risk of hypoglycemia associated with different insulin delivery systems in type i diabetes mellitus:...
TRANSCRIPT
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