1. LETTRE
À LA
RÉDACTION
Thérapie
DOI: 10.2515/therapie/2013063
© 2013 Société Française de Pharmacologie et de Thérapeutique
Clinically Relevant
Efficacy of Insulin
Therapy in Patients
with Type 2 Diabetes
Efficacité cliniquement pertinente de l’insulinothérapie chez les patients diabétiques de type 2
Rémy Boussageon1, John-Michael Gamble2, François
Gueyffier4,5,6 and Catherine Cornu3,4,5,6
1 Faculty of Poitiers, Department of General Practice, Poitiers, France
2 School of Pharmacy, Memorial University of Newfoundland, St.
John’s, Newfoundland and Labrador, Canada
3 Inserm, Clinical Investigation Centre (CIC201), Lyon
4 Lyon University, Lyon, France
5 CHU Lyon, Louis Pradel Hospital, Clinical pharmacology,
Lyon, France;
6 CNRS, UMR5558, Lyon, France
Text received July 5th, 2013; accepted september 3rd, 2013
Keywords: insulin; randomized controlled trial; type 2 diabetes mellitus
Mots clés : diabète sucré de type 2 ; essai clinique randomisé ; insuline
Abbreviations: see end of article.
The aim of type 2 diabetes (T2D) treatment is supposed to be
glycaemic control. This is often described as a glucocentric
approach or “treat-to-target” model. Treatment success is based on
how close we can get to and maintain euglycemia and is usually
measured by HbA1c. Hyperglycemia is often considered to be a
causal factor responsible for micro- and macrovascular complications. In other words, any intervention that lowers HbA1c is
expected to reduce the risk of developing chronic complications.
However, several large randomized controlled trials (RCTs) have
failed to provide convincing evidence supporting this hypothesis,
regardless of treatment option.[1] No oral antidiabetic drug, including metformin,[2] has demonstrated efficacy on patient-centered
outcomes (e.g. blindness, leg amputations, or cardiovascular mortality) in a double-blind placebo-controlled RCT. High-quality trials
demonstrating superior efficacy of insulin versus placebo for
patient-centered outcomes are suprisingly absent. In this analysis,
we discuss the current state of clinical trial evidence on insulin treatment for T2D and provide a summary of the data for patient-centered
outcomes.
About 28% of patients with T2D take insulin in the United
States[3] and France.[4] The American diabetes association and the
European association for the study of diabetes (EASD) issued a consensus statement recommending insulin as a well-validated tier
1 option for the metabolic management of hyperglycemia in T2D.[5]
But what is the evidence supporting the efficacy of insulin therapy
on micro- and macrovascular complications?
To answer this question, we present appropriate studies from
our systematic review that was published in BMJ in July 2011.[1]
Out of the 13 studies that were included in our systematic review,
only two can be used to evaluate the clinical efficacy of insulin therapy in patients with T2D: the University group diabetes program
(UGDP)[6] and the United Kingdom prospective diabetes study
(UKPDS 33).[7] The UGDP trial randomized patients into a fixedinsulin dosage arm (ISTD) vs a variable-insulin arm (IVAR) [aim:
maintain blood glucose at normal levels]. UKPDS randomized
patients to insulin (aim: fasting plasma glucose (FPG) <6 mmol/L) versus diet alone (aim: FPG <15 mmol/L). The other studies included in
our meta-analysis did not specifically study the effect of insulin therapy
(UKPDS 34 and HOME studies [metformin], PROactive (pioglitazone), Dargie et al.[8] [rosiglitazone], UGDP phenformin or tolbutamid), but rather treatment strategies that mixed several antidiabetic
drugs (action in diabetes and vascular disease: preterax and diamicron controlled evaluation [ADVANCE], action to control cardiovascular risk in diabetes [ACCORD], veterans affairs diabetes trial
[VADT],veteransaffairstrial[VA1997]),ortheydonotpresentresults
on the endpoints chosen for this paper (the Kumamoto study).[9]
There is a description of included studies in table I. These randomized trials involved patients with newly diagnosed T2D, with a
mean age of 52 years, and a fasting glucose of around 1.44 g/L. They
were followed up for 10 years. We present relative risks with 99%
condidence intervals of the two studies’ endpoints.[6,7] For UGDP,
they are from the results of our meta-analysis (the UGDP-b Study)[1]
and for UKPDS 33, these relative risks were published in the main
study.[7] Insulin did not change any of the endpoints studied in
UGDP[6] or UKPDS 33[7] (table II), including mortality and microor macrovascular complications.
In 2013, there is still no convincing evidence that insulin is
effective at reducing mortality or other patient-oriented outcomes,
such as blindness and leg amputations. However, the lack of evidence and the few good-quality studies available make it difficult
to come to a definite conclusion. It is important to note that the
patients who participated in UGDP and UKPDS had diabetes that
was recently diagnosed. Their results cannot be extrapolated to longterm T2D patients, who are often poorly controlled. The results of
three recent mega-trials (ACCORD, ADVANCE, and VADT), that
used insulin to achieve glycemic targets, raised doubts on the efficacy of intensive-insulin therapy in patients with long-term T2D.
Although the reasons for the excess mortality observed in the
ACCORD[10] study are not yet clear, it is worth noting that 77.3%
of patients used insulin in the intensive treatment group versus
55.4% in the standard group (p<0.0001).

2. 2
Boussageon et al.
Table I. Characteristics of studies evaluating the efficacy of insulin therapy in T2D based on clinically pertinent criteria.
Study
Participants
Design
Acronym
(n)
Males
Age
Publication
Intensive/
(%) (years)
Blinded
year
standard
UGDP
414
29
52
1982[6]
204/210
UKPDS 33
1807
47
53
1998[7]
911/896
BMI
Duration
of known
diabetes
(years)
Follow-up
(years)
% Patients
with previous
CV events
Initial HbA1c
(%)
FPG (g/L)
Final HbA1c
(%)
Insulin group
Standard
NA
<1
10
9.5%
FPG 1.43
NA
28
<1
10
?
7.1%
FPG 1.45 g/L
7.0%
7.9%
BMI: body mass index; FPG: fasting plasma glucose; NA: not available; T2D: type 2 diabetes
Table II. Results on the main endpoints available from included studies.
Study
Acronym
Publication
year
All-cause
mortality
Cardiovascular
mortality
UGDP
1982[6]
RR=1.00
CI 99%
[0.75 at 1.32]
RR=1.00
CI 99%
[0.55 at 1.81]
UKPDS 33
1998[7]
RR=0.95
CI 99%
[0.75 at 1.21]
RR=0.93
CI 99%
[0.67 at 1.29]
Renal failure
or doubling
of serum
creatinine level
Fatal
or non fatal
amputations
RR=1.03
RR=1.65
RR=1.00
RR=0.99
CI 99%
CI 99%
CI 99%
CI 99%
[0.62 at 1.70] [0.53 at 1.85] [0.39 at 7.00] [0.47 at 2.06]
RR=0.93
CI 99%
[0.51 at 1.68]
RR=3.13
CI 99%
[0.16 at 60.5]
RR=0.93
RR=0.97
RR=0.88
RR=0.79
CI 99%
CI 99%
CI 99%
CI 99%
[0.75 at 1.16] [0.66 at 1.43] [0.52 at 1.50] [0.42 at 1.49]
RR=0.61
CI 99%
[0.14 at 2.66]
RR=0.98
CI 99%
[0.39 at 2.50]
All
myocardial
infarctions
Non fatal
myocardial
infarction
All strokes
Visual
deterioration
or blindness
CI: confidence interval; RR: relative risk
The fact that insulin did not reduce patient-oriented outcomes
in these trials is worth reflecting on. Two recent reviews examine
the theoretical underpinnings (including cellular and molecular
mechanisms) of the potential negative clinical consequences of insulin.[11,12] From a pathophysiological point of view, insulin is
required for patients with absolute insulin deficiency, as is the case
for those with type 1 diabetes. However, the role of exogenous insulin is not as clear in T2D because of insulin resistance and high circulating levels of endogenous insulin.[11] Observational studies have
shown a link between endogenous insulin levels and cardiovascular
risk.[13] In a retrospective cohort study, insulin therapy was associated with increased total mortality (adjusted hazard ratio
[HR] =1.75; 95% confidence interval [CI]: 1.24 to 2.47 for low insulin exposure and HR=2.79; 95% CI: 2.36 to 3.30 for high insulin
exposure, compared to no exposure).[14] Insulin is also associated
with an increased risk of developing cardiovascular disease, especially in patients with diabetes, heart failure,[15,16] and cancer.[17]
The mechanism for the excess risks associated with insulin is not
clearly understood.[11,12] This may be explained by the fact that
patients with T2D, who use insulin, are generally older, have diabetes for a longer period of time, suffer from more comorbidities,
possess more cardiovascular risk factors,andhavemoresevereinsulin
© Société Française de Pharmacologie et de Thérapeutique
resistance. Although observational studies may partially adjust for
these factors in their analysis, residual confounding may be responsible for the reported associations. However, it is also possible that
hypoglycemia plays a role (via sympathoadrenal activation, abnormal cardiac repolarization, increased thrombogenesis, inflammation, and vasoconstriction), there is a direct atherogenic effect, or an
unknown specific effect of insulin may be responsible for the
increased risks seen in these studies.[11,12] Certain adverse effects
of insulin therapy are well known and greatly affect patients’ quality
of life. Hypoglycemia occurs frequently and is sometimes severe and
fatal. Insulin is the second leading cause of drug-related hospital stays
in people over 65.[18] Moreover, hypoglycemia has been associated
with vascular complications and mortality in patients with T2D.[19]
Insulin is also associated with substantial weight gain and we fully
understand the long-term consequences of this.
In conclusion, we believe that the current evidence for recommending insulin therapy to prevent patient-oriented outcomes in
patients with T2D is weak. Given such uncertainty surrounding the
efficacy of insulin therapy, its well-known adverse effects (weight gain
and hypoglycemia) and long-term safety concerns,[11] we believe
that in the absence of stronger randomized clinical trial evidence,
insulin therapy should be undertaken with caution in these patients.
Thérapie

3. Insulin Therapy in Type 2 Diabetes
3
Acknowledgements
American diabetes association (ADA) and the European association for the
study of diabetes (EASD). Diabetologia 2012; 55(6): 1577-96
6.
UGDP. Effects of hypoglycemic agents on vascular complications in patients
with adult-onset diabetes. VIII. Evaluation of insulin therapy: final report.
Diabetes 1982; 31: 1-81
7.
Intensive blood-glucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in patients with type 2
diabetes, UKPDS 33. Lancet 1998; 352: 837-53
8.
We thank Kent Neal (supported by the French Cochrane Center)
for proofreading the manuscript.
Dargie HJ, Hildebrandt PR, Riegger GA, et al. A randomized, placebocontrolled trial assessing the effects of rosiglitazone on echocardiographic
function and cardiac status in type 2 diabetic patients with New York Heart
association functional class I or II heart failure. J Am Coll Cardiol 2007; 49:
1696-704
9.
Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the
progression of diabetic microvascular complications in Japanese patients
with non-insulin dependent diabetes mellitus: a randomized prospective
6 year study. Diab Res Clin Pract 1995; 28: 103-17
Conflicts of interests. The authors have no conflict of interests to
declare.
Abbreviations. ACCORD: action to control cardiovascular risk
in diabetes. ADVANCE: action in diabetes and vascular disease:
preterax and diamicron controlled evaluation; CI: confidence
interval; EASD: European association for the study of diabetes;
FPG: fasting plasma glucose; ISTD: fixed-insulin dosage arm;
IVAR: variable-insulin arm; RCTs: randomized controlled trials;
T2D: type 2 diabetes; UGPD: University group diabetes program;
UKPDS 33: United Kingdom prospective diabetes study; VA:
veteran affairs trial; VADT: veterans affairs diabetes trial.
Authors’ contributions. Literature search, figures, study design,
data collection: Rémy Boussageon, Catherine Cornu. Data analysis,
data interpretation: Rémy Boussageon, John-Michael Gamble,
François Gueyffier, Catherine Cornu. Writing: Rémy Boussageon,
John-Michael Gamble.
Funding. No funding was received for this article.
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Correspondence and offprints: Rémy Boussageon, General practice,
11 route du Clos Bardien, 79290 Saint Martin de Sanzay, France.
Email: remy.boussageon2@wanadoo.fr
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