J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://jocmr.elmerjournals.com

Original Article

Volume 18, Number 8, August 2026, pages 567-584

Comparative Effectiveness of Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Injections on Glycemic Control in Pediatric Type 1 Diabetes: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis

↓ Figure 1. PRISMA 2020 flow diagram illustrating the selection process of included studies. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

↓ Figure 2. Risk of bias traffic light plot for included randomized controlled trials using the Cochrane RoB 2.0 tool. Traffic light plot showing judgments for each domain: D1 (randomization process), D2 (deviations from intended interventions), D3 (missing outcome data), D4 (measurement of the outcome), and D5 (selection of the reported result). Green (+) indicates low risk, yellow (?) indicates some concerns, and red (-) indicates high risk.

↓ Figure 4. Forest plot comparing the effect of continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) on HbA1c (%) in pediatric type 1 diabetes. The plot displays the mean difference (MD) with 95% confidence intervals (CIs) for individual studies and the pooled random effects estimate. SD: standard deviation; HbA1C: glycated hemoglobin.

↓ Figure 5. Baujat plot diagnostic for heterogeneity. Studies in the top-right quadrant (e.g., Blair et al 2019 [42], Taeb et al 2025 [41]) contribute most significantly to the overall heterogeneity and influence the pooled effect size.

↓ Figure 6. Subgroup analysis forest plot for HbA1c (%) stratified by study design. SD: standard deviation; HbA1C: glycated hemoglobin; MD: mean difference; CI: confidence interval.

↓ Figure 7. Meta-regression bubble plot illustrating the relationship between follow-up duration (months) and the mean difference in HbA1c. The size of each bubble corresponds to the weight of the study in the meta-analysis. HbA1C: glycated hemoglobin.

↓ Figure 8. Cumulative meta-analysis. Forest plot for HbA1c, displaying the evolution of the pooled mean difference (MD) and 95% confidence interval as studies were added chronologically by publication year. HbA1C: glycated hemoglobin.

↓ Figure 9. Leave-one-out sensitivity analysis. Forest plot for HbA1c, showing the pooled mean difference and heterogeneity (I²) when each study is iteratively omitted. HbA1C: glycated hemoglobin.

↓ Figure 10. Forest plot comparing the effect of continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) on HbA1c using standardized mean difference (SMD). The random-effects model (DerSimonian–Laird) was used. SD: standard deviation; HbA1C: glycated hemoglobin; CI: confidence interval.

↓ Figure 11. Forest plot comparing the risk of severe hypoglycemia between continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) groups. Results are presented as risk ratios (RR) with 95% confidence intervals (CIs). HbA1C: glycated hemoglobin.

↓ Figure 12. Contour-enhanced funnel plot for the meta-analysis of HbA1c to assess publication bias. Shaded regions correspond to significance levels (P < 0.01, P < 0.05, and P < 0.10).

↓ Figure 13. Trial sequential analysis (TSA) for HbA1c. The cumulative Z-curve (blue) is plotted against the information size. The red lines represent the trial sequential monitoring boundaries for benefit/harm and futility.

↓ **Table 1.** Characteristics of Included Randomized Controlled Trials
Study (first author, year)	Country	Study design	Sample size (n)	Age (mean/range)	Diabetes duration	Intervention (CSII)	Control (MDI)	Follow-up duration	Primary outcomes reported
^aStudy design involved a crossover element but was analyzed as parallel groups for the first phase or as a combined cohort over time. BMI: body mass index; CGMS: continuous glucose monitoring system; CSII: continuous subcutaneous insulin infusion; DKA: diabetic ketoacidosis; HbA1c: glycated hemoglobin; MDI: multiple daily injections; NPH: neutral protamine Hagedorn; QoL: quality of life; RCT: randomized controlled trial; T1D: type 1 diabetes; TDD: total daily dose.
Taeb et al, 2025 [41]	Libya	Parallel RCT	54 (27 CSII, 27 MDI)	9.2 years (MDI), 8.9 years (CSII)	Not reported	CSII pump	MDI	End of study	QoL, HbA1c
Blair et al, 2019 [42]	UK	Parallel RCT (pragmatic)	293 (144 CSII, 149 MDI)	7months–15 years	New onset	CSII (aspart)	MDI (glargine/detemir + aspart)	12 months	HbA1c, severe hypoglycemia, DKA, QoL, cost
Weintrob et al, 2004 [43]	Israel	Crossover RCT	23	8–14 years	2.8–11.9 years	CSII (lispro)	MDI (NPH + regular)	3.5 months/arm	Glycemic patterns (CGMS), HbA1c
Weintrob et al, 2003 [44]	Israel	Crossover RCT	23	9.4–13.9 years	Mean 5.8 years	CSII (lispro)	MDI (NPH + regular)	3.5 months/arm	HbA1c, adverse events, QoL
Doyle et al, 2004 [45]	USA	Parallel RCT	32 (16 CSII, 16 MDI)	8–21 years	Mean 6.8 years	CSII (aspart)	MDI (glargine + aspart)	16 weeks	HbA1c, TDD, hypoglycemia
DiMeglio et al, 2004 [46]	USA	Parallel RCT	42 (21 CSII, 21 MDI)	< 5 years	> 12 months	CSII (lispro)	MDI (NPH/Lente + lispro)	6 months	HbA1c, hypoglycemia, parenting stress
Fox et al, 2005 [47]	USA	Parallel RCT	26 (13 CSII, 13 MDI)	1–6 years	> 6 months	CSII (lispro)	MDI (NPH + rapid analog)	6 months	HbA1c, hypoglycemia, QoL
Wilson et al, 2005 [48]	USA	Parallel RCT	19 (9 CSII, 10 MDI)	1.7–6.1 years	Mean 1.4 years	CSII	MDI	12 months	HbA1c, severe hypoglycemia, DKA, QoL
Nabhan et al, 2009 [49]	USA	Crossover/parallel^a	35 (18 CSII first, 17 MDI first)	< 5 years	Mean 1.6 years	CSII	MDI	12 months	HbA1c, BMI, neurocognitive
Skogsberg et al, 2008 [50]	Sweden	Parallel RCT	72 (34 CSII, 38 MDI)	7–17 years	New onset	CSII (aspart)	MDI (NPH + aspart)	24 months	HbA1c, hypoglycemia, DKA, satisfaction
Nuboer et al, 2008 [51]	Netherlands	Parallel RCT	38 (19 CSII, 19 MDI)	6–12 years	> 1 year	CSII (aspart)	MDI (NPH/glargine + aspart/regular)	3.5 months (randomized phase)	QoL, impact of disease, HbA1c
Cohen et al, 2003 [52]	Israel	Crossover RCT	16	14.5–17.9 years	> 2 years	CSII (lispro)	MDI (NPH + regular)	6 months/arm	HbA1c, adverse events, QoL
Mueller-Godeffroy et al, 2018 [53]	Germany	Parallel RCT	211 (106 CSII, 105 MDI)	6–16 years	> 6 months	CSII	MDI	6 months	QoL, diabetes burden, HbA1c
de Beaufort et al, 1989 [54]	Netherlands	Parallel RCT	30 (15 CSII, 15 MDI)	Mean 9.5 years (CSII), 7.0 yrs (MDI)	New onset	CSII	MDI (1–2 injections/day)	24 months	HbA1c, C-peptide

↓ Table 1. Characteristics of Included Randomized Controlled Trials

Study (first author, year)

Country

Study design

Sample size (n)

Age (mean/range)

Diabetes duration

Intervention (CSII)

Control (MDI)

Follow-up duration

Primary outcomes reported

^aStudy design involved a crossover element but was analyzed as parallel groups for the first phase or as a combined cohort over time. BMI: body mass index; CGMS: continuous glucose monitoring system; CSII: continuous subcutaneous insulin infusion; DKA: diabetic ketoacidosis; HbA1c: glycated hemoglobin; MDI: multiple daily injections; NPH: neutral protamine Hagedorn; QoL: quality of life; RCT: randomized controlled trial; T1D: type 1 diabetes; TDD: total daily dose.

Taeb et al, 2025 [41]

Libya

Parallel RCT

54 (27 CSII, 27 MDI)

9.2 years (MDI), 8.9 years (CSII)

Not reported

CSII pump

MDI

End of study

QoL, HbA1c

Blair et al, 2019 [42]

Parallel RCT (pragmatic)

293 (144 CSII, 149 MDI)

7months–15 years

New onset

CSII (aspart)

MDI (glargine/detemir + aspart)

12 months

HbA1c, severe hypoglycemia, DKA, QoL, cost

Weintrob et al, 2004 [43]

Israel

Crossover RCT

8–14 years

2.8–11.9 years

CSII (lispro)

MDI (NPH + regular)

3.5 months/arm

Glycemic patterns (CGMS), HbA1c

Weintrob et al, 2003 [44]

Israel

Crossover RCT

9.4–13.9 years

Mean 5.8 years

CSII (lispro)

MDI (NPH + regular)

3.5 months/arm

HbA1c, adverse events, QoL

Doyle et al, 2004 [45]

USA

Parallel RCT

32 (16 CSII, 16 MDI)

8–21 years

Mean 6.8 years

CSII (aspart)

MDI (glargine + aspart)

16 weeks

HbA1c, TDD, hypoglycemia

DiMeglio et al, 2004 [46]

USA

Parallel RCT

42 (21 CSII, 21 MDI)

< 5 years

> 12 months

CSII (lispro)

MDI (NPH/Lente + lispro)

6 months

HbA1c, hypoglycemia, parenting stress

Fox et al, 2005 [47]

USA

Parallel RCT

26 (13 CSII, 13 MDI)

1–6 years

> 6 months

CSII (lispro)

MDI (NPH + rapid analog)

6 months

HbA1c, hypoglycemia, QoL

Wilson et al, 2005 [48]

USA

Parallel RCT

19 (9 CSII, 10 MDI)

1.7–6.1 years

Mean 1.4 years

CSII

MDI

12 months

HbA1c, severe hypoglycemia, DKA, QoL

Nabhan et al, 2009 [49]

USA

Crossover/parallel^a

35 (18 CSII first, 17 MDI first)

< 5 years

Mean 1.6 years

CSII

MDI

12 months

HbA1c, BMI, neurocognitive

Skogsberg et al, 2008 [50]

Sweden

Parallel RCT

72 (34 CSII, 38 MDI)

7–17 years

New onset

CSII (aspart)

MDI (NPH + aspart)

24 months

HbA1c, hypoglycemia, DKA, satisfaction

Nuboer et al, 2008 [51]

Netherlands

Parallel RCT

38 (19 CSII, 19 MDI)

6–12 years

> 1 year

CSII (aspart)

MDI (NPH/glargine + aspart/regular)

3.5 months (randomized phase)

QoL, impact of disease, HbA1c

Cohen et al, 2003 [52]

Israel

Crossover RCT

14.5–17.9 years

> 2 years

CSII (lispro)

MDI (NPH + regular)

6 months/arm

HbA1c, adverse events, QoL

Mueller-Godeffroy et al, 2018 [53]

Germany

Parallel RCT

211 (106 CSII, 105 MDI)

6–16 years

> 6 months

CSII

MDI

6 months

QoL, diabetes burden, HbA1c

de Beaufort et al, 1989 [54]

Netherlands

Parallel RCT

30 (15 CSII, 15 MDI)

Mean 9.5 years (CSII), 7.0 yrs (MDI)

New onset

CSII

MDI (1–2 injections/day)

24 months

HbA1c, C-peptide

↓ **Table 2.** GRADE Evidence Profile: Continuous Subcutaneous Insulin Infusion (CSII) vs. Multiple Daily Injections (MDI) for Pediatric Type 1 Diabetes
Outcome	No. of participants (studies)	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Effect estimate (95% CI)	Certainty of evidence (GRADE)	Importance
^aRisk of bias: downgraded one level due to lack of blinding (inherent to intervention) across most studies and “some concerns” in randomization/allocation concealment in older trials. ^bInconsistency: downgraded one level due to high statistical heterogeneity (= 84.5%) that was not fully explained by the subgroup analysis. ^cImprecision: downgraded one level due to wide confidence intervals crossing the line of no effect (1.0 for RR, 0 for MD) or small sample sizes. ^dImprecision (very serious): downgraded two levels because of very few events (rare outcome), resulting in extremely wide confidence intervals and fragility of the estimate. ^eInconsistency: downgraded one level due to variability in measurement tools (PedsQL, DQOLY, etc.) and conflicting direction of effect across studies. GRADE: Grades of Recommendations Assessment, Development, and Evaluation; HbA1c: glycated hemoglobin; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio.
Glycemic control (HbA1c)	659 (11 RCTs)	Serious (–1)^a	Serious (–1)^b	Not serious	Not serious	Not detected	MD –0.36% (–0.80 to 0.08)	⊕⊕◯◯	Critical
								Low
Severe hypoglycemia	596 (9 RCTs)	Serious (–1)^a	Not serious	Not serious	Serious (–1)^c	Not detected	RR 0.83 (0.46 to 1.50)	⊕⊕◯◯	Critical
								Low
Diabetic ketoacidosis (DKA)	597 (6 RCTs)	Serious (–1)^a	Not serious	Not serious	Very serious (–2)^d	Not detected	RR 1.40 (0.61 to 3.21)	⊕◯◯◯	Critical
								Very low
Quality of life (QoL)	180 (2 RCTs)	Serious (–1)^a	Serious (–1)^e	Not serious	Serious (–1)^c	Not detected	Narrative synthesis (mixed)	⊕◯◯◯	Important
								Very low

↓ Table 2. GRADE Evidence Profile: Continuous Subcutaneous Insulin Infusion (CSII) vs. Multiple Daily Injections (MDI) for Pediatric Type 1 Diabetes

Outcome

No. of participants (studies)

Risk of bias

Inconsistency

Indirectness

Imprecision

Publication bias

Effect estimate (95% CI)

Certainty of evidence (GRADE)

Importance

^aRisk of bias: downgraded one level due to lack of blinding (inherent to intervention) across most studies and “some concerns” in randomization/allocation concealment in older trials. ^bInconsistency: downgraded one level due to high statistical heterogeneity (= 84.5%) that was not fully explained by the subgroup analysis. ^cImprecision: downgraded one level due to wide confidence intervals crossing the line of no effect (1.0 for RR, 0 for MD) or small sample sizes. ^dImprecision (very serious): downgraded two levels because of very few events (rare outcome), resulting in extremely wide confidence intervals and fragility of the estimate. ^eInconsistency: downgraded one level due to variability in measurement tools (PedsQL, DQOLY, etc.) and conflicting direction of effect across studies. GRADE: Grades of Recommendations Assessment, Development, and Evaluation; HbA1c: glycated hemoglobin; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio.

Glycemic control (HbA1c)

659 (11 RCTs)

Serious (–1)^a

Serious (–1)^b

Not serious

Not detected

MD –0.36% (–0.80 to 0.08)

⊕⊕◯◯

Critical

Low

Severe hypoglycemia

596 (9 RCTs)

Serious (–1)^a

Not serious

Serious (–1)^c

Not detected

RR 0.83 (0.46 to 1.50)

⊕⊕◯◯

Critical

Low

Diabetic ketoacidosis (DKA)

597 (6 RCTs)

Serious (–1)^a

Not serious

Very serious (–2)^d

Not detected

RR 1.40 (0.61 to 3.21)

⊕◯◯◯

Critical

Very low

Quality of life (QoL)

180 (2 RCTs)

Serious (–1)^a

Serious (–1)^e

Not serious

Serious (–1)^c

Not detected

Narrative synthesis (mixed)

⊕◯◯◯

Important

Very low