Review Article Remission rates and predictors of continuous subcutaneous insulin infusions in type 2 diabetes: a systematic review and meta-analysis
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Int J Clin Exp Med 2019;12(7):7985-7990
www.ijcem.com /ISSN:1940-5901/IJCEM0077410
Review Article
Remission rates and predictors of
continuous subcutaneous insulin infusions in
type 2 diabetes: a systematic review and meta-analysis
Zhifen Qiu1, Haitao Shi2, Fengxia Wang3, Fupeng Liu4, Qing Yang5
1
Department of Cardiology, Tengnan Hospital of Zaozhuang Mining Group, Shandong, China; 2Department of
Medical Administration, Tengnan Hospital of Zaozhuang Mining Group, Shandong, China; 3Research and Teaching
Office of Medicine and Health, Department of Nursing II, Vocational Education Center of Tengzhou City, Shandong,
China; 4Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, 89
Guhuai Road, Jining, Shandong, China; 5Department of Nutrition, Affiliated Hospital of Jining Medical University,
Jining Medical University, 89 Guhuai Road, Jining, Shandong, China
Received April 5, 2018; Accepted May 7, 2019; Epub July 15, 2019; Published July 30, 2019
Abstract: Background: Continuous subcutaneous insulin infusions (CSII) can induce glycemic remission, a situation
in which patients are able to maintain normoglycemia without anti-diabetic medications. The current systematic
review and meta-analysis was conducted to assess remission rates of patients treated with CSII, aiming to identify
predictors associated with remission outcomes. Methods: MEDLINE, Cochrane Library, and EMBASE databases
were searched for clinical trials assessing remission rates of CSII in type 2 diabetes patients. Clinical characteris-
tics of remission and non-remission groups were calculated as weighted mean differences (WMD) with associated
95% confidence intervals (CI). Remission rates were calculated by dividing the number of remission patients by the
number of analyzed patients. Inverse variance statistical methods and fixed-effects analysis models were used to
calculate pooled effects sizes, identifying possible remission predictors of CSII therapy. Results: Five studies, includ-
ing 550 participants, were enrolled in the current study. Long-term drug-free remission rates of patients treated
with CSII were 72.0% at 3 months of follow-up, 62.5% at 6 months, 50.4% at 12 months, and 37.1% at 24 months.
Three trials compared clinical characteristics between remission and non-remission groups. Before CSII treatment,
the remission group showed higher levels of BMI (WMD, 0.78), LnHOMA-IR (WMD, 0.17), and LnHOMA-B (WMD,
0.22). After treatment, the remission group showed lower levels of FBG (WMD, -0.45) and PBG (WMD, -1.19), along
with higher levels of LnHOMA-B (WMD, 0.23). Additionally, the remission group showed greater improvements in
PBG (WMD, -1.85) and LnHOMA-IR (WMD, -0.20; p < 0.01). Conclusion: CSII treatment maintained more than 50%
drug-free remission rates within 12 months of follow-up. Certain clinical characteristics of participants can predict
remission outcomes, including BMI, FBG, PBG, LnHOMA-IR, and LnHOMA-B.
Keywords: Continuous subcutaneous insulin infusion, remission rate, type 2 diabetes, predictor, meta-analysis
Introduction point where glycemic control can no longer be
achieved without exogenous insulin supple-
Type 2 diabetes is chiefly caused by genetic mentation [4].
and environmental factors. There are two main
pathological defects in the disease, insulin There is mounting evidence, however, indicat-
resistance and β-cell dysfunction [1]. The natu- ing that continuous subcutaneous insulin infu-
ral history of the disease is characterized by sions [CSII] used in the early stages of type 2
progressive deterioration of β-cell function over diabetes improve β-cell function and insulin
time, a pathological process that occurs regard- resistance, resulting in an extended period of
less of lifestyle and existing pharmacological glycemic remission. For example, drug-free
interventions [2, 3]. Therefore, typical clinical remission rates after 1 year were significantly
treatment of this disease consists of the se- higher in the CSII group (51.1%), compared to
quential addition of anti-diabetic drugs. Insulin those in the oral hypoglycemic agents group
therapy is often considered ultimately when (26.7%), according to a randomized controlled
functional β-cell capacity deteriorates to the trial [5]. To date, some clinical trials have dem-
Remission rates and predictors of CSII
onstrated that CSII decidedly improves drug- and Meta-analysis (PRISMA) recommenda-
free remission rates in newly diagnosed type 2 tions. Study quality assessment addressed
diabetes patients. The current meta-analysis selection bias, description of losses or exclu-
was conducted to assess remission rates of sions, and assessment of efficacy.
patients treated with CSII, aiming to identify
predictors associated with remission outcom- Statistical analysis
es.
Identifying predictors associated with remis-
Methods sion outcomes, this study compared clinical
characteristics between remission and non-
Literature search remission groups, including age, BMI, HbA1c,
FBG, PBG, LnHOMA-IR, LnHOMA-B, and AIR.
This meta-analysis included clinical trials that For age and BMI, only the baseline was com-
assessed remission rates of CSII in type 2 dia- pared. For other clinical characteristics, values
betes mellitus patients. Electronic databases, at baseline, after CSII, and changes were
including MEDLINE (via PubMed), the Cochrane compared.
Library, and EMBASE (via OvidSP), were se-
arched for clinical trials using specific terms, Pooled outcomes were weighted mean differ-
including (‘insulin’ OR ‘continuous subcutane- ences (WMD) with associated 95% confidence
ous insulin infusion’ OR ‘intensive insulin thera- intervals (CI). Inverse variance statistical meth-
py’) AND ‘Type 2 diabetes’ AND ‘Remission’. ods and fixed-effects analysis models were
Reference lists were manually checked for used to calculate pooled effects sizes. I² test-
identified reports and relevant reviews. ing was conducted to assess the magnitude of
heterogeneity between studies, with values
Inclusion criteria: (1) Conducted in adults aged
higher than 50% deemed to have high hetero-
18 years or older, with newly-diagnosed type 2
geneity. A random-effects model was used to
diabetes mellitus; (2) Patients treated with CSII
prove the robustness of analysis results. As a
therapy; and (3) Reported remission rates. If
rule of thumb, tests for funnel plot asymmetry
studies that had more than one interventional
should only be used when there are at least 10
group, only the arm that received CSII therapy
studies included in the meta-analysis. When
was analyzed. Exclusion criteria: (1) Number of
included patients was less than 50; (2) Duration there are fewer studies, the power of the tests
of follow-ups was shorter than 1 year; and (3) is too low to distinguish chance from real asym-
Duplicate reports for the same studies. metry. Thus, publication bias was not tested in
the current meta-analysis.
Data extraction and quality assessment
Results
Two reviewers, independently, screened all ti-
tles and abstracts. They investigated full texts A total of 446 studies were identified through
according to inclusion criteria, independently electronic search methods. Of these, 433 were
extracting data using standardized data extrac- excluded based on the title and abstract, leav-
tion sheets. Divergences were resolved by con- ing 13 studies for further assessment. Five
sensus. Information extracted included study studies fulfilled the inclusion criteria, providing
characteristics (first author’s name, year of data for 550 participants [5-9]. The study selec-
publication, study design, execute time, dura- tion process is shown in Figure 1.
tion of follow-up, enrolled number, and complet-
ed number) and clinical characteristics of Table 1 provides general information concern-
remission and non-remission groups (age, sex, ing included studies. These 5 studies were pub-
body mass index [BMI], HbA1c, fasting blood lished between 2004 to 2017 [5-9]. In these
glucose [FBG], postprandial blood glucose studies, the patients were given CSII therapy
[PBG], insulin resistance LnHOMA-IR, β-cell for 14-21 days and followed-up for 1-2 years. Of
function LnHOMA-B, and acute insulin re- the 550 patients that completed CSII treat-
sponse [AIR]). ment, 455 patients accomplished 1-year fol-
low-ups, with a dropout rate of 17.3%. Patients
Risk of bias was examined according to Pre- included in this systematic review had a mean
ferred Reported Items for Systematic Reviews baseline HbA1c of 9.8-11% and mean baseline
7986 Int J Clin Exp Med 2019;12(7):7985-7990Remission rates and predictors of CSII
Compared with the non-remis-
sion group, the remission gro-
up showed significantly higher
baseline BMI (WMD, 0.78; 95%
Cl, 0.03 to 1.53; p = 0.04),
LnHOMA-IR (WMD, 0.17; 95%
Cl, 0.05 to 0.29; p < 0.01), and
LnHOMA-B (WMD, 0.22; 95%
Cl, 0.06 to 0.37; p < 0.01).
After CSII treatment, the remis-
sion group had lower levels of
FBG (WMD, -0.45; 95% Cl,
-0.68 to -0.22; p < 0.01) and
PBG (WMD, -1.19; 95% Cl,
-1.66 to -0.72; p < 0.01), along
with higher levels of LnHOMA-B
(WMD, 0.23; 95% Cl, 0.09 to
0.37; p < 0.01). Moreover, the
remission group showed great-
Figure 1. Study selection pro- er improvements in PBG (WMD,
cess. -1.85; 95% Cl, -3.07 to -0.63; p
< 0.01) and LnHOMA-IR (WMD,
-0.20; 95% Cl, -0.33 to -0.07; p
BMI of 25.1-25.3 kg/m2. For most enrolled < 0.01). Comparison results are shown in
patients, excellent blood glucose control was Figure 3.
achieved in 3-7 days. Table 2 shows the risk of
bias in included studies. All studies reported I² testing was conducted to assess the magni-
adequate efficacy of CSII therapy (indicating tude of heterogeneity for these comparisons.
that the study assessed glycemic remission There were four comparisons with significant
rates of participants receiving CSII treatment). heterogeneity, including HbA1c, FBG, PBG after
The dropout rate of these studies ranged from CSII therapy, and improvements in LnHOMA-
3.8% to 21.3%. B (I² = 57, 56, 74, and 52%, respectively).
However, these results were stable. No signifi-
Figure 2 shows remission rates of CSII at differ- cant changes were noted, according to the ran-
ent follow-up times. Five studies with 527 dom-effects model used to test robustness.
patients were included in remission rate analy-
These three trials also reported differences in
sis [5-9]. Pooling the data of these studies, the
acute insulin response (AIR) between remission
proportion of participants with long-term drug-
and non-remission groups [6-8]. This parame-
free remission was 72.0% (177 of 246 patients)
ter together could not be pooled together, as
at 3 months of follow-up, 62.5% (140 of 224 two studies presented data as medians and
patients) at 6 months, 50.4% (243 of 482 interquartile ranges. Briefly, the remission
patients) at 12 months, and 37.1% (33 of 89 group showed better levels and greater
patients) at 24 months. improvements in AIR after CSII treatment.
Three studies compared clinical characteristics Discussion
between remission and non-remission groups
[6-8]. They defined the remission group as The number of people with diabetes has risen
patients that had long term glycemic control > from 108 million in 1980 to 422 million in
12 months, without medication. The non-remis- 2014. The worldwide prevalence of diabetes
sion group was defined as patients that re- among adults over 18 years of age has risen
lapsed within 12 months. A total of 286 patients from 4.7% to 8.5%. Prevalence of diabetes has
(remission group 150, non-remission group continually risen, rapidly, in developing coun-
136) were enrolled for analysis of predictors tries, especially in China and India. This may be
associated with remission outcomes. due to population growth, aging, lack of physi-
7987 Int J Clin Exp Med 2019;12(7):7985-7990Remission rates and predictors of CSII
Table 1. Characteristics of included studies
CSII Achieving
Enrolled Completed Men BMI HbA1c Follow-up
Author Year Age treatment glycemic control
number number (%) (kg/m2) (%) (year)
(day) (day)
Li Y [7] 2004 126 113 48.6 61.9 25.1 ± 3.7 10.0 ± 2.2 14 6.3 2
Weng J [5] 2008 133 124 50.0 66.2 25.1 ± 3.0 9.8 ± 2.3 14 4.0 1
Chen A [6] 2012 187 118 51.6 66.1 25.0 ± 3.0 11.0 ± 2.1 14-21 3-5 1
Liu L [8] 2015 104 100 48.3 68.3 25.3 ± 3.0 10.9 ± 2.1 14 3.5 1
Shi X [9] 2017 63 60 45 NA 24.7 ± 3.2 10.2 ± 2.8 21 6.5 2
NA, not available; BMI and HbA1c are shown as mean ± standard deviation.
Table 2. Assessment of studies for risk of bias ment of diabetes are very
Selection Efficacy Stopped Dropout Outcome assessment important issues.
Author
bias assessed early rate (%) accurate
In 1997, Ilkova first report-
Li Y [7] No Yes No 10.3 Yes ed the possibility of CSII
Weng J [5] No Yes No 6.8 Yes therapy resulting in drug-
Chen A [6] No Yes No 21.3 Yes free remission rates in re-
Liu L [8] No Yes No 3.8 Yes cently diagnosed type 2 dia-
Shi X [9] No Yes No 4.8 Yes betes patients [13]. After-
ward, many trials were per-
formed, evaluating remis-
sion rates associated with CSII therapy in
patients recently diagnosed with type 2 diabe-
tes patients. In the current research, pooled
results of five trails with 482 patients showed
that the proportion of participants in drug-free
remission was 72.0% at 3 months of follow-up,
62.5% at 6 months, 50.4% at 12 months, and
37.1% at 24 months. Additionally, two of these
included trials compared remission rates of
CSII with other treatments. Remission rates
were significantly higher in both CSII and multi-
ple daily insulin injection (MDI) groups (51.1%
in CSII and 44.9% in MDI) than in the oral hypo-
glycemic agents group (26.7%) at 1-year follow-
Figure 2. Remission rates of CSII therapy at different up [5]. However, the CSII only group showed
follow-up times. lower remission rates, compared with the CSII
+ exenatide group at both 1-year (39.7% vs
cal activity, and obesity [10]. In 2010, a nation- 71.2%) and 2-year (34.9% vs 56.1%) follow-ups
al study including 46,239 adults reported prev- [9].
alence rates of diabetes among Chinese peo- The current study analyzed clinical characteris-
ple. This study indicated that age-standardized tics associated with remission outcomes of
prevalence levels of total diabetes and predia- CSII on type 2 diabetes. Pooled results from
betes were 9.7% and 15.5% [11]. Given the three trials indicated that remission groups
younger age of incidence, diabetes is not only a had: (1) Higher baseline BMI, LnHOMA-IR, and
major public health problem, but also an eco- LnHOMA-B; (2) Lower levels of FBG and PBG,
nomic problem. It has been predicted that the along with higher levels of LnHOMA-B after CSII
majority of people with diabetes living in devel- treatment; and (3) Better improvement in PBG
oping countries will be aged 45-64 years by and LnHOMA-IR. These three trials also indi-
2030, with a loss of some of their most produc- cated that remission groups had better levels
tive years to disease, disability, or death [12]. and greater improvement in AIR after CSII
Therefore, prevention, detection, and treat- treatment.
7988 Int J Clin Exp Med 2019;12(7):7985-7990Remission rates and predictors of CSII
Figure 3. Clinical characteristics between remission and non-remission groups. IV, Inverse variance statistical meth-
od; Fixed, fixed effect analysis model; Random, Random-effects analysis model; ES, effect size; *significant differ-
ences between remission groups and non-remission groups (p < 0.05 or p < 0.01).
Other than these predictors, there may be different data forms reported and the limitation
other parameters associated with long-term of studies included, including AIR, attitudes
drug-free remission, including: (1) Attitude, toward diabetes, ∆TDD, and AGR. Fourth, all
patients remaining in drug-free remission had included studies were performed in China.
higher scores in positive attitudes, (belief in) Thus, the results might not be generalizable to
importance of care, care ability, self-care other populations, considering ethnic differ-
adherence, and less negative attitudes [6]; (2) ences in obesity or fat deposition. Asians typi-
Decrement of total daily insulin dose after eug- cally have a higher prevalence of diabetes than
lycemia was achieved (∆TDD). More patients in white people, when matched for BMI and waist
the upper ∆TDD tertile (≥ 25.0 IU) remained in circumference [16].
glycemic remission, compared with those in
the lower tertile (≤ 13.5 IU) (91.4% vs. 65.6%, P In conclusion, the current study is the first to
= 0.004) [14]; and (3) Acute glucagon response evaluate remission rates and predictors of con-
(AGR), similar with LnHOMA-IR. The remission tinuous subcutaneous insulin infusions in type
group showed higher levels of AGR at baseline 2 diabetes. CSII treatment maintained more
and lower levels after CSII treatment [15]. than 50% drug-free remission rates within 12
months of follow-up. Certain clinical character-
However, there were several limitations to the istics of participants can predict drug-free
current study. First, only a few trials evaluated remission outcomes, including BMI, FBG, PBG,
different remission rates between CSII and LnHOMA-IR, and LnHOMA-B.
other treatments. Based on the results of two
randomized control trials, CSII groups showed Disclosure of conflict of interest
similar remission rates, compared with MDI
groups. They showed higher rates, compared None.
with oral hypoglycemic agent groups, and lower
Address correspondence to: Qing Yang, Department
rates, compared with the SCII + exenatide
of Nutrition, Affiliated Hospital of Jining Medical
group. However, more randomized control trials
University, Jining Medical University, 89 Guhuai
are necessary to evaluate remission rates of
Road, Jining, Shandong, China. Tel: 86-152-6618-
different therapies. Second, the sample size
3279; E-mail: yangqingsd192@126.com
was relatively small. There were only three tri-
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