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Risk of Hypoglycemia Associated with Different Insulin Delivery Systems in Type I Diabetes Mellitus: A Meta-analysis
1. 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
2. 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/
3. 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/
4. Prognosis
• Most DM type 1 patients do NOT achieve their
glycemic targets despite the advances in insulin
analogues and delivery systems.2
Sources
1. Nathan et al. N Engl J Med 2005
2. The Diabetes Control and Complications Trial Research Group. JAMA 2003
↑ Glycemic
Control
↓ Microvascular
& Macrovascular
Complications1
6. 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%
7. 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. 2008
Thabit et al. Endocrinology and metabolism clinics of North America. 2012
CSII: Continuous subcutaneous insulin infusion, MDI: Multiple Dose Injection, SMBG: Self monitoring blood glucose,
8. Closed-loop Insulin Delivery System
Image Source: Mayo Clinic. Available at http://www.mayo.edu/research/labs/artificial-
pancreas/overview
9. 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
10. 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
11. 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
13. Databases Used
• Comprehensive search of bibliographic
databases including
‒ PubMed
‒ Cochrane
‒ DynaMed
‒ Scopus
‒ CINAHL
‒ Clinicaltrials.gov
‒ Conferences
(ADA)
14. 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”
15. Included Studies
• Inclusion
– Clinical trial
– Diabetes (type I)
– Closed loop
– Open loop (as
comparison)
– English
• Excluded
– If older than 2005
16. 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
17. 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
29. 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)
30. 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.
31. 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.
32. Future Research
• Larger Studies are needed
• Longer duration studies are needed
• Develop better algorithms
http://professional.diabetes.org/admin/UserFiles/0%20-%20Sean/FastFacts%20March%202013.pdfEconomic Burden:$245 billion/yearAround 26 million children and adultsADA
https://www.aace.com/publications/algorithm
Intensive insulin therapy is associated with higher risk of hypoglycemia.
Hypoglycaemia exposure was assessed prospectively over 9–12 months using weekly 4-point capillary home blood glucose monitoring (HBGM), 5 days of CGM and prospective reporting of severe hypoglycaemia.
Sometimes called Artificial Pancreas
Continuous Glucose Monitoring
Outcome variableNumber of patients with at least 1 hypoglycemic event
Most of the studies were not foundAuthor was contacted for responseSome contacted with the link of published articlesSome responded with the promise to show the result once they haveNever responded
Explain
Explain
Report 1 model and justifyUse fixed effect modelRun sensitivity analysis
Talk about each definition
Talk about each definition
There is no publication bias in included studies (p=0.546)
Large studies show no difference and small studies show difference
