A Randomized Controlled Trial Comparing Efficacy and Safety of

Insulin Glargine 300 Units/mL Versus 100 Units/mL in Older People

With Type 2 Diabetes: Results From the SENIOR Study

KEVIN JONATHAN
406172069
 Preliminary
Therapies :
◦ several classes of oral antihyperglycemic
◦ Injectables  rapid-acting and basal insulins and glucagon-like peptide receptor agonists.

When insulin is used, a fine balance is required between achieving glycemic control and avoiding
hypoglycemia.
older people with diabetes more often require insulin. More prone to hypoglycemia for multiple
reasons :
◦ erratic food ingestion
◦ insufficient adjustment of insulin dose
◦ reduced responses to counterregulatory hormone
◦ lower blood glucose threshold for autonomic symptoms
◦ higher blood glucose threshold for cognitive dysfunction.
 Preliminary
Hypoglycemic events in older people are associated with:
◦ increased incidence of acute cardiovascular events
◦ impaired cognitive function
◦ Dementia
◦ Hospitalizations
◦ Mortality

Hypoglycemia and its consequences are an even greater burden in people ≥75
years of age than in those 65–74 years of age, with hospitalization rates twofold
higher.
care of older people is complicated by the diverse range of functional ability,
cognitive function, comorbid conditions, and frailty present in this group
 Basal insulin Glargine
Insuline glargine 100 units/mL (Gla-100)
Insuline glargine 300 units/mL (Gla-300)
Gla-300 provides more stable and prolonged steady-state pharmacokinetic and pharmacodynamic
profiles, with blood insulin levels that more closely resemble normal physiological conditions.

EDITION 1, 2, and 3 trials (Gla-300 vs Gla-100 safety and efficacy) :

comparable glycemic control over 6 months --> which was better sustained with Gla-300 throughout
the 12-month study period
significantly lower risk of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycemia at night
(0000–0559 h) and at any time of day (24 h) with Gla-300 compared with Gla-100.
Objective
compared the efficacy and safety of insulin glargine 300 units/mL (Gla-300) with
glargine 100 units/mL (Gla-100) in older people (≥65 years old) with type 2
diabetes
Study Design
Experimental -> Randomized Controlled Trial
Multinational, multicenter, phase 3B, two-arm parallel group study in older
people (≥65 years of age) with type 2 diabetes comprising a 4-week screening
period, followed by a 26-week treatment period, conducted in 162 centers
across 18 countries.

The study was approved by independent ethics review boards and conducted
according to Good Clinical Practice and the Declaration of Helsinki. All
participants provided written informed consent.
Inclusion Criteria
• Age ≥65 years
• Type 2 diabetes for ≥1 year treated with a pharmacologic antihyperglycemic
regimen for ≥8 weeks before screening
• HbA1c = 7.5–11% in insulin-naive participants or 7–10% in insulin-pretreated
participants
Exclusion Criteria
• Chronic use of short-acting insulin
• Participants not on a stable basal insulin dose
• Cognitive disorder and dementia (Mini-Mental State Examination score <24)
Randomization
Stratified Random Sampling
Participants were randomized 1:1 to receive Gla-300 or Gla-100. Stratified by :
•HbA1c at screening (<8.0%/≥8.0%)
•Previous use of insulin (naive/pretreated)
•Use of sulfonylurea or Meglitinide at screening (yes/no).
Study Participants
Total = 1,014 participants  randomized to receive Gla-300 (n = 508) or Gla-100
(n = 506). of these, 135 (26.6%) and 106 (20.9%) participants were ≥75 years of
age for Gla-300 and Gla-100.

Baseline characteristics were similar for the Gla-300 and Gla-100 groups
Study
Participants
(Baseline
Characteristics)
Treatment
Basal insulins were self-administered once daily (Evening administration was
recommended)
Administration occurred at the same time each day ±3 h
Starting doses  determined by previous dose history:
• Insulin-naive patients started on a dose of 0.2 units/kg
• Pretreated with basal insulin, starting dose equivalent to their median basal
insulin dose of the 3 days before baseline, unless receiving NPH insulin more
than once daily  dose : 20% lower than total daily dose
Treatment
Insulin dose adjusted every 3-4 days to achieve a target fasting self-monitored plasma
glucose (SMPG) level of 90–130 mg/dL (ADA-recommended)
Dose adjusted :
• increase 3 units if SMPG >130 mg/dL
•decrease 3 units (or an adjustment at the investigators’ discretion) if SMPG <90 mg/dL
or in the event of two or more symptomatic or one severe hypoglycemic episode in the
preceding week

Participants continued their previous antihyperglycemic drugs, if approved for use with
insulin, with the exception of thiazolidinediones, which were stopped at randomization.
Outcomes
• Primary efficacy end point :
 Change in HbA1cfrom baseline to week 26
• Secondary efficacy end points :
 Percentage of participants with one or more confirmed [≤70 mg/dL] or severe [≤54
mg/dL] hypoglycemic events occurring at any time of day (24 h) or at night (0000–0559
h or 2200–0859 h) over 26 weeks of treatment
 Change in fasting plasma glucose (FPG) from baseline to week 26
 Percentage of participants achieving HbA1c <7.5 and <7.0% at the end of 26 weeks of
treatment
Annualized rates of hypoglycemia
Data Analysis and Statistics
Noninferiority of Gla-300 versus Gla-100 in HbA1c change from baseline to week 26  Power
98% (460 randomized participants for each group)
On the basis of a true difference between the two groups of zero and a noninferiority margin of
0.3%
Assumes SD -> 1,1%
One-sided t test -> 2.5% significance level
 Change in HbA1c and FPG from baseline to week 26  multiple imputation approach for
missing data and ANCOVA using :
• fixed categorical effects of treatment group
• randomization strata
• continuous fixed covariates of baseline value.
Least squared mean and least squared mean differences  combined using the Rubin formula.
Data Analysis and Statistics
Main secondary end point and HbA1c target achievement  Cochran–Mantel–
Haenszel method
Noninferiority and, subsequently, superiority of Gla-300 compared with Gla-100
was assessed for the primary and main secondary end points using a hierarchical
step-down testing procedure
Study Participants
Glycemic Control
• Change in HbA1c
Gla-300  from 8.20% (0.91) [baseline] to 7.31% (0.91) [W26]
Gla-100  from 8.22% (0.92) [baseline] to 7.28% (0.84) [W26]
• Change in HbA1c (Participants ≥75 Years of Age)
Gla-300  from 8.17% (0.89) [baseline] to 7.29% (0.84) [W26]
Gla-100  from 8.18% (0.97) [baseline] to 7.39% (0.87) [W26]
• Plasma Glucose
reductions of 30.4 [2.2] mg/dL [Gla-300] and 31.8 [2.4] mg/dL [Gla-100], Similar results were
observed in participants ≥75 years of age
Hypoglycemia
Superiority of Gla-300 versus Gla-100  ITT population experiencing one or more confirmed or
severe hypoglycemic events occurring during either 2200–0859 h or 0000–0559 h  was not
detected
Annualized
Rates
HbA1c Target Achievement
Treatment Emergent Adverse Event
TEAEs  299 participants (58.9%) in the Gla-300 group and in 304 (60.2%) in the
Gla-100 group ,with infections (25.8% and 29.7% for Gla-300 and Gla-100,
respectively) the most commonly reported TEAEs.
The incidence of TEAEs in participants ≥75 years of age was similar to the overall
≥65 years population (59.3% for Gla-300 and 54.7% for Gla-100)
PICO
• (P) Patients
Older people (≥65 years) with type 2 diabetes
• (I) Intervention
Insulin Glargine-300
• C Comparison
Insulin Glargine-100
• (0) Outcome(s)
Reductions in HbA1c, Risk of confirmed and severe hypoglicemia, Change in FPG
 CHECKLIST OXFORD
1a. R- Was the assignment of patients to treatments randomised?
What is best? Where do I find the information?
Centralised computer randomisation is ideal and The Methods should tell you how patients were
often used in multi-centred trials. Smaller trials allocated to groups and whether or not
may use an independent person (e.g, the hospital randomisation was concealed.
pharmacy) to “police” the randomization.

This paper: Yes √ No  Unclear 

Comment:
Yes, this study used stratified random sampling. A total of 1,014 participants were randomized
to receive Gla-300 or Gla-100. Randomization was stratified by HbA1c at screening (<8.0/≥8.0%
[<64/≥64 mmol/mol]), previous use of insulin (naive/pretreated), and use of sulfonylurea or
meglitinide at screening (yes/no)
 1b. R- Were the groups similar at the start of the trial?
What is best? Where do I find the information?
If the randomisation process worked (that is, achieved The Results should have a table of "Baseline
comparable groups) the groups should be similar. The Characteristics" comparing the randomized groups
more similar the groups the better it is. on a number of variables that could affect the
There should be some indication of whether outcome (ie. age, risk factors etc). If not, there may
differences between groups are statistically be a description of group similarity in the first
significant (ie. p values). paragraphs of the Results section.

This paper: Yes √ No  Unclear 

Comment :
Overall, baseline characteristics were similar for the Gla-300 and Gla-100 groups ,although
participants ≥75 years of age had a lower mean estimated glomerular filtration rate, longer
duration of diabetes, a higher overall rate of diabetes-related complications, and a smaller
proportion were previously treated with insulin compared with the overall population.
 2a. A – Aside from the allocated treatment, were groups treated equally?
What is best? Where do I find the information?
Apart from the intervention the patients Look in the Methods section for the
in the different groups should be treated follow-up schedule, and permitted
the same, eg., additional treatments or additional treatments, etc and in Results
tests. for actual use.
This paper: Yes √ No  Unclear 
Comment:
Both groups administered basal insulins once daily. Any times of day were permissible provided
administration occurred at the same time each day ±3 h (Evening is recommended). insulin dose was
adjusted equally for both groups to achieve a target fasting self-monitored plasma glucose (SMPG)
level of 90–130 mg/dL. Participants in both groups continued their previous antihyperglycemic drugs
(except thiazolidinediones)
 2b. A – Were all patients who entered the trial accounted for? – and were they analysed in the
groups to which they were randomised?
What is best? Where do I find the information?
Losses to follow-up should be minimal – The Results section should say how many patients
preferably less than 20%. However, if few patients were randomised (eg., Baseline Characteristics
have the outcome of interest, then even small table) and how many patients were actually
losses to follow-up can bias the results. Patients included in the analysis. You will need to read the
should also be analysed in the groups to which results section to clarify the number and reason
they were randomised – ‘intention-to-treat for losses to follow-up.
analysis’.

This paper: Yes √ No  Unclear 

Comment:
Yes, of total 1014 participants, this study lost 61 participants (6%). This study used multiple
imputation approach for missing data to assess Change in HbA1c(primary end point) and FPG
from baseline to week 26.
 3. M - Were measures objective or were the patients and clinicians kept “blind” to which
treatment was being received?
What is best? Where do I find the information?
It is ideal if the study is ‘double-blinded’ – that is, First, look in the Methods section to see if there
both patients and investigators are unaware of is some mention of masking of treatments, eg.,
treatment allocation. If the outcome is objective placebos with the same appearance or sham
(eg., death) then blinding is less critical. If the therapy. Second, the Methods section should
outcome is subjective (eg., symptoms or describe how the outcome was assessed and
function) then blinding of the outcome assessor whether the assessor/s were aware of the
is critical. patients' treatment.

This paper: Yes No √ Unclear 

Comment:
No, SENIOR compared the efficacy and safety of insulin glargine 300 units/mL (Gla-300) with glargine 100
units/mL (Gla-100) in an open-label study.
1. How large was the treatment effect?

 Reductions in HbA1c --> comparable between treatment groups, with >50% of participants in either
age group achieving HbA1c of <7.5%. Reductions in FPG were also comparable between treatment
groups and between age groups, indicating that insulin was adjusted similarly in the overall
population and in participants ≥75 years of age. (98% +- 0.3% non inferioriy [Gla-300 vs Gla-100])
 Statistically significant reductions seen for rates of documented symptomatic hypoglycemia at any
time of day (24 h) for Gla-300
 Reductions in hypoglycemia for Gla-300 versus Gla-100 were more pronounced in individuals ≥75
years of age, with a significantly lower risk of documented symptomatic hypoglycemia at any time of
day (24 h) observed with Gla-300 compared with Gla-100 in this subgroup
 The incidence of TEAEs was similar between treatment groups for the overall population and for
participants ≥75 years of age
What is the measure? What does it mean?
Relative Risk  Supplementary Table

Absolute Risk Reduction (ARR) = risk of the outcome in the The absolute risk reduction tells us the absolute difference in the rates of
control group - risk of the outcome in the treatment events between the two groups and gives an indication of the baseline
group. This is also known as the absolute risk difference. risk and treatment effect. An ARR of 0 means that there is no difference
between the two groups thus, the treatment had no effect.
No Data
Relative Risk Reduction (RRR) = absolute risk reduction / Relative Risk Reduction (RRR) adalah komplemen dari RR dan mungkin
risk of the outcome in the control group. An alternative merupakan ukuran efek pengobatan yang paling sering dilaporkan. Ini
way to calculate the RRR is to subtract the RR from 1 (eg. memberi tahu kita pengurangan tingkat hasil pada kelompok perlakuan
RRR = 1 - RR) dibandingkan dengan kelompok kontrol.
No data
Number Needed to Treat (NNT) = inverse of the ARR and is The number needed to treat represents the number of patients we need
calculated as 1 / ARR. to treat with the experimental therapy in order to prevent 1 bad
outcome and incorporates the duration of treatment. Clinical significance
can be determined to some extent by looking at the NNTs, but also by
weighing the NNTs against any harms or adverse effects (NNHs) of
therapy.
No Data
2. How precise was the estimate of the treatment effect?
This study is reliable, for using valid and clear instrument to assess data.

Will the results help me in caring for my patient? (External Validity/Applicability)

The questions that you should ask before you decide to apply the results of the study to your
patient are:
 Is my patient so different to those in the study that the results cannot apply? No
 Is the treatment feasible in my setting? Yes
 Will the potential benefits of treatment outweigh the potential harms of treatment for my
patient? Yes