maintaining the A1C goal was 16.8 months for LM75/25 (95% CI 14.0-19.7) and 14.4 months for glargine (95% CI 13.4-16.8; P = 0.040). A1C goal was maintained in 202 LM75/25-treated patients (43%) and in 147 glargine-treated patients (35%; P = 0.006). No differences were observed in overall, nocturnal, or severe hypoglycemia. LM75/25 patients had higher total daily insulin dose (0.45 ± 0.21 vs. 0.37 ± 0.21 units/kg/day) and more weight gain (5.4 ± 5.8 vs. 3.7 ± 5.6 kg) from baseline. Patients taking LM75/25 and glargine with lower baseline A1C levels were more likely to maintain the A1C goal (P = 0.043 and P < 0.001, respectively).
CONCLUSIONS:
A modestly longer durability of glycemic control was achieved with LM75/25 compared with glargine. Patients with lower baseline A1C levels were more likely to maintain the goal, supporting the concept of earlier insulin initiation.
Of 900 patients receiving LM75/25 and 918 patients receiving glargine who completed initiation, only 473 and 419, respectively, had A1C ≤ 7.0%at 6 months and continued into maintenance.
The 2 groups were followed for 24 months and patients were removed from the study as per the reasons outlined with the majority being removed because of requiring rescue therapy (A1c > 7.5%).
Median time of maintaining the A1C goal was 16.8 months for LM75/25 (95% CI 14.0-19.7) and 14.4 months for glargine (95% CI 13.4-16.8; P = 0.040). A1C goal was maintained in 202 LM75/25-treated patients (43%) and in 147 glargine-treated patients (35%; P = 0.006). No differences were observed in overall, nocturnal, or severe hypoglycemia. LM75/25 patients had higher total daily insulin dose (0.45 ± 0.21 vs. 0.37 ± 0.21 units/kg/day) and more weight gain (5.4 ± 5.8 vs. 3.7 ± 5.6 kg) from baseline. Patients taking LM75/25 and glargine with lower baseline A1C levels were more likely to maintain the A1C goal (P = 0.043 and P < 0.001, respectively).
CONCLUSIONS:
A modestly longer durability of glycemic control was achieved with LM75/25 compared with glargine. Patients with lower baseline A1C levels were more likely to maintain the goal, supporting the concept of earlier insulin initiation.
HOWEVER, note that only 14-19% of the originally randomized group was able to maintaing glycemic control on premixed or basal regimen at 30 months ….
N Engl J Med. 2009 Oct 29;361(18):1736-47. Epub 2009 Oct 22.
Three-year efficacy of complex insulin regimens in type 2 diabetes.
Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK; 4-T Study Group.
Collaborators (163)
Source
Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom. rury.holman@dtu.ox.ac.uk
Erratum in
N Engl J Med. 2010 Nov 18;363(21):2078.
Abstract
BACKGROUND:
Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited.
METHODS:
In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain.
RESULTS:
Median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens (P=0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, P=0.006) or in the basal group (43.2%, P=0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (P=0.002). [corrected] Median rates of hypoglycemia per patient per year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (P<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups.
CONCLUSIONS:
Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin. (Current Controlled Trials number, ISRCTN51125379.)
AFTER THE 1ST YEAR, INVESTIGATORS COULD ADD A SECOND INSULIN IF THE A1C WAS >6.5% (IE. INTENSIFY)
ALL 3 GROUP S ACHIEVED THE SAME A1C AT 3 YEARS
BASAL START DID OFFER LESS WEIGHT GAIN OVER 3 YEARS
BASAL START DID OFFER LESS HYPOGLYCEMIA OVER 3 YEARS
BUT … NOTE THAT THE MAJORITY OF ALL 3 GROUPS REQUIRED THE ADDITION OF A SECOND INSULIN TO MAINTAIN GLYCEMIC CONTROL. THEREFORE, THE 4T STUDY TAUGHT US THAT ALL ROADS EVENTUALLY LEAD TO A BASAL-BOLUS TYPE REGIMEN WHEN YOU WANT TO MAINTAIN GLYCEMIC CONTROL OVER THE LONG TERM …
Consider progressing beyond basal insulin alone in the following scenarios.
Providing individualized dosage instructions to patients will help simplify the management of diabetes and give them a sense of control about their disease.
THERE ARE 3 WAYS TO APPROACH DOSING OF BASAL-BOLUS
IF STARTING FROM SCRATCH, USE WEIGHT-BASED METHOD
IF THE THE PATIENT IS ALREADY ON BASAL INSULIN, THEN ONE COULD INTRODUCE THE BOLUS DOSE AS 10% AS THEY DID IN 4T.
ALTERNATIVELY, JUST PICK A NUMBER BETWEEN 5-10 UNITS AS THE BASAL DOSE AT EACH MEAL.
IF STARTING FROM SCRATCH, USE A WEIGHT-BASED METHOD
ALTERNATIVELY, PICK A # BETWEEN 5 AND 10 AND START
In this first example, the physician would instruct the patient to continue increasing the bedtime dose of insulin by 1 unit/day until before-breakfast blood glucose reaches recommended glycemic target.
Eligible patients are randomized to receive either Standard glycemic care or insulin glargine. In addition, each group is further randomized to receive either Omega-3 PUFA or placebo.
Checked – SI Units
Gerstein HC et al. NEJM. June 11, 2012,10.1056/NEJMoa1203858
Gerstein HC et al. NEJM. June 11, 2012,10.1056/NEJMoa1203858
