Efficacy and safety of insulin in type 2 diabetes: Meta-analysis of randomised controlled trials

Abstract

Background:
It is essential to anticipate and limit the social, economic and sanitary cost of type 2 diabetes (T2D), which is in constant progression worldwide. When blood glucose targets are not achieved with diet and lifestyle intervention, insulin is recommended whether or not the patient is already taking hypoglycaemic drugs. However, the benefit/risk balance of insulin remains controversial. Our aim was to determine the efficacy and safety of insulin vs. hypoglycaemic drugs or diet/placebo on clinically relevant endpoints.

Methods:
A systematic literature review (Pubmed, Embase, Cochrane Library) including all randomised clinical trials (RCT) analysing insulin vs. hypoglycaemic drugs or diet/placebo, published between 1950 and 2013, was performed. We included all RCTs reporting effects on all-cause mortality, cardiovascular mortality, death by cancer, cardiovascular morbidity, microvascular complications and hypoglycaemia in adults ≥ 18 years with T2D. Two authors independently assessed trial eligibility and extracted the data. Internal validity of studies was analyzed according to the Cochrane Risk of Bias tool. Risk ratios (RR) with 95 % confidence intervals (95 % CI) were calculated, using the fixed effect model in first approach. The I(2) statistic assessed heterogeneity. In case of statistical heterogeneity, subgroup and sensitivity analyses then a random effect model were performed. The alpha threshold was 0.05. Primary outcomes were all-cause mortality and cardiovascular mortality. Secondary outcomes were non-fatal cardiovascular events, hypoglycaemic events, death from cancer, and macro- or microvascular complications.

Results:
Twenty RCTs were included out of the 1632 initially identified studies. 18 599 patients were analysed: Insulin had no effect vs. hypoglycaemic drugs on all-cause mortality RR = 0.99 (95 % CI =0.92-1.06) and cardiovascular mortality RR = 0.99 (95 % CI =0.90-1.09), nor vs. diet/placebo RR = 0.92 (95 % CI = 0.80-1.07) and RR = 0.95 (95 % CI 0.77-1.18) respectively. No effect was found on secondary outcomes either. However, severe hypoglycaemia was more frequent with insulin compared to hypoglycaemic drugs RR = 1.70 (95 % CI = 1.51-1.91).

Conclusions:
There is no significant evidence of long term efficacy of insulin on any clinical outcome in T2D. However, there is a trend to clinically harmful adverse effects such as hypoglycaemia and weight gain. The only benefit could be limited to reducing short term hyperglycemia. This needs to be confirmed with further studies.

Full text

R E S E A R C H A R T I C L E Open Access
Efficacy and safety of insulin in type 2
diabetes: meta-analysis of randomised
controlled trials
Sylvie Erpeldinger
1
, Michaela B. Rehman
2*
, Christophe Berkhout
3
, Christophe Pigache
1
, Yves Zerbib
1,4
,
Francis Regnault
1
, Emilie Guérin
1
, Irène Supper
1
, Catherine Cornu
5,6,7
, Behrouz Kassaï
5,6,7
, François Gueyffier
5,7
and Rémy Boussageon
8
Abstract
Background: It is essential to anticipate and limit the social, economic and sanitary cost of type 2 diabetes (T2D),
which is in constant progression worldwide.
When blood glucose targets are not achieved with diet and lifestyle intervention, insulin is recommended whether
or not the patient is already taking hypoglycaemic drugs. However, the benefit/risk balance of insulin remains
controversial. Our aim was to determine the efficacy and safety of insulin vs. hypoglycaemic drugs or diet/placebo
on clinically relevant endpoints.
Methods: A systematic literature review (Pubmed, Embase, Cochrane Library) including all randomised clinical
trials (RCT) analysing insulin vs. hypoglycaemic drugs or diet/placebo, published between 1950 and 2013, was
performed. We included all RCTs reporting effects on all-cause mortality, cardiovascular mortality, death by
cancer, cardiovascular morbidity, microvascular complications and hypoglycaemia in adults ≥18 years with
T2D. Two authors independently assessed trial eligibility and extracted the data. Internal validity of studies
was analyzed according to the Cochrane Risk of Bias tool. Risk ratios (RR) with 95 % confidence intervals (95 % CI)
were calculated, using the fixed effect model in first approach. The I
2
statistic assessed heterogeneity. In case of
statistical heterogeneity, subgroup and sensitivity analyses then a random effect model were performed. The alpha
threshold was 0.05. Primary outcomes were all-cause mortality and cardiovascular mortality. Secondary outcomes
were non-fatal cardiovascular events, hypoglycaemic events, death from cancer, and macro- or microvascular
complications.
Results: Twenty RCTs were included out of the 1632 initially identified studies. 18 599 patients were analysed:
Insulin had no effect vs. hypoglycaemic drugs on all-cause mortality RR = 0.99 (95 % CI =0.92–1.06) and
cardiovascular mortality RR = 0.99 (95 % CI =0.90–1.09), nor vs. diet/placebo RR = 0.92 (95 % CI = 0.80–1.07) and
RR = 0.95 (95 % CI 0.77–1.18) respectively. No effect was found on secondary outcomes either. However, severe
hypoglycaemia was more frequent with insulin compared to hypoglycaemic drugs RR = 1.70 (95 % CI = 1.51–1.91).
Conclusions: There is no significant evidence of long term efficacy of insulin on any clinical outcome in T2D.
However, there is a trend to clinically harmful adverse effects such as hypoglycaemia and weight gain. The only
benefit could be limited to reducing short term hyperglycemia. This needs to be confirmed with further studies.
Keywords: Meta-analysis, Type 2 Diabetes Mellitus, Hypoglycaemic drugs, Insulin, Mortality, Morbidity, Randomised
Controlled Trials
* Correspondence: michaela.rehman@gmail.com
2
Department of Cardiology, CHU de Poitiers, 86000 Poitiers, France
Full list of author information is available at the end of the article
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Erpeldinger et al. BMC Endocrine Disorders (2016) 16:39
DOI 10.1186/s12902-016-0120-z
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Background
In 2030, according to the World Health Organization
[1], 366 million people worldwide will live with type 2
diabetes (T2D). This increase is linked to aging of the
population, the rise of obesity, the change in diagnostic
criteria of diabetes and more extensive screening [2].
Compared with the non-diabetic population of the same
age, all-cause mortality: (hazard ratio: 1.80 (95 % CI:
1.71 to 1.90) and cardiovascular mortality: 2.32 (95 % CI:
2.11–2.56) are increased in T2D [2].
Insulin is a natural vital treatment in type 1 diabetes,
because of the total absence of insulin secretion. In T2D
the lack of insulin is relative and endogenous insulin
levels are very high. [3, 4] In T2D, insulin is often pre-
scribed when blood glucose targets are not met despite
maximal dosages and combinations of oral hypoglycaemic
drugs.
The American Diabetes Association (ADA) and the
European Association for the Study of Diabetes (EASD)
published a consensus statement recommending insu-
lin as a well-validated tier 1 option for the metabolic
management of hyperglycaemia in T2D [5].
ADA/EASD [5] and the NICE [6] guidelines recom-
mend metformin as the first line oral hypoglycaemic
agent. However, although metformin is still considered
as the first line drug, a recent meta-analysis has shown a
controversial benefit/risk balance for metformin [7].
Another recent meta-analysis [8] demonstrated no
efficacy of sulfonylureas on cardiovascular morbidity or
mortality in T2D. Furthermore, studies analysing the
efficacy of metformin or sulfonylureas on clinical end-
points are scarce.
For these reasons, our objective is to analyse the
efficacy of insulin on clinically relevant endpoints in
T2D.
To answer this question we performed this meta-
analysis of randomized clinical trials (RCT) analysing the
short, medium and long-terms effects of insulin on
clinical outcomes in T2D. Clinical outcomes were defined
as mortality, morbidity and main adverse effects (such as
total and severe hypoglycaemic events).
Methods
Our methodology adheres to the PRISMA guidelines
(see PRISMA checklist: Additional file 1)
Data sources
Clinical trials were identified searching: Pubmed,
Embase and Cochrane Library. We included all trials,
with no language resctriction, published from January
1950 to April 2013. Keywords used were: “type 2
diabetes”,“diabetes mellitus”;“mortality”;“sudden death”;
“sudden death”,“cardiac”;“macrovascular”;“cardiovas-
cular or coronary disease”;“stroke”;“peripheral vascular
disease”;“microvascular”;“retinopathy”;“neuropathy”;
“diabetic nephropathy”;“kidney disease”;“hypoglycaemia”;
“hypoglycaemic agents”;“insulin”;“insulin, lente”;“insulin
aspart”;“insulin lispro”;“short-acting insulin”,“long-
acting”;“insulin isophane”;“insulin ultralente”.We
restricted our search to randomized clinical trials (RCTs),
systematic reviews and meta-analyses of RCTs. We manu-
ally searched the reference lists of systematic reviews to
check they had all already been identified in our study.
Search strategy is illustrated in the Additional file 2.
Study selection
We included RCTs comparing insulin regimens vs. a
hypoglycaemic drug or placebo/diet in T2D patients
aged 18 to 80 years. By excluding patients over the age
of 80, we excluded patients in which moderate hyper-
glcaemia is sometimes accepted, to reduce the risk of
hypoglycaemia. Insulin was either administered alone or
in combination with another hypoglycaemic agent. For
example: Insulin vs. hypoglycaemic dug, (Insulin +
hypoglycaemic drug) vs. (hypoglycaemic drug), Insulin vs.
placebo, Insulin vs. diet.
Two investigators independently assessed eligibility
(FR and EG). In case of discrepancy, a third observer
adjudicated the eligibility (FG or SE). The extraction
forms and the risk of bias assessments are attached as
Additional file 2.
Quality assessment
Two authors (FR and EG) independently assessed trial
quality. Internal validity was analyzed with the Cochrane
Risk of Bias tool [9]. These articles were then rated ac-
cording to methodological quality: good, moderate or low.
Outcomes
Primary outcomes were all-cause mortality and cardio-
vascular mortality. Secondary outcomes were non-fatal
cardiovascular events, (such as myocardial infarction and
stroke), hypoglycaemic events (total and severe), death
from cancer and macro- or microvascular complications
(such as blindness, or retinopathy). Hypoglycaemia re-
quiring the intervention of a third party was considered
as severe.
Two reviewers (FR and EG) independently extracted
the data for all the outcomes of interest.
Principal summary measures and statistical analysis
Analyses were done using Revman software version 5
(www.cc-ims.net/revman).
For all studies we calculated risk ratios (RR) with 95 %
confidence intervals, (95 % CI), using the fixed effect
model in first approach. Heterogeneity was investigated
with the I
2
statistic. It measures the proportion of overall
variation attributable to between study heterogeneity.
Erpeldinger et al. BMC Endocrine Disorders (2016) 16:39 Page 2 of 15
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I
2
values of 25 %, > 50 % and > 75 % refers respectively to
a low, substantial and considerable degree of hetero-
geneity. In case of statistical heterogeneity, we tried to
explain this with subgroup and sensitivity analyses then
with a random effect model. Statistical significance was
defined with an alpha threshold at 0.05.
Results
Figure 1 shows the selection of studies. The list of the
trials that were excluded after reviewing the abstract is
available on request (under reasons for exclusion). 20
trials were included in the final analysis, 8 were identi-
fied as citations from other meta-analyses. The 20 trials
compared insulin regimens vs. hypoglycaemic drugs
(Table 1). Four of the 20 studies also compared insulin
versus placebo or diet alone (Table 2). UGDP [10] and
UKPDS 33 [11] were the only studies analysing mortality
as a primary outcome. Eleven trials were graded as mode-
rate quality, 9 as good. For all other studies, primary and
secondary outcomes were surrogate endpoints whereas
morbidity, mortality and hypoglycaemic events were
reported as adverse events. Study characteristics are
shown in Tables 1 and 2.
Primary outcomes
Insulin regimens did not affect mortality compared to
placebo or diet alone (RR: 0.92, 95 % CI: 0.80 to 1.07)
(Fig. 2). Results remained non-significant when insulin
regimens were compared to hypoglycaemic drugs (RR:
0.99, 95 % CI 0.92–1.06) (Fig. 3). Insulin regimens showed
no efficacy on cardiovascular mortality versus placebo/
diet (RR: 0.95, 95 % CI 0.77 to 1.18) (Fig. 4), nor versus
Fig. 1 Study Flow Chart
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Table 1 Insulin versus hypoglycaemic drugs
Studies Methodological quality:
Low/moderate/good
(Blinding Yes/No)
Participants (Ins/C) TreatmentsTreatments Follow-up (weeks) Inclusion criteria Primary outcome
Alvarsson
2009 [32]
Moderate (No) 51 (23/28) Insulin/glibenclamide 104 FBG: [6; 12 mmol/L]
35–75 years
HbA1c, metabolic
control
Aschner
2012 [33]
Good (No) 515 (250/265) Met/S + Insulin Glargine/Sitagliptin 24 [7 %; 11]
35–70 years
BMI = [25–45 kg/m
2]
HbA1c
Bunck
2009 [34]
Moderate (No) 69 (33/36) Met + Insulin glargine/exenatide 52 [6,5 %; 9,5]
35–75 years
BMI = [25–40 kg/m
2]
Metabolic control
Davies
2009 [35]
Good (No) 233 (117/118) OHD (Met/S/TZD) + Insulin
glargine/exenatide
51 [7,5 %;10 %]
BMI > 27 kg/m
2
HbA1c
Diamant
2010 [36]
Moderate (No) 467 (234/233) OHD (Met/Met-S) + Insulin
glargine/exenatide
26 [7 %; 11 %] - BMI : [25-40 kg/m
2
] HbA1C
Gallwitz
2011 [37]
Moderate (No) 363 (181/182) Met + Insulin Aspart/exenatide 26 [6,5 %; 10] HbA1c
Gerstein
2006 [38]
Moderate (No) 405 (206/199) OHD + Insulin glargine/conventional 24 [7,5 %; 11 %]
BMI: [21–41 kg/m
2
]
18–80 years
HbA1c
Gerstein
2012 [39]
Good (No) 12527 (6273/6264) Lifestyle recommendations and
OHD + Glargine/Conventional
care/omega3/placebo
6 years Recent diabetes/Glucose Intolerance/ Composite of CV
events
Hartemann
2011 [40]
Moderate (No) 27 (13/14) OHD (Met/S) + Insulin
NPH/Pioglitazone
24 [7,5 %; 9,5 %]
BMI > 26 kg/m
2
18–80 years
HbA1c
Heine 2009
[41]
Moderate (No) 551 (267/282) OHD (Met/S) + Insulin
Glargine/Exenatide
26 [7 %; 10 %]
BMI: [25–45 kg/m
2
]
35–75 years
HbA1c
Hollander
2009 [42]
Moderate (No) 217 (107/110) OHD (Met + Sitagliptin) + Insulin
Detemir/+/−S
26 [7,5 %; 10 %]
BMI < 40 kg/m
2
HbA1c
Nauck 2007
[43]
Moderate (No) 501 (248/253) OHD (Met/S) + Insulin
Aspart/Exenatide
52 [7 %; 11 %]
BMI : [25–40 kg/m
2
]
30–75 years
HbA1c
Nauck 2012
[44]
Good (No) 1037 (364/351/322) Met + S + Taspoglutide
10/taspoglutide
20/Insulin Glargine
24 [7 %; 10 %]
BMI : [25–45 kg/m
2
]
18–75 ans
HbA1c
Reynolds
2007 [45]
Moderate (No) 40 (20/20) OHD (Met/S) + Insulin
Aspart/Rosiglitazone
26 [8 %; 12 %] HbA1c, metabolic
control
Rosenstock
2006 [46]
Good (No) 217 (105/112) OHD (Met/S) + Insulin
Glargine/Rosiglitazone
24 [7,5 %; 11 %]
BMI > 25 kg/m
2
>18 years
HbA1c
UKPDS 24
1998 [47]
Good (No) 458 (178/231/49) Insulin/Chlorpropamide or
Glyburide/Metformin
6 years Diet failure
UKPDS 33
25–60 years
HbA1c/FPG
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hypoglycaemic drugs (RR: 0.99, 95 % CI 0.90 to 1.09)
(Fig. 5).
Secondary outcomes
Compared to placebo or diet alone, insulin regimens did
not affect sudden death (RR: 0.75, 95 % CI 0.45 to 1.27)
(Fig. 6), myocardial infarction (RR: 1.07, 95 % CI 0.90 to
1.28) (Fig. 7), strokes (RR: 0.88, 95 % CI 0.59 to 1.32)
(Fig. 8) or leg amputations (RR; 0.92, 95 % CI 0.48 to
1.74) (Fig. 9),
Results remained non-significant when insulin regi-
mens were compared to hypoglycaemic drugs. (Figs. 10,
11, 12 and 13)
Insulin regimens did not affect blindness (RR: 1.10,
95 % CI: 0.76 to 1.60) (Fig. 14), or renal failure or
doubling of serum creatinine level (RR: 0.68, 95 % CI,
0.43 to 1.06) (Fig. 15), compared to placebo or diet alone.
Regarding retinal photocoagulation, the only avail-
able data was from UKPDS 33 [11] which compared
insulin versus diet. In the insulin group, there was a
significant decrease in retinal photocoagulations (RR:
0.70, 95 % CI: 0.53 to 0.94).
No data was available for neuropathy.
Compared to oral hypoglycaemic drugs, the risk of
hypoglycaemic events and major hypoglycaemia were
significantly higher in the insulin group (RR: 2.62; 95 % CI
2.48 to 2.77 and RR: 2.78, 95 % CI 2.30 to 3.36 respec-
tively) (Figs. 16 and 17)
Data from UGDP and UKPDS on these criteria have
not been published and it was not possible to assess the
effect of insulin vs. placebo/diet.
The only data available on death from cancer were
from UKPDS [12] and UGDP [13], versus placebo/diet.
Results were not significant, (RR: 0.82, 95 % CI 0.58 to
1.15) (Fig. 18). There is no data analysing insulin vs.
hypoglycaemic drugs.
Discussion
This meta-analysis from 20 RCT analysing 18,599 T2D
patients showed no benefit of insulin vs. hypoglycaemic
drugs or vs. diet/placebo on all-cause mortality, cardio-
vascular mortality, micro and macro vascular complica-
tions, except for retinopathy requiring photocoagulation.
This last result comes from a single open label trial, and
it is not possible to test its reproducibility. Moreover,
regarding all types of hypoglycaemic events, insulin is
significantly more harmful than other active treatments.
There is no increase in death by cancer with insulin
therapy vs. placebo/diet. (Fig. 18)
Data comparing the efficacy of insulin versus diet/
placebo on cardiovascular mortality are scarce. Only two
studies (2,426 patients) analysed mortality as a primary
outcome: UGDP [10] and UKPDS 33 [11]. The other stu-
dies were based on surrogate outcomes, like HbA1c or
other forms of ‘metabolic control’. Neither of these studies
showed significant results regarding cardiovascular or all-
cause mortality.
Table 2 Insulin versus hypoglycaemic drugs and placebo or diet
Studies Methodological quality:
low, moderate, good
(BlindingY/N)
Participants (I/C) Treatment Follow-up
(weeks)
Inclusion criteria Primary outcome
Blicklé 2009 [48] Moderate (No) 102 (103/108) OHD (Met/S) + Insulin
Glargine/Lifestyle
management
36 weeks [7 %; 8 %]
[40y; 75y]
BMI: [24;35 kg/m
2
]
HbA1c
Russell Jones
2006 [49]
Good (No) 581 (234/115/232) OHD (Met/S) + Insulin
Glargine/Liraglutide
placebo/Liraglutide
26 [7 %; 10 %]
BMI < 40 kg/m
2
HbA1c
UKPDS 33 [13] Good (No) 3041 (911/1234/896) Insulin/Chlorpropamide
or glibenclamide/diet
10 years 25-65 years
FBG 6,1–15 mmol/L
CV Morbimortality
UGDP [13,50–55] Good (Yes) 1027 (414/204/204/205) Insulin/Tolbutamide/
Phenformin/placebo
10 years Diabete < 1 year Mortality
Iinsulin, Ccontrol, OHD oral hypoglycaemic drugs, Met metformin, Ssulphonylureas, TZD thazolidones, BMI body mass index, CV cardiovascular
Fig. 2 Death (Insulin vs. placebo/diet)
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The small number of trials accessing these outcomes
could explain the lack of significant results regarding all-
cause mortality and cardiovascular mortality. Among
these studies, two compare insulin with agents that have
been withdrawn from the market, (tolbutamide, a sulfo-
nylurea and phenformin, in the University Group Dia-
betes Program study). The sensitivity analysis removing
these two studies did not affect the results, but cancelled
heterogeneity across trials.
Results of our comparison with placebo/diet should be
taken with caution, as we cannot exclude a 20 % reduc-
tion or a 7 % increase in all-cause mortality. We cannot
exclude a reduction of 23 % or an 18 % increase in
cardiovascular mortality either.
Clinical efficacy of insulin needs to be demonstrated
with long-term trials. Insulin is currently prescribed
to millions of patients without a proven benefit. The
only two long-term studies available have significant
Fig. 3 Death (Insulin vs. hypoglycaemic drug)
Fig. 4 Cardiovascular death (Insulin vs. placebo/diet)
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Fig. 5 Cardiovascular death (Insulin vs. hypoglycaemic drug)
Fig. 6 Sudden death (Insulin vs. placebo/diet)
Fig. 7 All myocardial infarctions (Insulin vs. placebo/diet)
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Fig. 9 Amputation (Insulin vs. placebo/diet)
Fig. 10 Sudden death (Insulin vs. hypoglycaemic drug)
Fig. 8 Stroke (Insulin vs. placebo/diet)
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weaknesses. The first, the UKPDS trial was open label
and treatment could be increased according to blood
glucose levels in the diet control group. 16 % of
patients received insulin in the diet alone group [11].
Moreover, this study has major methodological short-
comings (was not double-blind, endpoints were added
andfollow-upwaslengthenedduringthetrialafter
observing negative results) [12–14]. Finally, concomi-
tant treatments were not reported in the publications
[15]. The second study was interrupted, because of
increased mortality in the tested agent group, tolbuta-
mide, which has been withdrawn from the market.
The UGDP trial included T2D patients, according to
diagnostic criteria in use at the time of patient recruitment
(i.e., from 1961 to 1965) and was open label (comparisons:
standard dose insulin vs adapted insulin vs placebo). After
a 10-year follow-up (12.5 years on average), there were 15
to 18 % dropouts. The insulin regimens and concomitant
treatments were different to those used today.
Our meta-analysis demonstrates no efficacy of insulin
vs. placebo/diet on macrovascular complications (fatal or
global). Furthermore, insulin does not decrease relevant
microvascular outcomes such as blindness or renal
failure either. However, significant results are found for
Fig. 11 All myocardial infarctions (Insulin vs. hypoglycaemic drug)
Fig. 12 All strokes (Insulin vs. hypoglycaemic drug)
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Fig. 13 Amputation (Insulin vs. hypoglycaemic drug)
Fig. 14 Blindness (Insulin vs. placebo/diet)
Fig. 15 Renal Failure or doubling of serum creatinine (Insulin vs. placebo/diet)
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retinopathy requiring laser photocoagulation. This effect
should be taken with caution since it is derived from the
single UKPDS trial, whose limits we have already under-
lined. The number needed to treat is about 30 at 10 years.
We analysed all types of insulin regimens, although
“biphasic insulin aspart”or biphasic insulins are reported
to induce a better metabolic control (estimated from
fasting blood glucose and HbA1c) than other regimens
(conventional insulin or other analogue insulin) [15].
We made this choice because there is no evidence that
any insulin regimen was better at preventing clinically
relevant outcomes like mortality or macro- or micro-
vascular complications; and because there was too little
data to analyse each single insulin regimen separately.
As the efficacy of insulin has not been proven, the safety
analysis is essential. Our meta-analysis confirms that
Fig. 16 All hypoglycaemic events (Insulin vs. hypoglycaemic drug)
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compared to other hypoglycaemic drugs, there is a
serious risk of hypoglycaemia with insulin. According
to UKPDS [11] theNNHisabout5to6at10yearsfor
hypoglycaemia and 91 each year for a major hypoglycaemic
event.
Previous meta-analyses have reported that various
insulin regimens increase hypoglycaemia equally [16].
The link between severe hypoglycaemia and mortality
has been reported in several studies [17] or, indirectly,
when comparing conventional to intensive treatments
Fig. 17 Major hypoglycaemic events (Insulin vs. hypoglycaemic drug)
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[18–21]. Insulin treatment could therefore be considered
as a high risk treatment option.
It is noteworthy that insulin is the second cause of
drug-related hospital admissions in patients over 65 [22].
In two U.S. representative surveys over a 4 year period,
Geller and al. estimated there were nearly 100,000
emergency department visits per year for insulin-related
hypoglycaemia and errors [23], among which almost
one-third required hospitalization. The estimated rate of
severe neurological sequelae was 60 %. Patients over 80
treated with insulin were more than twice as likely to
visit the emergency department and nearly 5 times as
likely to be hospitalized. Moreover there is some
evidence that hypoglycaemia may increase the risk of
dementia [24].
Another well-known side effect of insulin-based regi-
men is weight gain [25], which secondarily increases
insulin resistance.
The fact that insulin has shown no impact on clinically
relevant outcomes is of major importance. Theoretically,
insulin has potential negative clinical consequences, due
to the underlying cellular and molecular mechanisms
[3, 4]. From a patho-physiological point of view it is
understandable that insulin is vital in the case of absolute
insulin deficiency, such as type 1 diabetes. However, in
T2D, where insulin resistance and high circulating levels
of endogenous insulin are key concepts, the role of
exogenous insulin is unclear. Observational studies have
shown an association between endogenous insulin levels
and cardiovascular risk, [26] and do not seem to be in
favour of exogenous insulin either. In a retrospective
cohort study, insulin therapy was associated with an
increase in total mortality, (adjusted hazard ratio [HR] =
1.75; 95%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) [27]. Other observational stu-
dies suggest an increased risk of cancer [28]. Our meta-
analysis of RCTs shows no increase in deaths by cancer
and cancer cases were not reported in many of the
included studies. However, these results are to be taken
with caution due to the possible lack of power of our
meta-analysis. In vitro, the mitogenic effect of insulin is
well established [29, 30].
The underlying mechanism of the higher risk asso-
ciated with insulin is unclear. Positive associations could
be explained by confounding factors: patients with T2D
using insulin are usually older, with a longer history of
diabetes, more comorbidities, at higher cardiovascular
risk and with greater insulin resistance. Although obser-
vational studies may partially adjust for these factors,
residual confounding factors may be responsible for the
reported associations. However, it is also possible that
hypoglycaemia plays a role (via sympathoadrenal activa-
tion, abnormal cardiac repolarization, increased throm-
bogenesis, inflammation and vasoconstriction [3, 4]) or
that a direct atherogenic/mitogenic effect exists (cell
growth, differentiation and proliferation [29, 30]), or that
there is another specific effect of insulin that remains
unknown.
Implications for clinical practice
Insulin for T2D should only be used when no other
treatment is available, to prevent short-term acute
complications (such as hyperosmolar coma or ketoaci-
dosis in case of an infection) or when the lack of insulin
per se assigns patients in a high risk group.
This meta-analysis, as well as two other recent meta-
analyses on metformin [7] and sulfonylureas [8], dis-
credits blood glucose and HbA1c as valid surrogate
outcomes for morbidity in T2D. The HbA1c target
should be reconsidered since “the lower the better”
model is censored by the increased mortality in the
ACCORD study [18]. “The lower the better”and “treat
to target”models, greatly increased requirements for
insulin in patients with T2D (in the UK: 137,000 patients
in 1991 vs. 421,000 in 2010 [31]).
The most appropriate treatment target in T2D is reduc-
tion in global cardiovascular risk. Although statins and
angiotensin converting enzyme inhibitors have shown
their efficacy to reduce cardiovascular mortality, for now,
insulin has not.
Implications for research
Further long-term studies are needed to establish
whether insulin is beneficial in T2D.
Conclusions
In T2D, insulin is recommended as an alternative or in
combination with oral hypoglycaemic drugs when blood
Fig. 18 Death from cancer (Insulin vs. placebo/diet)
Erpeldinger et al. BMC Endocrine Disorders (2016) 16:39 Page 13 of 15
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

glucose targets are not achieved. Our meta-analysis does
not support these recommendations, showing no long
term benefit on cardiovascular risk or other clinical
outcomes. Moreover our analysis has shown harmful
adverse effects such as hypoglycaemia. The only benefit
could be limited to reducing short term hyperglycaemia
to improve symptoms (thirst, polyuria, asthenia, blurred
sight) and to avoid acute complications (infection,
hyperosmolar coma). Therefore, there is a great need for
further studies.
Additional files
Additional file 1: PRISMA checklist. (DOC 62 kb)
Additional file 2: Appendix with search strategy. (DOCX 28 kb)
Abbreviations
95%CI, 95 % confidence interval; ADA/EASD, American Diabetes Association/
European Association for the Study of Diabetes; HR, hazard ratio; NICE,
National Institute for Health and Care Excellence; RR, risk ratio; T2D, type 2
diabetes; UGDP, University Group Diabetes Program; UKPDS, United
Kingdom Prospective Diabetes study
Acknowledgments
The authors would like to thank Bernd Richter for his commentary and
proofreading the English. Permission was obtained for this acknowledgment.
SE and RB had full access to all the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis.
Funding
There was no funding for this work.
Availability of data and materials
All data and materials are from published papers and are available.
Authors’contributions
SE, EG, FR, and FG conceived the study. SE, FR, EG, CC and RB extracted the
data and reviewed the selected papers. SE, FR, EG, FG and RB performed the
statistical analysis. SE, MR, CB, YB, IS, BK, FG and RB drafted the manuscript.
SE, MR, CC, FG and RB interpreted the results and performed a critical review.
All authors gave final approval of the version to be published; agree to be
accountable for all aspects of the work in ensuring that questions related to
the accuracy or integrity of any part of the work are appropriately
investigated and resolved.
Competing interests
All authors have completed the Unified Competing Interest form at
www.icmje.org/coi_disclosure.pdf and declare that they do not have any
financial interests that may be relevant to the submitted work.
Consent for publication
not applicable
Ethics approval and consent to participate
Not required.
Author details
1
University college of General Medicine, University Claude Bernard Lyon 1,
Lyon, France.
2
Department of Cardiology, CHU de Poitiers, 86000 Poitiers,
France.
3
Department of General Medicine, University Lille-Nord de France,
Lille 2, Lille, France.
4
SCF SHS/S2HEP (EA 4148), University Claude Bernard
Lyon 1, Lyon, France.
5
UMR 5558, CNRS, Université Claude Bernard Lyon 1,
Lyon, France.
6
Clinical Investigation Centre, INSERM CIC1407, Lyon, France.
7
Clinical Pharmacology and Clinical Trials Department, Hospices Civils de
Lyon, Lyon, France.
8
Department of General Medicine, Université de Poitiers,
Poitiers, France.
Received: 9 March 2016 Accepted: 28 June 2016
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