Author: Steven Smith

# Case Study: GLP-1 and related incretin therapies

#### Steven Smith

## Case

Suppose we need to identify users of GLP-1 receptor agonists and related incretin-based therapies from EHR prescribing data, pharmacy claims data, or both. To accomplish this, we need a medication list that includes relevant RxNorm product concepts and, when available, corresponding NDCs.

This vignette walks through two approaches:

1. a transparent step-by-step workflow that starts with a curated list of ingredient names; and
2. a compact workflow using `search_drug()`.

The examples use precomputed data by default so the vignette can be built without querying the live RxNorm API. To rebuild the examples with live API calls, set:

    Sys.setenv(RXREF_BUILD_VIGNETTES_ONLINE = "true")

## Defining the ingredient list

For this example, we start with a prespecified list of GLP-1 receptor agonists and related incretin-based therapies:

- exenatide
- liraglutide
- lixisenatide
- dulaglutide
- albiglutide
- semaglutide
- tirzepatide

Tirzepatide is included here because many applied studies group it with GLP-1-based incretin therapies, although it is a dual GIP/GLP-1 receptor agonist rather than a GLP-1 receptor agonist alone.

    glp1.names <- c(
      "semaglutide",
      "exenatide",
      "liraglutide",
      "lixisenatide",
      "dulaglutide",
      "albiglutide",
      "tirzepatide"
    )

## Option 1: Step-by-step medication list construction

### Identify ingredient RxCUIs

First, we use `find_ingredients()` to identify ingredient-level RxCUIs. For this example, we retain concepts with TTY = `"IN"`, corresponding to RxNorm ingredient concepts. You can see available TTY values and descriptions with `tty_catalogue()`.

    if (run_live) {
      glp1.ings <- find_ingredients(glp1.names) |>
        filter(tty == "IN") |>
        distinct(
          input,
          ingredient_rxcui = rxcui,
          ingredient_name = name,
          ingredient_tty = tty
        )
    } else {
      glp1.ings <- read_rxref_example("glp1_ings.rds")
    }

    glp1.ings
    #> # A tibble: 7 × 4
    #>   input        ingredient_rxcui ingredient_name ingredient_tty
    #>   <chr>        <chr>            <chr>           <chr>
    #> 1 albiglutide  1534763          albiglutide     IN
    #> 2 dulaglutide  1551291          dulaglutide     IN
    #> 3 exenatide    60548            exenatide       IN
    #> 4 liraglutide  475968           liraglutide     IN
    #> 5 lixisenatide 1440051          lixisenatide    IN
    #> 6 semaglutide  1991302          semaglutide     IN
    #> 7 tirzepatide  2601723          tirzepatide     IN

### Expand ingredients to product RxCUIs

Next, we use `products_for_ingredients()` to identify product concepts related to the ingredient RxCUIs.

By default, this workflow focuses on active RxNorm concepts. This is usually appropriate for current medication list construction. For studies covering older calendar periods, users may want to include historical RxNorm concepts as well.

    product_ttys("default")
    #> [1] "SCD"  "SBD"  "GPCK" "BPCK"
    product_ttys("extended_product")
    #>  [1] "SCD"   "SBD"   "GPCK"  "BPCK"  "SCDG"  "SBDG"  "SCDF"  "SBDF"  "SBDFP"
    #> [10] "SCDFP" "SCDGP"

The default product TTY set is intended to capture product concepts that are commonly useful for medication list construction and NDC mapping. A broader product-related set is available with `product_ttys("extended_product")`. Users can also supply their own character vector of TTYs.

In this example, we include combination products. That means products containing a GLP-1-related ingredient plus one or more other ingredients may be retained.

    if (run_live) {
      glp1.prods <- products_for_ingredients(
        glp1.ings$ingredient_rxcui,
        ttys = product_ttys("default"),
        include_combos = TRUE,
        concept_status = "active"
      )
    } else {
      glp1.prods <- read_rxref_example("glp1_prods.rds")
    }

    glp1.prods |>
      head(30)
    #> # A tibble: 30 × 5
    #>    ingredient_rxcui product_rxcui name                       tty   n_ingredients
    #>    <chr>            <chr>         <chr>                      <chr>         <int>
    #>  1 1440051          1858995       3 ML insulin glargine 100… SCD               2
    #>  2 1440051          1859000       3 ML insulin glargine 100… SBD               2
    #>  3 1534763          1534800       0.5 ML albiglutide 60 MG/… SCD               1
    #>  4 1534763          1534820       0.5 ML albiglutide 100 MG… SCD               1
    #>  5 1551291          1551295       0.5 ML dulaglutide 1.5 MG… SCD               1
    #>  6 1551291          1551300       0.5 ML dulaglutide 1.5 MG… SBD               1
    #>  7 1551291          1551304       0.5 ML dulaglutide 3 MG/M… SCD               1
    #>  8 1551291          1551306       0.5 ML dulaglutide 3 MG/M… SBD               1
    #>  9 1551291          2395777       0.5 ML dulaglutide 6 MG/M… SCD               1
    #> 10 1551291          2395779       0.5 ML dulaglutide 6 MG/M… SBD               1
    #> # ℹ 20 more rows

Combination products may appear when `include_combos = TRUE`. Depending on the function, ingredient fields for combination products may be summarized across ingredients, while product-level rows remain one row per product concept. Users should inspect ingredient fields and `n_ingredients` before deciding whether to include or exclude fixed-dose combination products.

### Include historical RxNorm concepts when needed

For historical studies, formulary reconstruction, or claims data spanning older calendar periods, users may want to include both active and historical RxNorm concepts.

    glp1.prods_historical <- products_for_ingredients(
      glp1.ings$ingredient_rxcui,
      ttys = product_ttys("default"),
      include_combos = TRUE,
      concept_status = "active_and_historical"
    )

Historical concepts can be useful when reconstructing medication exposure during older study periods. However, some historical concepts may have less complete clinical attribute information than active concepts. Users should review route, dose form, ingredient count, and NDC mappings carefully when including historical concepts.

### Map product RxCUIs to NDCs

Next, we identify NDCs associated with the product RxCUIs. Not all RxCUIs map to NDCs, so some product concepts may not have corresponding NDC values.

    if (run_live) {
      glp1.ndc.map <- map_rxcui_to_ndc(
        unique(glp1.prods$product_rxcui),
        status = "ACTIVE"
      )
    } else {
      glp1.ndc.map <- read_rxref_example("glp1_ndc_map.rds")
    }

    glp1.ndcs <- glp1.ndc.map |>
      left_join(
        glp1.prods,
        by = c("rxcui" = "product_rxcui")
      ) |>
      left_join(
        glp1.ings |>
          select(ingredient_rxcui, ingredient_name),
        by = "ingredient_rxcui"
      ) |>
      distinct(
        ingredient_rxcui,
        ingredient_name,
        product_rxcui = rxcui,
        ndc11,
        ndc_status,
        name,
        tty
      ) |>
      arrange(ingredient_name, product_rxcui, ndc11)

    glp1.ndcs |>
      head(30)
    #> # A tibble: 30 × 7
    #>    ingredient_rxcui ingredient_name product_rxcui ndc11   ndc_status name  tty
    #>    <chr>            <chr>           <chr>         <chr>   <chr>      <chr> <chr>
    #>  1 1551291          dulaglutide     1551300       000021… ACTIVE     0.5 … SBD
    #>  2 1551291          dulaglutide     1551300       000021… ACTIVE     0.5 … SBD
    #>  3 1551291          dulaglutide     1551300       000021… ACTIVE     0.5 … SBD
    #>  4 1551291          dulaglutide     1551300       500903… ACTIVE     0.5 … SBD
    #>  5 1551291          dulaglutide     1551300       500906… ACTIVE     0.5 … SBD
    #>  6 1551291          dulaglutide     1551306       000021… ACTIVE     0.5 … SBD
    #>  7 1551291          dulaglutide     1551306       000021… ACTIVE     0.5 … SBD
    #>  8 1551291          dulaglutide     1551306       000021… ACTIVE     0.5 … SBD
    #>  9 1551291          dulaglutide     1551306       500903… ACTIVE     0.5 … SBD
    #> 10 1551291          dulaglutide     1551306       500906… ACTIVE     0.5 … SBD
    #> # ℹ 20 more rows

At this point, we have a product-level and NDC-level medication list that can be used to query EHR prescribing data, pharmacy dispensing data, or pharmacy claims data.

## Option 2: Use `search_drug()` for a compact workflow

The same goal can often be accomplished in one step with `search_drug()`. This function combines ingredient searching, product expansion, optional route filtering, and optional NDC mapping.

Suppose we want NDCs for the same ingredient list, and we want to include active, obsolete, and unspecified NDCs.

    if (run_live) {
      alt.glp1.ndcs <- search_drug(
        term = glp1.names,
        return = "ndc",
        concept_status = "active",
        ndc_status = c("ACTIVE", "OBSOLETE", "UNSPECIFIED")
      )
    } else {
      alt.glp1.ndcs <- read_rxref_example("alt_glp1_ndc.rds")
    }

    alt.glp1.ndcs |>
      arrange(ingredient_name, product_rxcui, ndc11) |>
      head(30)
    #> # A tibble: 30 × 7
    #>    ingredient_rxcui ingredient_name product_rxcui product_name product_tty ndc11
    #>    <chr>            <chr>           <chr>         <chr>        <chr>       <chr>
    #>  1 1551291          dulaglutide     1551300       0.5 ML dula… SBD         0000…
    #>  2 1551291          dulaglutide     1551300       0.5 ML dula… SBD         0000…
    #>  3 1551291          dulaglutide     1551300       0.5 ML dula… SBD         0000…
    #>  4 1551291          dulaglutide     1551300       0.5 ML dula… SBD         5009…
    #>  5 1551291          dulaglutide     1551300       0.5 ML dula… SBD         5009…
    #>  6 1551291          dulaglutide     1551306       0.5 ML dula… SBD         0000…
    #>  7 1551291          dulaglutide     1551306       0.5 ML dula… SBD         0000…
    #>  8 1551291          dulaglutide     1551306       0.5 ML dula… SBD         0000…
    #>  9 1551291          dulaglutide     1551306       0.5 ML dula… SBD         5009…
    #> 10 1551291          dulaglutide     1551306       0.5 ML dula… SBD         5009…
    #> # ℹ 20 more rows
    #> # ℹ 1 more variable: ndc_status <chr>

Here, `concept_status` controls whether active or historical RxNorm concepts are considered. The `ndc_status` argument controls which NDC status categories are returned.

For example, to include historical RxNorm concepts and broader NDC status categories, use:

    search_drug(
      term = glp1.names,
      return = "ndc",
      concept_status = "active_and_historical",
      ndc_status = c("ACTIVE", "OBSOLETE", "UNSPECIFIED")
    )

This can be useful for studies spanning older calendar periods, but users should carefully inspect the resulting concepts and NDCs before finalizing an exposure definition.

## Comparing the two approaches

The step-by-step approach is more verbose, but it makes each decision explicit:

1. identify ingredient RxCUIs;
2. expand ingredients to product concepts;
3. decide whether to include combination products;
4. decide whether to include active concepts only or active and historical concepts;
5. map product RxCUIs to NDCs.

The `search_drug()` approach is more compact and is useful for common workflows where users want a product list or NDC list from one or more drug names.

To compare the NDCs from the step-by-step workflow against the compact workflow:

    glp1.ndcs |>
      filter(!is.na(ndc11)) |>
      arrange(ingredient_name, product_rxcui, ndc11) |>
      head(30)
    #> # A tibble: 30 × 7
    #>    ingredient_rxcui ingredient_name product_rxcui ndc11   ndc_status name  tty
    #>    <chr>            <chr>           <chr>         <chr>   <chr>      <chr> <chr>
    #>  1 1551291          dulaglutide     1551300       000021… ACTIVE     0.5 … SBD
    #>  2 1551291          dulaglutide     1551300       000021… ACTIVE     0.5 … SBD
    #>  3 1551291          dulaglutide     1551300       000021… ACTIVE     0.5 … SBD
    #>  4 1551291          dulaglutide     1551300       500903… ACTIVE     0.5 … SBD
    #>  5 1551291          dulaglutide     1551300       500906… ACTIVE     0.5 … SBD
    #>  6 1551291          dulaglutide     1551306       000021… ACTIVE     0.5 … SBD
    #>  7 1551291          dulaglutide     1551306       000021… ACTIVE     0.5 … SBD
    #>  8 1551291          dulaglutide     1551306       000021… ACTIVE     0.5 … SBD
    #>  9 1551291          dulaglutide     1551306       500903… ACTIVE     0.5 … SBD
    #> 10 1551291          dulaglutide     1551306       500906… ACTIVE     0.5 … SBD
    #> # ℹ 20 more rows

## Choosing active versus historical concepts

For many current medication lists, `concept_status = "active"` is a good default. This limits the workflow to active RxNorm concepts.

Historical concepts may be appropriate when:

- the study period includes older calendar years;
- medication exposure is being reconstructed from historical claims;
- users need to capture products that may no longer be active in RxNorm;
- obsolete NDCs are intentionally included.

However, active and historical RxNorm concepts should not be confused with NDC status. These are separate choices:

- `concept_status` controls which RxNorm concepts are considered.
- `ndc_status` controls which NDC status categories are returned.

For example:

    search_drug(
      term = "semaglutide",
      return = "ndc",
      concept_status = "active_and_historical",
      ndc_status = c("ACTIVE", "OBSOLETE", "UNSPECIFIED")
    )

## Practical considerations

Medication list construction often requires study-specific decisions. Before using the resulting list in an analysis, users should consider:

- whether to include fixed-dose combination products;
- whether to include branded products, clinical products, packs, or all product-related TTYs;
- whether the study period requires historical RxNorm concepts;
- whether active NDCs only are sufficient, or obsolete/unspecified NDCs should also be included;
- whether route, dose form, or strength restrictions are needed;
- whether the final list should be reviewed clinically.

For strict reproducibility, users should save the final product list, NDC list, and package/API versions used to construct the medication exposure definition.