Risk of Hypoglycemia Associated with Different Insulin Delivery Systems in

Type I Diabetes Mellitus: A Meta-analysis

Eman Biltaji,1,2 Kaitlin Kuo, 1,2 Mukul Singhal,1,2

Carrie McAdam Marx, 1,2 Joanne LaFleur, 1,2,3 Gregory Stoddard4

1. Department of Pharmacotherapy, University of Utah

2. Pharmacotherapy Outcome Research Centre (PORC), University of Utah

3. VA Salt Lake City Health Care Systems, Salt Lake City, Utah, USA.

4. Orthopedic Surgery Operations, University of Utah

DM Type I Statistics: USA• Incidence:

– More than 15,000 child and 15,000 adult/year

– Approximately 80 people/day• Prevalence:

– Around 3 million– Between 2001 and 2009, increase in

prevalence in people under age 20 is 23%

Source: JFDR. Diabetes type 1 facts. Available at: https://jdrf.org/about-jdrf/fact-sheets/type-1-diabetes-facts/

DM type 1 Management • Management • Problems

– Complex treatment algorithms

– Different insulin • Types• Combinations• Delivery systems

– Frequent Monitoring– Side effects

Source: American Society of Clinical Endocrinologists. https://www.aace.com/

Prognosis

• Most DM type 1 patients do NOT achieve their glycemic targets despite the advances in insulin analogues and delivery systems.2

Sources1. Nathan et al. N Engl J Med 20052. The Diabetes Control and Complications Trial Research Group. JAMA 2003

↑ Glycemic Control

↓ Microvascular & Macrovascular Complications1

Why?

Treatment Side Effects

Hypoglycemia

Hyperglycemia

Insulin Therapy

Source: Cryer. Diabetologia 2002

Hypoglycemia• Choudhary (Diabet Med 2010)

– Patient reported non-severe hypoglycemia:• 2.7 episodes/patient/week• Commonly during the night

• Juvenile Diabetes Research Foundation (Diabetes Care 2010)– Nocturnal hypoglycemia duration:

• ≥ 1 hour → 47%• ≥ 2 hours → 23%• ≥ 3 hours → 11%

Improving glycemic control…

Insulin Delivery System

Open Loop

MDI

CSII Alone

CSII + SMBG

Closed Loop

CSII + automatic monitoring

Dual Hormone

Sources: Farmer et al. The Journal of pharmacy and pharmacology. 2008Thabit et al. Endocrinology and metabolism clinics of North America. 2012

CSII: Continuous subcutaneous insulin infusion, MDI: Multiple Dose Injection, SMBG: Self monitoring blood glucose,

Closed-loop Insulin Delivery System

Image Source: Mayo Clinic. Available at http://www.mayo.edu/research/labs/artificial-pancreas/overview

Benefits

Open loop• More patient control• With CGM, provides

real time information on glucose values and trends

Closed loop• Improve glycemic

control• More convenient

– No need for human interaction

– Less frequent monitoring

– Improve QoL

• Avoid hypoglycemia ?Source: Thabit et al. Endocrinology and metabolism clinics of North America. 2012

Risks

Open loop• Not enough control• Needs CGM

– Compliance to wear device

• Hypoglycemia– Nocturnal

• Patient education

Closed loop• Insulin accumulation• Inappropriate

algorithms• Individual variability• Reliability and

accuracy of monitoring

Source: Thabit et al. Endocrinology and metabolism clinics of North America. 2012

Objective

• To assess the risk of hypoglycemia associated with closed-loop insulin delivery system compared to open-loop insulin delivery system among type 1 diabetic patients

Methods

Databases Used

• Comprehensive search of bibliographic databases including

‒ PubMed‒ Cochrane ‒ DynaMed‒ Scopus

‒ CINAHL‒ Clinicaltrials.gov‒ Conferences

(ADA)

Search Terms(Closed loop insulin) OR (Artificial pancreas)

AND

Diabetes

AND

(Trial OR Trials) AND Clinical

OR ((Random or randomly or randomized) AND (Trial OR Trials))

OR “clinical trial” OR “clinical trials” OR “controlled clinical trial” OR “controlled clinical trials”

Included Studies

• Inclusion– Clinical trial– Diabetes (type I)– Closed loop– Open loop (as

comparison)– English

• Excluded– If older than 2005

Statistical Analysis

• Odds ratio as effect estimate• Forrest plot → Pooled estimate• Funnel plot → Publication bias• L’Abbe plot → Effect of study size on

outcome• Sub group analysis/ Sensitivity analysis• Meta regression → Effect of baseline

independent variables• Software: Stata 12 IC/ Stata 13 IC

Sub group Analysis

• Adults vs. children• Study duration (<1 months vs. >1 months)• Hypoglycemia definition (<3.9 mmol/dL vs.

<3.5mmol/dL)• Type of hypoglycemia

Results

Figure 1. Study Selection Flowchart Initial Search

(n=511)

Final Cohort (n=8)

Abstracts Reviewed (n=244)

Full Article Reviewed (n=29)

Studies before 2005 (n=150) Duplicative Studies (n=117)

Not Matching inclusion criteria (n=192) Contacting Authors (n=23)

Not reporting outcome of interest (n=21)

Table 1. Study characteristics of the included studies

Study, Year DesignStudy Duration

Mean HbA1c (%)

Mean DM (years)

Mean Age (years)

Mean CSII (years)

Breton et al, 2012 (sCTR)Multicentere Randomized crossover 22 hours 7.9 16.9 29.3 8.1

Breton et al, 2012 (eCTR)Multicentere Randomized crossover 22 hours 7.5 21.7 38 3.1

Nimri et al, 2013Multicentere Randomized crossover 24 hours 8.1 13.5 23.8 5.5

Dauber et al, 2013 RCT crossover 28 hours 8.1 2.1 5.1 .

Haidar et al, 2013 RCT crossover (open-label) 30 hours 7.9 26.5 47.1 0.25

Bruttomesso et al, 2009 crossover 44 hours 7.4 20.5 42 .

Elleri et al, 2013 RCT crossover (open-label) 72 hours 7.9 5.7 15 .

Phillip et al, 2013Multicentere Randomized crossover 72 hours 8 7 13.8 4.8

Bergenstal et al, 2013 Multicenter RCT Parallel 3 month 7.2 26.9 43.2 0.5

DM: Diabetes Mellitus, CSII: Continuous subcutaneous insulin infusion, RCT: randomized controlled trials, , Sev: Severe, US: United States

Table 2. Number of events of the included studies

Study, YearParticipants (CL/OL) CL/ OL Type

Hypoglycemia definition

CL/OL Pt at least one event

Breton et al, 2012 (sCTR) 25 (25/25) CSII+CGM+Algo/CSII+CGM < 3.9mmol/dL 11/17Breton et al, 2012 (eCTR) 12 (12/12) CSII+CGM+Algo/CSII+CGM < 3.9mmol/dL 8/9

Nimri et al, 2013 12 (12/12) CSII+CGM+Algo/CSII+CGM <3.5mmol/l 1/2

Dauber et al, 2013 10 (10/10) CSII+CGM+Algo/CSII+CGM < 3.9mmol/dL 5/2

Haidar et al, 2013 15 (15/15)Dual hormone/CSII+CGM <3 mmol/l 1/8

Bruttomesso et al, 2009 6 (6/6) CSII+CGM+Algo/CSII+CGM < 3.9mmol/dL 3/2

Elleri et al, 2013 12 (12/12) CSII+CGM+Algo/CSII+CGM < 3.9mmol/dL 11/8

Phillip et al, 2013 54 (54/54) CSII+CGM+Algo/CSII+CGMrequiring assistance 0/0

Bergenstal et al, 2013 247 (121/126) CSII+CGM+Algo/CSII+CGM

requiring assistance 0/4

Algo: Algorithm, CGM: Continuous glucose monitoring, CSII: Continuous subcutaneous insulin infusion, CL: Closed-loop, Noct: Nocturnal, OL: Open-loop, Sev: Severe

Table 3. Number of events By Hypoglycemia Type

Study, YearCL/OL Pt at least one event Noct CL/OL

Day CL/OL

Post exe CL/OL

Post prand CL/OL

Sev CL/OL

Breton et al, 2012 (sCTR) 11/17 10/15 . 5/8 1/7 .Breton et al, 2012 (eCTR) 8/9 7/6 . 4/1 2/1 .

Nimri et al, 2013 1/2 0/0 . . 1/1 .

Dauber et al, 2013 5/2 5/2 0/0 . . .

Haidar et al, 2013 1/8 0/5 . 1/2 . .Bruttomesso et al, 2009 3/2 3/2 2/0 . . .

Elleri et al, 2013 11/8 7/7 11/6 . . .

Phillip et al, 2013 0/0 . . . . 0/0

Bergenstal et al, 2013 0/4 . . . . 0/4

Algo: Algorithm, CGM: Continuous glucose monitoring, CSII: Continuous subcutaneous insulin infusion, CL: Closed-loop, Noct: Nocturnal, OL: Open-loop, Sev: Severe

Figure 1. Forrest Plot of included studies

Figure 2. Forrest Plot without dual hormone study

Figure 3. Funnel plot

Figure 4. L’Abbe plot depicting the result of studies

Figure 5. Subtype of hypoglycemia: Daytime (p=0.02)

Figure 6. Meta regression- Baseline DM duration

Coefficient; 95%CI =-0.144; -0.257, -0.032 (P=0.018)

Major Findings• Among algorithm-based closed-loop insulin delivery system

users, there is not a statistically significant decrease in the risk of hypoglycemia even after subgroup analysis.

• There is a statistically significant hypoglycemia risk reduction among dual-hormone based closed-loop system, according to the results of a single trial.

• Patients using closed-loop system have significantly more hypoglycemic events during daytime. (p=0.02)

• Diabetes duration will affect the risk of hypoglycemia in closed-loop system users; the longer the duration, the less the events are. (p=0.018)

Limitations

• Many studies had small sample size. • Many studies had short follow-up time.• Hypoglycemia events were not always

reported.• Hypoglycemia definition variation• Only including binary outcomes.• Language bias.

Conclusion

• Currently, there is no statistically significant difference in hypoglycemia risk among type I DM patients on closed loop insulin delivery compared to open loop.

Future Research

• Larger Studies are needed• Longer duration studies are needed• Develop better algorithms

Acknowledgements

• Dr. Jaewhan Kim• Dr. Osama Shoair

Questions and Comments