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The American Journal of Managed Care May 2019
Evaluation of Value-Based Insurance Design for Primary Care
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The Presurgical Episode: An Untapped Opportunity to Improve Value
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Clarification of References to Medication Adherence Scale
Open Doors to Primary Care Should Add a “Screen” to Reduce Low-Value Care
Betsy Q. Cliff, MS; and A. Mark Fendrick, MD
From the Editorial Board: Daniel B. Wolfson, MHSA
Daniel B. Wolfson, MHSA
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Cost-Effectiveness of DPP-4 Inhibitor and SGLT2 Inhibitor Combination Therapy for Type 2 Diabetes
Manjiri Pawaskar, PhD; S. Pinar Bilir, MS; Stacey Kowal, MS; Claudio Gonzalez, MD; Swapnil Rajpathak, MD; and Glenn Davies, DrPH
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Cost-Effectiveness of DPP-4 Inhibitor and SGLT2 Inhibitor Combination Therapy for Type 2 Diabetes

Manjiri Pawaskar, PhD; S. Pinar Bilir, MS; Stacey Kowal, MS; Claudio Gonzalez, MD; Swapnil Rajpathak, MD; and Glenn Davies, DrPH
This study evaluates the long-term cost-effectiveness of treatment involving combination therapy with dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors compared with an alternative with sulfonyureas prior to insulin initiation on a background of metformin.

The base-case analysis compares a pathway with patients on a background of metformin remaining on DPP-4 inhibitors when adding SGLT2 inhibitors as a second intensification therapy prior to insulin initiation versus a pathway in which patients intensify to insulin initiation from metformin + SU. These pathways reflect intervention effects as summarized in Table 2.40-43 The deterministic base-case analysis was supplemented with probabilistic sensitivity analysis to capture potential variation in results due to known parameter variation as captured in distributions around parameters.

Additionally, a series of scenario analyses were defined to assess the impact of key model inputs and assumptions. Among these, potential variation in treatment effects across all lines of therapy within a pathway (eg, for A1C, hypoglycemic event rates, body mass index [BMI]) were tested using 95% CIs for each line from their respective primary data source. An alternate intensification regimen utilizing neutral protamine Hagedorn (NPH) insulin in place of other basal insulin was also explored, due to its generic nature and thus potential preferred use by some payers.

Generalizability across somewhat different diabetes populations was also tested via alternate cohort definitions. These include older patients (≥65 years) with a higher A1C target threshold of 8% to affect treatment intensification and patients with lower and higher baseline A1C levels (7% and 9%, based on the range found in published trial populations).40

Evidence from the CANVAS, CVD-REAL, and EMPA-REG trials suggests that SGLT2 inhibitor therapies convey additional CVD protective effects,16,21,22 lowering risk of heart failure and/or myocardial infarction and stroke. Therefore, a set of analyses tested these potential benefits, as well as the impact of insulin glargine17 and a weighted average DPP-4 inhibitor effect on heart failure.46 However, no additional effect on CVD-related mortality was implemented with these individual components, to avoid any potential double counting of effects given the mortality risk offset through these other cardiovascular events.

Scenarios with discounting (25%, 50%) across branded product pricing, including DPP-4 inhibitors, SGLT2 inhibitors, and basal insulin, were also performed. Given negotiations between payers and manufacturers, the wholesale acquisition costs that define treatment costs in the base-case analyses do not reflect the true reimbursement rates and therefore are likely to overestimate the incremental costs and cost-effectiveness ratio associated with pathway 1.


Base-case analysis results indicate that pathway 1—in which patients intensify to triple therapy with DPP-4 inhibitors and SGLT2 inhibitors before transitioning to triple therapy with DPP-4 inhibitors and basal insulin—improves life-years and QALYs by 0.133 and 0.240, respectively, compared with a generic pathway (transitioning from metformin + SU to triple therapy including metformin + SU + basal insulin). This is simultaneously associated with a relatively limited increase in overall medical costs over a patient’s lifetime ($15,548), as shown in Table 3, along with total costs, life-years, and QALYs per pathway. Overall, higher total treatment costs in pathway 1 are partially offset by lower costs associated with managing complications in comparison with a more generic medication pathway. These results translate to an ICER for pathway 1 of $64,784/QALY.

Probabilistic sensitivity analysis confirms the robustness of results, showing an acceptable mean ICER of $75,943/QALY. Given sampling to account for variation in parameters values, results remain cost-effective at $100,000/QALY approximately 60% of the time (see eAppendix Figure).

The majority of scenarios tested continued to provide QALY improvement with limited cost increases; ICERs remained under thresholds approved in real-world settings (Figure 216,17,21,22),31 with only 1 scenario (older baseline age) resulting in an ICER higher than $100,000/QALY. Simultaneously varying input values across all lines of therapy in each pathway to reflect 95% CI values in A1C led to an 8% increase or a 51% decrease in the ICER, for a total range of $31,945 to $70,126/QALY. However, similar explorations of 95% CI variation in hypoglycemic event rates and BMI had negligible impact on ICERs, with only 1% to 2% change from baseline. Use of a fully generic sequence, assuming NPH insulin rather than more often branded basal insulins (eg, glargine), had limited impact on the ICER, leading to a $60,031/QALY ICER (a decline of ~7%).

Despite sensitivity of the ICER value to changes in population characteristics, such as A1C level, interpretation would not necessarily change. Patients with different baseline A1C levels (7%, 9%) continue to benefit from pathway 1, with consistent incremental QALY benefits ranging from 2.5 to 3 quality-adjusted months. Coupled with therapy switching rules (eg, that therapy should be changed upon reaching A1C >7.5%), different baseline levels mean that patients may stay on initial lines of therapy for more or fewer years than in the base case; associated changes to treatment-related cost differences mean that ICERs range from less than $40,000/QALY to just over $90,000/QALY.

In addition to consistently favorable results given potential alternate key treatment effects and assumptions about the patient population, the ICER fell below even the most stringent of traditional willingness-to-pay thresholds ($50,000/QALY) when considering the impact on potential CVD event risks across all lines of therapy, including both protective effects (SGLT2 inhibitors) and potential harms associated with other medications. Individual consideration of SGLT2 inhibitor benefits led to ICER reductions of 6% to 11%, whereas simultaneously considering potential harms associated with early transition to insulin decreased the ICER by 26%.

Finally, price discounting to more accurately reflect costs associated with the pathways under consideration showed an ICER of $50,493/QALY with 25% discounts. Larger discounting of branded products at a 50% level led to an ICER of $36,201/QALY.

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