• Subcutaneous insulin injection (CSII) is associated with an improvement in mean Quality-Adjusted Life Years of 0.36754 gained vs Multiple Daily Insulin injections • Incremental Cost/Effect Ratio “ICER” 54160 £ per QALY • ICER sensitive to variations in CSII costs (device & consumables), ESRD cost (dialysis) & discount rate

1. 1
Dr. Kaouthar Lbiati_The London School of Economics_01/2016
TITLE
Cost-effectiveness of the use of Continuous
Subcutaneous Insulin Injection (CSII) compared
to Multiple Daily Insulin Injections (MDI) on the
long term progression of diabetic nephropathy
ABSTRACT
Objective
The aim of this study is to model exclusively the long term renal complications in a cohort of
patients with type1 diabetes mellitus (T1DM) and microalbuminuria throughout their life-span
and to estimate, from a third party perspective, the cost-effectiveness of the use of Continuous
Subcutaneous Insulin Injection (CSII) compared to Multiple Daily Insulin Injections (MDI) on
the progression of renal disease.
Methods
A previously validated model, taking a lifetime perspective, is used to construct a series of
Markovs and simulate the progression of long term renal complications related to T1DM in two
different groups according to baseline levels of glycosylated hemoglobin HbA1C (above/equal or
under 10%) in each group receiving either therapeutic intervention CSII or MDI. The model also
estimates, from a health insurance perspective quality-adjusted life years ‘QALYS’ and costs for

2. 2
each health-state to determine the Incremental Cost Effectiveness Ratio ‘ICER’ of CSII compared
with MDI. A discount rate of 3.5% per annum was applied to both costs and preference weights.
Results
In terms of renal disease outcomes, no significant differences were identified between study
subgroups; those with initially good glycaemic control (HbA1c under 10%) and poor glycaemic
control (HbA1c above or equal to 10%). CSII was associated with an improvement in mean
Quality-Adjusted Life Years of 0.36754 gained. Mean direct life cost were 19.906,27 £; higher
with CSII compared to MDI (99 843.07£ for CSII and 79 936.80 £ for MDI). Incremental
Cost/Effect Ratio “ICER” was 54160 £ per QALY gained. The ICER, in this model, was sensitive
to variations in the costs of both interventions particularly direct costs related to the CSII
intervention, cost of ESRD and also to the applied discount rate.
Conclusion
Based on a Willingness to pay upper threshold of £ 30,000, used in the analysis according to
NICE guidelines, CSII appeared to have a relative value for money compared to MDI in terms of
progression of diabetic nephropathy in a random T1DM population with microalbuminuria. The
improvement in mean Quality-Adjusted Life Years and conflicting cost-effectiveness evidence
related to the use of CSII in T1DM within the UK population suggest target subgroups at high
risk of developing ESRD need to be identified and an ancillary cost-effectiveness study to be
highly recommended in these subgroups in order to investigate further the effect of CSII versus
MDI on the progression of renal disease in these subgroups.
INTRODUCTION
What does this study add?
 CSII associated with an improvement in mean Quality-Adjusted Life Years of 0.36754
gained vs MDI
 Incremental Cost/Effect Ratio “ICER” 54160 £ per QALY
 ICER sensitive to variations in CSII costs (device & consumables), ESRD cost (dialysis) &
discount rate
 Identification of a T1DM subgroup poorly controlled (on MDI to be switched to CSII) and
analysed in an ancillary cost-effectiveness study comparing the effect of CSII versus MDI
on the progression to ESRD/death in exclusively poorly controlled T1DM subjects
o CSII Subgroup characteristics: microalbuminuria, baseline HbA1C >= 8.5%,
disabling hypoglycemia- prone (at least 2 hospitalisations/year).
o Expected HbA1C improvement with CSII: 2% (base case)
o Renal Replacement Therapy cost to be included in the analysis

3. 3
Diabetes affects an estimated 3.75 million people in the UK of which approximately
250,000 cases of Type 1 diabetes (1, 2). T1DM represents a burden to the National
Health Service (NHS) accounting for £35 million of the UK drug budget (3)
A poor glycemic control, as measured by glycosylated haemoglobin HbA1C, can lead to
long term microvascular complications such as nephropathy and death. Diabetes Control
and Complications Trial Research Group “DCCT” has reported reductions in
microvascular complications of 21 to 49% with every 1% reduction in HbA1c (4).
Diabetic nephropathy initially characterized by micro or macroalbuminuria leads to a
gradual decline of the renal function and may progress to End Stage Renal Disease
‘ESRD’, which is defined by the need for long-term dialysis or renal replacement
therapy (5). The costs of ESRD treatment are rather high, with a 0.7% share of the
national expenditures in the UK (6). Thus, prevention of ESRD is not only important
from a medical but also from an economic viewpoint.
The prognosis of people with type 1 diabetes changed dramatically with the introduction
of insulin therapy in 1922 (7). The cumulative survival of patients diagnosed with type 1
diabetes before 18 years of age has improved over time and was reported to be 95% to
97% at 20 years after diagnosis (8).

4. 4
Evidence indicates that even long-acting insulin analog–based injection regimens are not
as effective as Continuous Subcutaneous Insulin Injection ‘CIIS’ in lowering glycaemia
in most poorly controlled T1DM patients with elevated HbA1C (9).
The aim of this study is to compare the cost-effectiveness of the use of (CSII) over
Multiple Daily Insulin Injections (MDI), according to baseline levels of glycosylated
hemoglobin (HbA1C above or under 10%) in each comparative group, on the progression
of renal complications in a cohort of patients with T1DM and microalbuminuria using a
validated model (10).
Methods
Model design
The model consists of a series of sub-models simulating type 1 diabetes patients at risk of
progression to the more severe health-states. Each possible stage of progression is
represented as a health state.
Figure 1: schematic representation of the Markov model

5. 5
Cohort Markov models were used to estimate annual probabilities of transitioning
between states assuming a reference value for HbA1c that is equivalent to 10%. Each
health state is associated with an annual cost and a utility value that is combined with the
number of annual time cycle (s) the patient spends in that health state. The model uses a
lifetime horizon fixed at 100 years.
Transition probabilities
Microalbuminuria is considered to be a risk factor for macroalbuminuria. However,
patients may not progress to macroalbuminuria. Others may regress to normoalbuminuria
(11). In this model, we chose to omit the cases of regression from micro-albuminuria to
normo-albuminuria.
Transition probabilities adjusted the risk for microalbuminuria, macroalbuminuria in
patients with HbA1C levels different from 10% by using the method of Eastman et al
(12). The transition probabilities for ESRD are assumed to be independent of HbA1C
levels.
Utilities
It was conservatively assumed that utility of a T1DM patient with microalbuminuria is
equivalent to a T1DM patient with no diabetes complications, utilities do not differ
between different stages of albuminuria. Thus, the same disutility was applied to patients
with macroalbuminuria. Patients were assumed not to suffer from additional reduction in
health-related quality of life.

6. 6
Quality-adjusted life years were summed across time and patients. We used an annual
discount rate of 3.5% as recommended by NICE (13) to estimate total and average
discounted quality-adjusted life year.
Costs
The analysis is conducted from a health care perspective. Thus, only direct costs were
considered. Costs were summed across time and patients to provide total and average
discounted cost estimates (annual discount rate 3.5%).
Annual costs of CSII include the pump costs (assuming a 4 year life span), insulin costs,
consumable supplies. We assumed that CSII users change consumables every 3 days and
that MDI users inject three times per day.
Both CSII and MDI therapy were assumed to incur the same costs for blood glucose
testing, outpatient costs, annual screening procedures for microalbuminuria and
macroalbuminuria.
The annual costs of patients with ESRD were calculated as a weighted average of the
costs of haemodialysis or peritoneal dialysis (14).

7. 7
We have omitted cases of ESRD with renal replacement therapy based on the assumption
of frequent shortages of HLA compatible kidneys. We recognize this might be a
limitation in our study.
Clinical interventions / strategies
Background
MDI requires at least three injections of insulin per day, whereas CSII offers continuous
delivery of subcutaneous infusions of insulin with adjustments in the delivery rate or dose
size when necessary. Lower rate of hypoglycemia are associated with CSII. Nevertheless,
CSII requires more equipment and training at initiation than MDI and thus tends to be
more expensive on a short-term basis (15, 16).
Efficacy / effectiveness
A robust meta-analysis of paediatric and adult studies revealed a 0.6% improvement in
HbA1C for CSII compared with MDI therapy (17). Insulin pump therapy has shown
improvement in HbA1c in the short term and if longer follow-up periods were to show
continued improvement, the risk of diabetes complications would be reduced (18).
The interaction between baseline HbA1C and treatment modality (CSII versus MDII)
emerged as an independent predictor of treatment effect (19) and a model was derived
wherein the treatment effect predicts that in a patient with a baseline HbA1C of 10%,
CSII would reduce the HbA1C by an additional 0.65% compared with MDI.

8. 8
This has been confirmed in a pooled analysis of randomized controlled trials which has
shown that in T1DM subjects who have failed to achieve good control on MDI and were
switched to CSII, the fall in HbA1C in these patients is directly proportional to the initial
HbA1C on MDI. Thus, the best improvement was seen in the worst-controlled subjects.
For example, when the starting HbA1C is 10% on MDI, the fall in HbA1C on switching
to CSII is likely to be approximately 2%. But, in relatively well-controlled subjects with
an HbA1C of 7%, the difference in HbA1C could be less than 0.5% (20).
Quality of life
Currently, there is insufficient knowledge regarding the effect of CSII on quality of life
(18). However, a study shows quality of life to be better with CSII than MDI (21) and in
a survey conducted in the U.S, more than half of the health care diabetes specialists who
themselves have T1DM were being treated by CSII (22).
Sensitivity analysis
Sensitivity analysis, allows the effects of parameter uncertainty to be captured and their
effect to be tested on the study findings. Tornado diagrams were performed and a one
way sensitivity analysis has followed accordingly.
Results

9. 9
No significant differences in terms of progression of renal disease were to be found
between subgroups with good glycaemic control HbA1c (<10%) and poor glycaemic
control (HbA1c >= 10%).
T1DM treatment with CSII was projected to improve QALYs by 0.36754 years compared
with MDI. The mean discounted lifetime direct medical costs associated for T1DM with
CSII in the UK was projected to be 99843.07 £ compared with 79936.80 £ for MDI.
The incremental difference in costs of 19906.27 translated into a cost per life-year gained
of 54160 £ with CSII therapy versus MDI.
Based on a Willingness to pay upper threshold of £ 30,000 used in the analysis according
to NICE guidelines, CSII appears, in this model, to have a relative value for money
compared to MDI in terms of progression of diabetic nephropathy in a random T1DM
population with microalbuminuria.
Sensitivity analysis
Two tornado diagrams were performed. The cost of CSII intervention has the largest
share in the sensitivity of the ICER followed to by the annualized cost of MDI and the
discount rate applied. The Net Cost Benefit expressed as the Incremental Effect x
Willingness To Pay – Incremental Cost in the second diagram was sensitive to the cost of
the ‘ESRD’ treatment.

10. 10
A one way sensitivity analysis shows that for an annualized cost of CSII below a
threshold of 1860.535 £ (vs 2700 £ / year in the analysis), CSII is cost-effective compared
to MDI. Conversely, for values above threshold, the benefit decreases in favour of MDI.
Discussion
First, we acknowledge our model has some limitations. It starts with microalbuminuria as
an entry health state rather than healthy state. Evidence shows the cumulative incidence
of microalbuminuria in T1DM to range between 12.6% and 33% (23, 24) and the
incidence of T1DM to increase by 2.5% per year in children under 16 years of age (10).
Finne et al (8) reported the cumulative incidence of ‘ESRD’ to be 2.2% at 20 years and
7.8% at 30 years after diagnosis. Cost of dialysis is expected to raise in the future, due to
technological advancement and better-tolerated dialysis solutions. Thus, increasing the
potential for savings by preventing ESRD through the use of cost-effective strategies;
specifically in target groups, is key from an economic view.
Second, evidence has shown CSII to be associated with improved glucose control (25)
and fewer hypoglycemic events compared with MDI (26). Disabling hypoglycemia is
associated with high rates of hospitalisations and high costs (13) and a significant adverse
effect on health related quality of life (27, 28). Had we modeled the episodes of
hypoglycemia, perhaps overall costs would have been offset by hospitalisations costs and
ICER would have been in favor of CSII. Our appreciation is supported by Scuffham and
Carr who (29) who focused solely on hypoglycemia and ketoacidosis over an eight-year

11. 11
period and found CSII to be cost-effective in patients with severe and/or unpredictable
hypoglycaemia requiring hospitalization more than twice a year.
Third, our study did not find any significant difference between subgroups; (HbA1c
under 10%) and (HbA1c above or equal to 10%) in terms of renal outcomes. However,
T1DM treatment with CSII was projected to improve (QALYs) by 0.36754 years
compared with MDI with an ICER of 54160. Although CSII appears, in this model, to
have a relative value for money compared to MDI in terms of progression of diabetic
nephropathy, the improvement in mean QALYs and conflicting findings from three
studies comparing CSII with MDI in the UK, reporting (ICERs) of £11,500, £26,300 and
£32,800 for an improvement in HbA1c levels of 1.2% (30), suggests that the efficacy of
CSII in the most appropriate groups of patients could be a key determinant of cost
effectiveness. As such, we believe the population design in our model didn’t allow for
such subgroups to be accurately defined and corresponding results to be revealed
accordingly.
We conclude that further studies comparing CSII with MDI are needed in a subgroup of
patients switched from MDI and enrolled in CSII arm with lower HbA1C baseline
threshold (15), worse glucose control (HbA1C >= 8.5%), and hypoglycemia-prone
assuming an improvement of 2% in HbA1C levels (21).
Fourth, the results of sensitivity analyses have shown ICER to be sensitive to variations
in the cost of interventions mainly cost of CSII. The disadvantage of the pricing structure
applied to CSII is that the overall cost is sensitive to variations in the life-span and to

12. 12
greater use of consumables. However, it may be possible to extend the warranty on some
devices through advances in technology i.e. replacement of an insulin pump set every 7
years rather than the base case of 4 years or if discounting was to be made available by
manufacturers’ (mainly on consumables), the absolute net effect would be greater for
CSII pumps and would lead to an ICER well within the acceptable range for cost-
effectiveness in the UK.
Finally, our analysis has underestimated total costs related to loss of productivity, nursing
care or intangible costs. Yet, it is unclear whether a societal perspective leads to smaller
or larger savings than a health care perspective. For instance, treatment avoids
productivity loss due to renal failure and so do copayments for the treatment of renal
failure, but insulin pumps copayments lead to additional costs.
In Conclusion, although our model did not find any significant differences between good
glycaemic control vs poor glycaemic control subgroups, and showed CSII to have a
relative value for money compared to MDI in terms of progression of diabetic
nephropathy in a random T1DM population with microalbuminuria, we believe future
results of an ancillary study on a subgroup of patients with lower HbA1C baseline
threshold, a worse glucose control (HbA1C >= 8.5%), and hypoglycemia- prone
assuming an improvement of 2% in HbA1C levels with CSII compared with MDI would
contribute to NHS savings by preventing ESRD in this high risk T1DM population.
Abbreviations

13. 13
T1DM Type 1 Diabetes Mellitus
CSII Continuous Subcutaneous Insulin Infusion
MDI Multiple Daily Injections
HbA1C glycosylated haemoglobin
PDR Proliferative Diabetic Retinopathy
Glossary
Diabetes: a chronic condition in which the body cannot properly use its main energy source the sugar
glucose. This is due to either the pancreas not producing enough of the hormone insulin, or the body being
unable to effectively use the insulin produced. Insulin helps glucose enter the body’s cell from the
bloodstream and then be processed by them. Diabetes is marked by an abnormal build-up of glucose in the
blood, and can have serious short-and long-term effects on many of the body’s systems, especially the
blood vessels and nerves.
Insulin: a hormone produced by the pancreas. Its main action is to enable body cells to absorb glucose from
the blood and use it for energy.
Insulin pump: a device worn close to the body that delivers insulin subcutaneously
Glycosylated haemoglobin HbA1C: a measure of long term blood glucose control, higher levels of HbA1C
indicates poorer control of glucose levels.
Hypoglycemia (low blood glucose): a common and dangerous condition for many people with type 1
diabetes. It can be caused by eating less than usual, taking more exercise than normal or too much insulin
administered. A Disabling hypoglycaemia is defined as the repeated and unpredictable occurrence of
hypoglycaemia that results in persistent anxiety about recurrence and is associated with a significant
adverse effect on quality of life
Diabetic Nephropathy: is defined by increased urinary albumin excretion (UAE) in the absence of other
renal diseases and Diabetic nephropathy is categorized into stages according to the American Diabetes

14. 14
Association: microalbuminuria (UAE>= 20 g/min and <or=199 g/min or 30–299 mg/24 h or 30–299 mg/g)
and macroalbuminuria (UAE>= 200 g/min or >= 300 mg/24 h or >=300 mg/g)
ESRD: end stage renal disease is measured by the clearance of creatinine in the blood. Clearance
of creatinine is performed to investigate whether any deficiency in the glomerular filtration eGFR (one of
the most important kidney functions) occurs. When clearance of creatinine is less than 15 to 30 ml/min, we
talk about ESRD. It is treated with dialysis or renal replacement.
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Appendix A
Table 2: CSII pump system currently available in the UK from the dominant market players. Source: North East
advisory group report for Omnipod Subcutaneous insulin pump system

17. 17
Annex1: Results
Strategy Cost (£)
Incremental
Cost (£)
Effect
(QALYs)
Incremental
Effect
(QALYs)
Cost/Effect
Incremental
Cost/Effect
(ICER)
MDI 79936.8
19906.27
7.06567
0.36754
11313
54160
CSII 99843.1 7.43322 13432
Table 1: Results of cost-effectiveness analysis

18. 18
Figure 2: cost-effectiveness analysis of Continuous Subcutaneous Insulin Injection CSII versus Multiple Daily
Injections MDI according to the willingness to pay (threshold = 30.000 £)

19. 19
Figure 3: a) Tornado diagram with ICER; b) Tornado diagram; analysis of Net Cost Benefit

20. 20
Appendix B
Figure1: Curve of outcomes for CSII subjects with HbA1c >=10%
dialysis

21. 21
Figure 2: Curve of outcomes for CSII subjects with HbA1c <10%
Figure 4: one-way sensitivity analysis of the CSII cost parameter

22. 22
Figure 3: Survival curve for CSII subjects with HbA1c >=10%
Figure 4: Survival curve for CSII subjects with HbA1c <10%

23. 23
Figure 5: curve of outcomes for MDI subjects with HbA1C >=10%
Figure 6: Survival curve for MDI subjects with HbA1C > 10%

24. 24
Figure 7: curve of outcomes for MDI subjects with HbA1C < 10%
Figure 8: Survival curve for MDI subjects with HbA1C <10%