Levemir Clinical Studies Flashcards
1
Q
STUDY: Question
A
Answer
2
Q
HEISE 2004: POPULATION, AIM OF STUDY, AND PRODUCTS STUDIED
A
T1D; CLAMP STUDY; WITHIN SUBJECT VARIABILITY; NPH, GLARGINE, AND DETEMIR. 54 randomized (32 males, 22 females) but only 51 completers.
3
Q
HEISE 2004: WAS IT CROSSOVER OR PARALLEL GROUP? RANDOMIZED? HOW MANY CENTERS?
A
Double-blind, Randomized, Parallel group, Involved a “clamp procedure” and the following 3 treatment groups, detemir, glargine, NPH; Single-center
4
Q
HEISE 2004: What were the inclusion or exclusion criteria?
A
Note that this study does not explicitly state inclusion or exclusion criteria. Simply describes patient population.
5
Q
HEISE 2004: The goal of this study was to compare __________ (within subject, inter subject) variability of the glucose-lowering effect between insulin detemir, NPH insulin, and insulin glargine in patients with __________ (type1, type 2) diabetes.
A
Within-subject; type 1
6
Q
HEISE 2004: A1c of the patients were about: 7, 7.5, or 8
A
about 7.5
7
Q
HEISE 2004: Duration of diabetes was about: 10, 15, or 20 years
A
about 20
8
Q
HEISE 2004: Were the patients overweight?
A
No.
9
Q
HEISE 2004: How many patients were in each arm: 10-15, 15-20, 20-25, greater than 25
A
54 subjects randomized; 51 subjects completed the trial: 18 on insulin detemir, 17 on NPH insulin, and 16 on insulin glargine
10
Q
HEISE 2004: How many dosing days? How did patients prep for the dosing days?
A
4 days of dosing. On the first day, they were randomized to receive 1 of 3 trial drugs for the remainder of the trial. On each dosing day, subjects reported to the study site the morning after an overnight fast.
11
Q
HEISE 2004: T or F: Variability with insulin detemir was 27% compared to 59% with NPH and 46% with glargine.
A
TRUE. But this was the variability over 12 hours. The 24 hour variability was 27%, 68%, and 48% for detemir, NPH, and glargine and are the more important values to recall.
12
Q
HEISE 2004: What was the clamp glucose (80, 90, or 100mg/dL)? How long clamped at this before getting study drug?
A
Biostator at least 4 hours before study drug with blood glucose target value of 100 mg/dL (“clamp” procedure)
13
Q
HEISE 2004: What type of insulin was given with the Biostator?
A
Human regular IV
14
Q
HEISE 2004: T or F: This trial was too small to show statistical significance.
A
FALSE
15
Q
HEISE 2004: When was the last time basal insulin could be given prior study drug? Short or rapid acting?
A
basal insulin could be taken 12-24 hours before trial drug administration, whereas no insulin could be taken the morning of the dosing day
16
Q
HEISE 2004: What was the interval between study days?
A
5 to 21 days
17
Q
HEISE 2004: When was the clamp ended?
A
24 hours or earlier if the blood glucose increased to greater than 200 mg/dL without any glucose having been administered for at least 30 minutes
18
Q
HEISE 2004: What was the primary endpoint?
A
Not stated explicitly. Measured and compared 5 PD and 3 PK endpoints.
19
Q
HEISE 2004: What were the overall differences in within subject variability (CV) for the GIR-AUC[0-24 h]?
A
Overall, the GIR profiles for insulin detemir were generally more consistent. within-subject variability over 24 hours (ie, GIR-AUC[0–24 h]) was significantly lower for insulin detemir compared with NPH insulin and insulin glargine (27% vs 68% vs 48%)
20
Q
HEISE 2004: Why was a limitation the fixed dose of 0.4 units/kg?
A
The CV might be different for different dose levels. However, the comparisons are based on the the ratio of CVs and therefore unlikely to be affected by dose levels.
21
Q
HEISE 2004: According to Heise, what is the concentration of detemir in 1 unit of insulin: 6, 8, 12, or 24 nmol/L? How does that compare to glargine, NPH and regular insulin.
A
24 nmol/L. COMMENT: Technically, detemir is 2400 nmol/mL. The other insulins have a concentrations of 600 nmol/mL (according to Heise 6 nmol/L). The point is 1 unit of insulin detemir has 4 times the molecules as the other insulins to produce the exact same glucose lowering effect.
22
Q
HEISE 2004: According to the authors, potentially how much less hypoglycemia would you expect with insulin detemir vs glargine? NPH?
A
An estimate hyper- and hypoglycemia can be derived from the prediction intervals: on oncedaily an unusually pronounced maximum effect (potentially hypoglycemia) will occur about: every 2 yrs with detemir, 24 times a year with NPH, and 10 times a year with glargine
23
Q
TRANSITION/HOLLANDER 2011: POPULATION, AIM OF STUDY, AND PRODUCTS STUDIED
A
T2D; INSULIN AND DPP-4 INHIBITOR NAIVE; once-daily Det + SITA + MET versus SITA + MET ± SU
24
Q
TRANSITION/HOLLANDER 2011: What was the target for detemir titration: 56-93, 70-110, or 72-108 mg/dL? How often was detemir titrated?
A
Insulin detemir was titrated weekly to a prebreakfast FPG target 72-108 mg/dL PG measurement
25
TRANSITION/HOLLANDER 2011: What was the decrease in A1c between detemir and SU groups: 1.1 and 0.5, 1.3 and 0.9, or 1.44 and 0.89%?
Mean A1C decreased by 1.44% with Det + SITA + MET vs 0.89% decrease with SITA + MET ± SU (P value less than 0.001 comparison between groups)
26
TRANSITION/HOLLANDER 2011: Which had significantly more severe hypoglycemia? Overall hypoglycemia?
No significant difference in either surprisingly.
27
TRANSITION/HOLLANDER 2011: Which group gained more weight, detemir or SU?
Neither. They both lost a small amount of weight without signficant difference.
28
KLEIN 2007: POPULATION, AIM OF STUDY, AND PRODUCTS STUDIED
T2D; CLAMP STUDY; PD (PARTICULARLY DURATION OF ACTION)
29
KLEIN 2007: How was Klein different in design from Heise by population and study design?
T2D; Crossover where each patient received each drug; Heise was T1DM, not crossed over, and each patient received the same drug on 4 different days
30
KLEIN 2007: About how many patients were in the study compared to Heise: half, same, or twice as many?
Half. Only 27 men. Heise had 54 randomized (32 males, 22 females) but only 51 completers.
31
KLEIN 2007: Author's conclusions with the PD parameter GIR between glargine and detemir?
About the same in T2D. Detemir seems to be as well suited as glargine for once daily administration in T2D.
32
KLEIN 2007: What did Klein study demonstrate about the properties of all marketed long acting insulins?
Dose dependancy…the larger the dose, the longer the duration, the higher the peak.
33
KLEIN 2007: Compared to the Heise clamp study in T1D, what were the doses of glargine and detemir? What was the clamped glucose level: (80, 90, or 100mg/dL) compared to Heise at 100mg/dL?
Heise 0.4units/kg. Klein 0.4, 0.8, and 1.4units/kg. Heise clamp was 100mg/dL. Klein subjects were clamped at 90mg/dL.
34
KLEIN 2007: What were the patients randomized to? How many clamps did each patient receive after randomization?
Randomized to either detemir or glargine group. 6 clamps each. Each group received experimental drug NN344 at 3 different doses and either glargine or detemir at 0.4, 0.8, and 1.4 units/kg.
35
KLEIN 2007: When were the peaks of all the insulins used in the study: 6-8, 9-11, 10-12, or 11-13 hours?
9-11 hours after injection
36
KLEIN 2007: When was "end of duration" defined, BG rise above: 100, 126, 150, or 200mg/dL? What was it in Heise 2004?
Klein greater than 126mg/dL; Heise greater than 200mg/dL
37
KLEIN 2007: T or F: The population studied in Klein were men and woman with T2D were insulin naive.
False. 27 insulin treated men with T2D already on insulin (not naive).
38
KLEIN 2007: Within subject variability was ____ (47, 57 , or 67%) for detemir and ___ (57, 153, or 215%) with glargine.
Within subject variability was 57% for detemir and 215% with glargine.
39
KLEIN 2007: How was the within subject variability with detemir compared to glargine: similar, better, or worse?
Better.
40
MENEGHINI 2013 (1768): POPULATION, AIM OF STUDY, AND PRODUCTS STUDIED
T2D; QD DETEMIR VS GLARGINE; ADD-ON TO MET
41
MENEGHINI 2013 (1768): When were doses of basal given?
Anytime in the evening from 1 hour before the last main meal until bedtime, with a starting dose of 10 U
42
MENEGHINI 2013 (1768): Were metformin doses allowed to be changed?
No
43
MENEGHINI 2013 (1768): Did detemir meet non-inferiority with glargine for once daily dosing? Does that make detemir inferior?
No. The estimated between-treatment difference (detemir–glargine) was 0.30% (95% CI: 0.14–0.46%) in the full analysis set and 0.35% (95% CI: 0.19–0.51%) in the per protocol analysis set. COMMENT: It was within the 0.4% difference in the mean, but since the margin of 95% CI values exceeded 0.4%, non-inferiority for detemir could not be confirmed. Technically, the study met the CONSORT criteria G which is inconclusive. Glargine had a statistically better A1c drop but still possible the drugs are non-inferior just not with this study data.
44
MENEGHINI 2013 (1768): What two significant positives for detemir came from the study?
Overall hypoglycemia stat sign lower for detemir (although both were low and no stat sign with nocturnal) and weight (mean body weight decreased by 1.1 lb with insulin detemir and increased by 2.2 lb with insulin glargine). PERSONALLY some of the weight and hypoglycemia advantages could be attributed to less efficacy in the study. Comparisons could really only be made if A1c drops were similar.
45
MENEGHINI 2013 (1768): What was a potential reason for less A1c decrease for detemir?
1. FPG were still decreasing with detemir, but stabilized after 12 weeks in glargine group. This ‘lag’ in correction of FPG may have contributed to the difference in HbA1c observed between the two groups at 26 weeks. 2. Glycaemic excursions were lower during the day with glargine than with detemir, also contributing to the difference in HbA1c.
46
MENEGHINI 2013 (1768): How could the A1c decreases been more optimized in the study?
a titration algorithm prescribing more frequent insulin dose adjustments, such as was done in several patient self-adjustment studies, and supported by ADA/EASD guidelines, might have achieved greater HbA1c improvement. This study only titrated once a week.
47
NOVEL 2/HOLLANDER 2008; POPULATION, AIM OF STUDY, AND PRODUCTS STUDIED. What was another name for this study?
T2D; BASAL BOLUS; DETEMIR (QD OR BID) VS GLARGINE (QD); NOVEL 2.
48
NOVEL 2/HOLLANDER 2008: Which OAD was not allowed?
SU and alpha glucosidase inhibitors (Precose/acarbose and Glyset/miglitol)
49
NOVEL 2/HOLLANDER 2008: Both detemir and glargine were started in the evening as oncedaily dosing. What was decision point to go from once to twice daily?
detemir patients were to be transferred to twice daily dosing if their pre-breakfast blood glucose was less than 108 mg/dL and pre-dinner was greater than 108 mg/dL
50
NOVEL 2/HOLLANDER 2008: What was the the mealtime insulin and how was it titrated?
All patients received aspart at mealtimes and titrated to achieve a 2-hour postprandial target of less than 162 mg/dL. MY OPINION This almost guarantees detemir (or any basal) to go BID given the pre-dinner goal trigger for moving to BID was 108mg/dL and the post prandial goal (i.e., after lunch) was 162 mg/dL. Basal insulin shouldn’t be expected to lower blood sugar any further (should maintain BG).
51
NOVEL 2/HOLLANDER 2008: What were the PG goals for basal dose titration?
Titrated to achieve a prebreakfast (and predinner for BID dosing) target of less than 108 mg/dL. OPINION: Not good practice as food intake during the day and bolus insulin are the drivers of pre-supper glucose not basal insulin. Therefore with this titration plan, the basal is being adjusted based on bolus coverage (or lack of).
52
NOVEL 2/HOLLANDER 2008: When the same post hoc test was applied to data for the detemir group, it was found that 82.7% of patients should have completed the trial on a twice-daily regimen rather than the _____ (47.2%, 57.2%, 67.2%) who actually did.
57.2% were on BID dosing. If allowed and protocol enforced, the same amount of patients would have been switched to BID dosing for glargine and detemir (if protocol followed more strictly) which was 83-84%.
53
NOVEL 2/HOLLANDER 2008: In the post hoc analysis it was found that had the glargine cohort been allowed to switch from once- to twice-daily dosing, ______ (63.8%, 73.8%, 83.8%, 93.8%) would have met the criterion for doing so.
83.8%
54
NOVEL 2/HOLLANDER 2008: Important conclusion from authors regarding BID dosing of detemir?
No better A1c change with loss of weight advantage and requiring more insulin.
55
NOVEL 2/HOLLANDER 2008: What study had similar results with qd/bid dosing of detemir vs glargine? What was a big difference in the population?
Rosenstock 2008. In the Rosenstock study, the patients were insulin naive prior to enrollment and no bolus insulin was used.
56
NOVEL 2/HOLLANDER 2008: T or F: In this trial, BID doses of both insulin glargine and insulin detemir were titrated to prebreakfast and predinner blood glucose goals of less than 108 mg/dL.
False. Glargine wasn't BID.
57
NOVEL 2/HOLLANDER 2008: Compared to baseline, the A1c change was significant at the end of 52 weeks for insulin detemir. This was ________ (superior/non-inferior) when compared to the A1c change of insulin glargine at 52 weeks.
Compared to baseline, the A1c change was significant at the end of 52 weeks for insulin detemir. This was non-inferior when compared to the A1c change of insulin glargine at 52 weeks.
58
NOVEL 2/HOLLANDER 2008: What two studies of glargine BID do authors refer to when discussing the disadvantage of using basal insulin BID?
Garg and Albright. Both were T1D studies using off label glargine BID. In Garg, BID total daily dose was 40.5U vs once daily 31.0U. In Albright, BID total daily dose was 44U vs once daily 26U.
59
BLONDE TITRATE 2009: POPULATION, AIM OF STUDY, AND PRODUCTS STUDIED
T2D; COMPARE 2 FASTING TARGETS USING SAME TITRATION ALGORITHM; DETEMIR IN INSULIN NAIVE NOT CONTROLLED ON OADS
60
BLONDE TITRATE 2009: Primary endpoint of the study?
Proportion of patients reaching A1c of less than 7% at 20 weeks.
61
BLONDE TITRATE 2009: What were two FPG targets in the study?
80-110 mg/dL and 70-90 mg/dL.
62
BLONDE TITRATE 2009: When was detemir dosed and how many times a day?
Once daily in evening starting with 0.1-0.2 U/kg or 10 U once daily at dinner or bedtime.
63
BLONDE TITRATE 2009: Describe the titration algorithm?
subjects self-titrated their insulin dose every 3 days according to the mean of their SMPG values for the previous 3 days
64
BLONDE TITRATE 2009: How did the two groups compare with efficacy? Safety?
the 70-90 mg/dL target statistically did better from a percent reaching target (64% vs 55%) and A1c (6.77% vs 7%). As expected, total dose was more and FPG better for the lower target group. Hypoglycemia was similar in both groups.
65
BLONDE TITRATE 2009: Why was the upper limit of A1c for inclusion set at less than 9% (a bit lower than typical T2D studies)?
To eliminate patients at later stages of diabetes progression that typically require bolus insulin as this was a basal insulin study. A1c of more than 9% generally requires basal AND bolus coverage.
66
BLONDE TITRATE 2009: Glycemic control was superior in the 70-90 mg/dL group compared to that in the 80-110 mg/dL group. This was accomplished with __________ (similar, less, more) hypoglycemia, weight change, and dosing of detemir?
Similar.
67
BLONDE TITRATE 2009: What was clinically significant regarding the use of the 303 algorithm according to the authors?
With an overall A1c decrease to mean 6.9%, patients can adjust their once daily dose of basal insulin with a simple titration algorithm with low risk of hypoglycemia, and little effect on weight.
68
BLONDE TITRATE 2009: T or F: This trial demonstrates that IDet can provide recommended ADA A1c target goals when used QD in insulin-naïve patients with type 2 diabetes.
True.
69
BLONDE TITRATE 2009: T or F: Patients self titrated the QD detemir dose at dinner or bedtime using the 303-based algorithm. If the dinner blood glucose was found to be above goal, a second dose of 4U of IDet was started at breakfast and the 303-based algorithm was also used.
False. Detemir was only dosed once daily in the TITRATE study.
70
KING 2009: POPULATION, AIM OF STUDY, AND PRODUCTS STUDIED
T2D; ONCE DAILY GLARGINE VS DETEMIR USING CGM
71
KING 2009: WAS IT CROSSOVER OR PARALLEL GROUP? RANDOMIZED?
Double-blind, Randomized, Crossover
72
KING 2009: What was the meal and dosing routine in the evening?
last meal of the day was at 6 pm and basal insulin (ie, study drug) was injected at 8 pm.
73
KING 2009: How were the patients titrated?
Each day, subjects returned to the treatment center, had doses adjusted to achieve a “target” glucose value of 70-120 mg/dL between midnight to 6 am, the “basal period”, with less than 5% of the readings less than 70 mg/dL
74
KING 2009: At what point did the patients switch to the other drug?
Once a subject achieved 2 consecutive days at the glucose target, his or her basal insulin treatment was switched to the other study drug and the process was repeated
75
KING 2009: What values were compared: the basal period or the 24 hour period? Which day(s) of readings were compared: a. all the days on the sensor, b. all time periods once achieving target glucose levels, OR c. on the second day after achieving target glucose levels?
Both. The CGM data for the two treatments were compared from a 24-h period (starting at 08:00 hours) on the second consecutive day (c) after achieving target glucose levels. The primary endpoint of the study was the between treatment comparison of the mean glucose values during the basal period.
76
KING 2009: Primary endpoint of the study?
between-treatment comparison of the mean glucose values during the basal period (midnight-6 am)
77
KING 2009: How did the mean blood glucose profiles compare?
Similar
78
KING 2009: Were the two insulins considered bioequivalent over the 24 hour period based on AUC?
Yes. AUC readings over 24 hours were 2932.2 mg.h/dL for glargine and 3114.5 mg.h/dL for detemir.
79
KING 2009: How many days did it take to achieve glycemic control?
3-4 days. mean of 3.8 days with detemir and 3.5 days with glargine (P=0.360).
80
KING 2009: Were the final doses similar?
Yes. the mean dose of detemir was similar to that of glargine: 26.3 and 26.6 units/day, respectively.
81
KING 2009: What was important about the "basal period"? Was bolus insulin allowed?
This was the period where the basal insulin was titrated in order to be able to compare the 24 hour period (assumed that the insulin lasted 24 hours). Bolus insulin was an exclusion criteria and not allowed to be used in the study.
82
KING 2009: What was the control of the patients prior to enrollment: relatively good or bad?
Relatively good. The baseline A1c was 7.1+/-0.9%.
83
KING 2009: The study design of King was \_\_\_\_. Pick all that apply: Randomized, Double blind, Open label, Crossover
The study design of King was Randomized, Double blind, Crossover.
84
KING 2009: Baseline characteristics for King were _____ years. A. A1C 8.1%, BMI 40, and type 2 diabetes = 9, B. A1C 7.5%, BMI 36.4, and type 2 diabetes = 6.5, C. A1C 7.1%, BMI 34.9, type 2 diabetes = 8.4
Baseline characteristics for King were C. A1C 7.1%, BMI 34.9, type 2 diabetes = 8.4 years.
85
KING 2009: T or F: Patients were monitored by a continuous glucose monitoring sensor for 24 hours a day.
TRUE
86
KING 2009: What was compelling about the study setting?
Real life setting in an ambulatory clinic.
87
HEISE PIEBER REVIEW: Did this review PK or PD data for glargine and detemir? Which types of studies were included in the review?
Glucose clamp studies. PD data.
88
HEISE PIEBER REVIEW: Ethnic populations studied in all the studies reviewed?
Caucasians with the exception of one study in Japanese.
89
HEISE PIEBER REVIEW: How was the review done given the different methodologies used in the studies?
The data was reanalyzed to make it more comparable.
90
HEISE PIEBER REVIEW: What are the only 3 studies that made direct comparisons between glargine and detemir with clamps? Which appeared to be an outlier?
Klein (T2), Heise (T1) and Porcellati (T1). Porcellati showed a rapid decline over 12 hours for detemir.
91
HEISE PIEBER REVIEW: How was "duration of action" defined for the purposes of the data comparison?
Time of study drug administration to glucose above 150 mg/dL
92
HEISE PIEBER REVIEW: T or F: In isoglycemic clamp studies, insulin detemir has shown less within-subject variability compared to insulin glargine.
TRUE
93
HEISE PIEBER REVIEW: Which study showing a flat profile for glargine has never been reproduced?
Lepore. In the label. COMMENT Incidently, this was done at the same institution as Porcellati study in Perugia, Italy.
94
HEISE PIEBER REVIEW: How was the "onset of action" defined for the purposes of the data comparison? Which studies used this definition?
Time after dosing in which the IV insulin clamping the glucose was decreased by 50% (reference to the insulin level 20 min prior to study drug). Lepore, Plank, and Porcellati used this in their studies. Remember, onset of action didn't define the beginning of "duration of action" for data comparison (it was time of administration of study drug).
95
HEISE PIEBER REVIEW: Glargine had two studies which showed _____ (between/within) subject variability compared to detemir.
Glargine had two studies which showed between subject variability compared to detemir.
96
HEISE PIEBER REVIEW: Detemir had two studies which showed _____ (between/within) subject variability compared to glargine.
Detemir had two studies which showed within subject variability compared to glargine.
97
HEISE PIEBER REVIEW: What two conclusions were drawn from the review?
1. Both insulins have dose dependent duration of actions. 2. Both insulins have a duration of action was close to 24 hours in T1 and in excess of 24 hours in T2 at doses 0.35-0.8 units/kg.
98
HEISE PIEBER REVIEW: Two clamp studies that demonstrated dose dependent duration of action?
Plank and Klein.
99
KURTZHALS: What marketed products were studied? What was compared?
Compared the insulin and IGF-I receptor binding properties and metabolic and mitogenic potencies of aspart, lispro, glargine, and detemir.
100
KURTZHALS: If the metabolic potency of detemir on a molar basis is 27% of that of human insulin, how does the marketed detemir have similar metabolic potency?
The formulation of detemir is 4 times as concentrated than human insulin.
101
KURTZHALS: Metabolic potencies correlated well with _________ (insulin receptor affinities / IGF-I receptor affinities / insulin receptor off-rates).
Metabolic potencies correlated well with insulin receptor affinities.
102
KURTZHALS: Mitogenic potencies in general correlated better with ___________________ (insulin receptor affinities / IGF-I receptor affinities / insulin receptor off-rates) than with insulin receptor off-rates.
Mitogenic potencies in general correlated better with IGF-I receptor affinities than with insulin receptor off-rates.
103
KURTZHALS: The 2 rapid-acting insulin analogs aspart and lispro were ____________ (similar / increased / decreased) compared to human insulin on all parameters, except for a slightly ________ (decreased / elevated) IGF-I receptor affinity of lispro.
The 2 rapid-acting insulin analogs aspart and lispro were similar compared to human insulin on all parameters, except for a slightly elevated IGF-I receptor affinity of lispro.
104
KURTZHALS: The 2 long-acting insulin analogs, glargine and detemir, differed significantly from human insulin. Glargine had a _________ (2- to 4-fold / 3- to 5-fold / 6- to 8-fold) increased IGF-I receptor affinity (and mitogenic potency) compared with human insulin.
The 2 long-acting insulin analogs, glargine and detemir, differed significantly from human insulin. Glargine had a 6- to 8-fold increased IGF-I receptor affinity and mitogenic potency compared with human insulin.
105
KURTZHALS: What is the clinical implications of the elevated IGF-I receptor affinity and mitogenic potency?
The clinical safety implications of the elevated IGF-I receptor affinity and mitogenic potency of insulin glargine are not clear.
106
YENIGUN: What was the PREDICTIVE study? When did it start and how long did it run?
Global, observational, prospective study to study patients being put on detemir. Started in 2004 and was continuing at time of publication (2009)
107
YENIGUN: This study looked at the _________ (US/European) cohort of the PREDICTIVE trial?
This study looked at the European cohort of the PREDICTIVE trial?
108
YENIGUN: This subgroup analysis identified patients who were switched from QD or BID _____ (NPH, regular, glargine) to once daily detemir as part of a basal-bolus regimen.
Patients switched from once or twice daily glargine to once daily detemir.
109
YENIGUN: About how many T1D and T2D patients were looked at: a. 100 T1DM and 200 T2DM, b. 200 T1DM and 500 T2DM c. 500 T1DM and 800 T2DM
c. 500 T1DM and 800 T2DM
110
YENIGUN: Conclusions of the Yenigun study regarding glycemic parameters, weight, and hypoglycemia?
Switching from glargine to once daily detemir as part of a basal bolus regimen was associated with improvements in glycemic parameters, weight, and hypoglycemia.
111
YENIGUN: How many weeks of follow up was reported?
12 weeks.
112
YENIGUN: How was hypoglycemia events documented and compared?
Compared the 4 weeks on glargine prior to transferring to Idet, and detemir during the 4 weeks immediately before the 12-week followup visit (weeks 9-12) using patient recall and diary entries.
113
YENIGUN: Patients with T2DM switching from glargine bid to detemir qd, the mean daily dose was (similar / increased / decreased) by 9%. What happened to the A1c?
Mean daily dose decreased by 9%. This decrease in dose is typical when switching from bid to qd basal dosing. A1c dropped 0.89%.
114
YENIGUN: Except for patients with T2DM switching from bid to qd, the mean total daily insulin dose increased by 1-5%. Why is this still considered reasonable and expected clinically (opinion)?
This increase is very small and an increase is expected for such a significant A1c reduction (-0.31 to -0.51%). The significant weight loss (as opposed to gain) despite increase in dose with reduction in A1c associated with this switch is unique to detemir.
115
ROSENSTOCK 2008: POPULATION, AIM OF STUDY, AND PRODUCTS STUDIED
T2D; INSULIN NAIVE ADD-ON TO OAD; DETEMIR VS GLARGINE WITHIN LABEL INDICATIONS
116
ROSENSTOCK 2008: How was the dosing different with detemir and glargine (favoring glargine for FPG reduction)?
Both insulins were dosed in the evening. However, glargine was dosed appropriately (OPINION) at bedtime and detemir was administered 1 hour before or after dinner (not ideal; OPINION), to allow for the possibility that recipients might be switched to a twice daily schedule, in which case a more even distribution of the dose across 24 hours would be achieved. OPINION This allowed for maximum peak effect of glargine in the morning (9-11 hours; Klein) where detemir was well past its peak (12-15 hours; assuming dinner 18:00 and breakfast 08:00)
117
ROSENSTOCK 2008: What allowed for starting a morning dose of detemir and why was that biased (OPINION) towards BID dosing?
Patients were allowed to receive a morning dose of detemir if: their pre-dinner PG was greater than 7.0 mmol/L (126mg/dL) AND their pre-breakfast PG was less than 7.0 mmol/L [unfair; OPINION] OR nocturnal hypoglycemia (“major episode” or PG greater than 72mg/dL) precluded achievement of the FPG target [fair; OPINION]
118
ROSENSTOCK 2008: What percent of detemir patients were switched to twice daily? How many were switched at investigator discretion and not following the protocol?
55% switched to BID detemir. 2/3 followed protocol criteria and 1/3 were due to investigator discretion.
119
ROSENSTOCK 2008: What were the disadvantages of going twice daily with detemir? Advantages?
No advantages. A1c and hypo rates were similar. However, the weight benefit typically seen with detemir was lost with BID dosing and consistent with twice daily more insulin was used.
120
ROSENSTOCK 2008: What was the authors opinion about the two products ability to be forced titrated?
Clinically significant improvements in glycemia with similar low risk in hypoglycemia.
121
ROSENSTOCK 2008: What were one of the authors hypothesis of patient lifestyle for difference in dosing patterns with detemir and weight gain?
differences in eating patterns may have contributed to dosing schedule and weight gain
122
ROSENSTOCK 2008: Select the true statement(s): a. It compared treatment with insulin detemir to treatment with insulin glargine as add-on therapy to OADs in insulin-naive patients with type 2 diabetes., b. Its duration was 26 weeks., c. Its primary endpoint was baseline adjusted A1C at the end of treatment., d. In this study, over 50% of all insulin detemir subjects achieved A1C
a. It compared treatment with insulin detemir to treatment with insulin glargine as add-on therapy to OADs in insulin-naive patients with type 2 diabetes., and c. The primary endpoint was baseline adjusted A1C at the end of treatment.
123
ROSENSTOCK 2008: T or F: A1C decreased by a mean of 1.1% with both basal insulins, and the mean A1C was comparable between the groups (7.3% with insulin detemir and 7.3% with insulin glargine); therefore, these data did not meet the criteria for non-inferiority for insulin detemir vs glargine.
False. A1C decreased by a mean of 1.5% with both basal insulins, and the mean A1C was comparable between the groups (7.2% with insulin detemir and 7.1% with insulin glargine). These data met the criteria for non-inferiority for insulin detemir vs glargine.
124
ROSENSTOCK 2008: The post-hoc analysis of the blood glucose levels show that ___ (61% / 65% / 81% / 87%) glargine treated patients should have been treated with twice daily regimen if the algorithm had been applied strictly. Similarly ___ (61% / 65% / 81% / 87%) of patients would have been treated with twice daily detemir.
87% glargine treated patients would have been treated with twice daily regimen if the algorithm had been applied strictly. Similarly 81% would have been treated with twice daily detemir. Therefore, while the dosing algorithm reflected labeling, it clearly resulted in an unequal comparison with regard to the anti-hyperglycemic profiles of the two drugs, which appeared to be very similar.
125
ROSENSTOCK 2008: Mean daily dose of detemir was ____ (similar / increased / decreased) compared to glargine.
Mean daily dose of detemir was increased compared to glargine due to bid dosing. After 52 weeks the mean daily dose of insulin detemir was 0.78 U/kg (0.52 U/kg on once daily and 1.00 U/kg on twice daily) The mean daily dose of glargine was 0.44 U/kg.
126
ROSENSTOCK 2008: What study had similar results with qd/bid dosing of detemir vs glargine? What was a big difference in the population?
Hollander 2008 (NOVEL 2). In the NOVEL 2 study, the patients were NOT insulin naive prior to enrollment and bolus insulin was used (BASAL BOLUS study).
127
ROSENSTOCK 2008: T or F: A1C at the end of study was similar for patients on QD and BID insulin detemir (7.1%).
True.
