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Original Research

# Antidiabetic Drugs Consumption in France Over a Decade: An Observational Study

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De Bandt David, MD, MSc<sup>1,2,*</sup>, Johanna Mezence, MD<sup>1</sup>, Claire Rives Lange, MD<sup>3,4</sup>, Dominik Menges, MD, PHD<sup>5</sup>, Claire Carette, MD, PHD<sup>3,6</sup>

## ARTICLE INFO

**Key words:**

Antidiabetic drugs

Diabetes

Healthcare expenditures

Public health

## ABSTRACT

**Aims:** The prevalence of type 2 diabetes has increased in France over the past decade, with changes in available pharmacologic treatments. This study aimed to assess trends in the sales of antidiabetic drugs in France over the last decade.

**Methods:** This retrospective cohort study used data from French national health insurance databases. Defined daily doses per 1000 inhabitants per day (DDD/TID), expenditures associated, and the proportion of the population receiving treatment were analyzed from January 2013 to December 2022.

**Results:** Between 2013 and 2022, the proportion of patients purchasing at least one antidiabetic drug per month increased from 3.07% to 4.12%, with average monthly consumption rising from 82.62 to 101.68 DDD/TID. Biguanides were the most sold antidiabetic drug, followed by sulfonylureas and insulin. The greatest increases in consumption and expenditures were observed for GLP-1 analogs and SGLT2 inhibitors.

**Conclusion:** The consumption and cost of antidiabetic drugs increased with the diabetes prevalence. GLP-1 analogs and SGLT2 inhibitors accounted for the main growth, reflecting their growing clinical adoption and evidence of efficacy, while sales of sulfonylureas and DPP4 inhibitors remained substantial despite concerns regarding their benefit-risk profiles. In 2022, expenditures for GLP-1 analogs surpassed insulin. These findings have implications for healthcare policy and resource allocation planning.

## Introduction

Diabetes is a common disease in the general population, affecting an increasing number of people worldwide. According to the World Health Organization (WHO), approximately 463 million people worldwide had diabetes in 2019.<fnref n="1" /> In France, the prevalence of diabetes increased from 4.6% in 2012 to 5.3% in 2020, affecting 3.5 million people.<fnref n="2" /> Diabetes is characterized by an elevation of glycemia caused by insulinopenia and insulinoresistance.<fnref n="3" />,<fnref n="4" /> Consequently, glucose in the blood is less utilized, leading to hyperglycemia and ketogenesis. Acute complications of diabetes include ketoacidosis and hyperosmolar hyperglycemia, which can progress to coma. It also has several long-term clinical consequences by causing micro and macroangiopathies, which lead to retinopathy, nephropathy, neuropathy with damage to small vessels, and atheroma-

tous lesions in large vessels. Infections are also more frequent with a higher risk of complications. In France in 2020, the incidence rate of hospitalization for acute myocardial infarction, cerebral strokes, plantar perforating ulcers, lower limb amputation, and terminal kidney failure in patients aged 45 and over suffering from diabetes was approximately 17.5%. For these reasons, diabetes is a condition of very high public health importance.<fnref n="5" />⁻⁷

Hygienic and dietary rules form the basis of care for people with diabetes.⁸,⁹ Antidiabetic medications are a mainstay of diabetes treatment. Insulin is used in patients whose insulin production is insufficient, particularly in type 1 diabetes or advanced type 2 diabetes. Other antidiabetic drugs are used in type 2 diabetes when the patient does not require insulin. These treatments work differently depending on the therapeu-

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<footnote n="1"><sup>1</sup> Family Medicine Department, Simon Veil Health Science UFR, University of Versailles Saint Quentin, Saint Quentin, France</footnote>

<footnote n="2"><sup>2</sup> Center for Research in Epidemiology and Population Health, (INSERM U 1018), University of Versailles, Saint-Quentin-en-Yvelines, University Paris-Sud, Villejuif, France</footnote>

<footnote n="3"><sup>3</sup> Nutrition Department, Hopital Européen Georges Pompidou, AP-HP, Paris Cité University, Paris, France</footnote>

<footnote n="4"><sup>4</sup> INSERM, UMR1153, Methods Team, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Paris, France</footnote>

<footnote n="5"><sup>5</sup> Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich (UZH), Zurich, Switzerland</footnote>

<footnote n="6"><sup>6</sup> CIC1418, Hopital Européen Georges Pompidou, AP-HP, Paris Cité University, Paris, France</footnote>

<footnote>* Address correspondence to: David De Bandt, Maison de Santé Pluriprofessionnelle de Saint Nom la Bretèche, 78860 Saint-Nom-la-Bretèche, France.
E-mail address: david.debandt@gmail.com (D.B. David).</footnote>
tic class, for some of which the mechanisms of action are still not well understood. Currently, biguanides are the first-line oral antidiabetics. They work by reducing hepatic gluconeogenesis, insulin resistance, and intestinal glucose absorption.¹⁰ Other treatments work by increasing insulin production like sulfonylureas, decreasing intestinal glucose absorption like alpha-glucosidase inhibitors, or enhance insulin secretion and sensitivity by the action on incretin activity like DPP4 inhibitors or GLP1 analogs. SGLT2 inhibitors are the latest drugs to receive market authorization for diabetes treatment in France in 2020. These drugs increase glucose excretion through the urinary tract.

Treatments for diabetes are delivered by pharmacies only with a medical prescription and are fully or partially covered by French health insurance. The increase in diabetes prevalence has likely led to a rise in the consumption of antidiabetic medications and associated expenditures. Other factors, such as clinical guidelines and socio-economic changes, may have also influenced prescribing habits. However, there is a lack of recent data on the consumption of antidiabetic medications and the associated costs incurring in the French social security system that may increase with the prevalence of diabetes. This data is crucial for better examining the determinants of prescriptions and healthcare expenditures, especially in the context of drug shortages, as is currently the case for GLP1 analogs.

The aim of this study was to describe the consumption of antidiabetic medications in outpatient care in France from 2013 to 2022 using national sales data from the French health insurance system. Secondary objectives were to assess the costs associated with antidiabetic medications for French health insurance.

## Materials and Methods

### Databases

This observational retrospective cohort study was conducted using data from the anonymized open-access Medic'AM database, which includes all medications sold in community pharmacies in France and reimbursed by French health insurance.¹¹ Monthly sales data are available for each individual product (defined by CIP13 code), along with corresponding ATC2 to ATC5 codes, the number of boxes sold, and the amount reimbursed by French health insurance. The Medic'AM database does not include medications provided in hospitals or for individuals in home hospitalization. Excluding hospital data helps limit biases as antidiabetic treatment in hospitals often differs from treatment in the outpatient setting (e.g., more frequent insulin administration to improve glycaemic control and decrease mortality) due to the stress hyperglycaemia.¹² Hence, only medications sold in community pharmacies were analyzed to better understand patient consumption habits in the outpatient setting. Data for all antidiabetic medications (defined as ATC2 code A10) from January 2013 to December 2022 were extracted and sorted by CIP13 code for analysis.

The National Health Insurance Information System (SNIIRAM) database was also consulted to determine the number of patients pharmacologically treated for diabetes in the general French population.¹³ The SNIIRAM database is the national French database aggregating all healthcare services reimbursed by the French health insurance for each patient. Anonymized data were extracted to estimate the number of patients purchasing at least one antidiabetic medication in each month from January 2013 to December 2022.

Information was extracted from the database of the National Institute of Statistics and Economic Studies (INSEE) on the evolution of the French population as of January 1st of each year from 2013 to 2022.¹⁴ The data covers metropolitan France as well as the overseas departments and territories, in line with Medic'AM. The 2022 data is based on statistical extrapolations from civil registry data and estimates of migration balance from 2021.

This study used publicly available, anonymized open-access databases, and thus no ethical approval was required.

### Outcomes

To analyze antidiabetic medication consumption, the primary outcome measure was the defined daily doses per thousand inhabitants per day (DDD/TID) from January 2013 to December 2022. The DDDs were first determined for each individual antidiabetic drug belonging to the class of antidiabetic medications according to the WHO.¹⁵ Based on the DDD, the number of boxes sold, the number of doses per box, and the concentration of the active ingredient per dose, the monthly DDD sold for each drug were calculated. When there was a combination of antidiabetic medications, DDD were calculated individually for each drug in the combination. DDD/TID were calculated by dividing the DDD by the French population size based on INSEE data.

Additionally, defined daily doses per thousand patients pharmacologically treated for diabetes per day (DDD per thousand person with diabetes per day; DDD/TDD) were calculated by dividing the DDD by the number of patients purchasing at least one box of antidiabetic medication each month from January 2013 to December 2022.¹⁴

Monthly reimbursement data for expenditures associated with antidiabetic medication sales by French health insurance were calculated in million Euros based on Medic'AM data. Expenditures were adjusted for inflation using the Harmonized Index of Consumer Prices for France, with December 2022 as the reference.¹⁶

DDD/TID, DDD/TDD, and expenditures were calculated overall and for each individual class of antidiabetic medications: GLP1 analogs, biguanides, alpha-glucosidase inhibitors, DPP4 inhibitors, SGLT2 inhibitors, sulfonylureas, glitazones, insulins, and other oral antidiabetic agents representing less than 1% of total antidiabetic drugs sold.

Last, the proportion of patients treated with antidiabetic drugs in the French population was estimated by dividing the number of patients purchasing at least one box of antidiabetic medication each month by the total size of the French population within the corresponding year.

### Data Analysis

The evolution of DDD/TID, DDD/TDD, associated expenditures, and the proportion of patients purchasing at least one antidiabetic medication per month in the French population from January 2013 to December 2022 were analyzed descriptively. For presentation of the results, average annual DDD/TID, DDD/TDD, and expenditures were calculated based on monthly estimates. Additionally, means over the full study period were calculated based on monthly data. The average annual proportion of treated patients in the general population was calculated as the mean of monthly estimates.

We analyzed total DDD/TID, DDD/TID by antidiabetic medication class, and associated expenditures descriptively to rank them by consumption and expenditures and identify trends over time. Results were expressed in mean values with 95% confidence intervals (95% CI).

All analyses were conducted in R (version 2023.12.1).

## Results

### Population Analysis

The French population increased from 65.56 million inhabitants in January 2013 to 68.04 million in January 2022, following a linear growth trend, representing a 3.78% increase over the study timeframe. The number of patients purchasing at least one antidiabetic medication per month also showed a linear increase from an average monthly value of 2.01 million in 2013 to 2.80 million in 2022, indicating a 39.23% increase. The number of patients purchasing at least one antidiabetic medication increased at a faster rate than the general French population. In consequence, the proportion of treated patients increased from 3.07% in 2013 to 4.12% in 2022 (Appendix I).
Table

Average monthly consumption and average monthly expenditures for antidiabetic drugs between January 2013 and December 2022.

<table><thead><tr><th rowspan="2">Drug</th><th colspan="2">Drug consumption (DDD/TID)</th><th colspan="2">Healthcare expenditures (Million Euros)</th></tr><tr><th>Mean</th><th>95% CI</th><th>Mean</th><th>95% CI</th></tr></thead><tbody><tr><td>Insulin</td><td>18.17</td><td>17.86; 18.47</td><td>40.25</td><td>39.57; 40.92</td></tr><tr><td>GLP1 analogs</td><td>5.01</td><td>4.39; 5.64</td><td>23.30</td><td>22.13; 26.47</td></tr><tr><td>Other antidiabetics</td><td>4.45</td><td>4.40; 4.51</td><td>1.89</td><td>1.83; 1.94</td></tr><tr><td>Biguanides</td><td>30.61</td><td>30.17; 31.04</td><td>21.89</td><td>21.48; 22.30</td></tr><tr><td>Alpha-glucosidase inhibitors</td><td>0.72</td><td>0.67; 0.77</td><td>0.74</td><td>0.69; 0.80</td></tr><tr><td>DPP4 inhibitors</td><td>12.03</td><td>11.88; 12.18</td><td>24.67</td><td>24.09; 25.25</td></tr><tr><td>SGLT2 inhibitors</td><td>1.63</td><td>1.03; 2.23</td><td>4.26</td><td>2.63; 5.90</td></tr><tr><td>Sulfonylureas</td><td>19.03</td><td>18.64; 19.43</td><td>5.49</td><td>5.13; 5.85</td></tr><tr><td>Glitazones</td><td>&lt;0.01</td><td>0.000004; 0.00008</td><td>&lt;0.01</td><td>0.00001; 0.0002</td></tr><tr><td>Overall</td><td>90.52</td><td>89.20; 91.85</td><td>120.51</td><td>117.96; 123.05</td></tr></tbody></table>

Antidiabetic Drug Consumption

The average of overall antidiabetics sold per month from January 2013 to December 2022 was 90.52 DDD/TID. Biguanides were the most frequently sold antidiabetics with a monthly average of 30.61 DDD/TID over the same period. Sulfonylureas, insulin, and DPP4 inhibitors followed with 19.03, 18.17, and 12.03 DDD/TID respectively. GLP1 analogs and other AD were sold at 5.01 DDD/TID and 4.45 DDD/TID respectively. SGLT2 inhibitors began to be sold in 2020, at a monthly average of 1.63 DDD/TID over the full study period. Alpha-glucosidase inhibitors were sold less with a monthly average of 0.72 DDD/TID. Glitazones represented less than 0.01 DDD/TID, as their market authorization ended in 2014 (Table).

Average monthly sales of antidiabetic medications overall increased from 82.62 DDD/TID (95% CI: 80.09; 85.10) in 2013 to 101.68 (95% CI: 98.74; 104.62) in 2022, representing a 23.07% increase. Meanwhile, the average monthly sales of overall antidiabetics among patients purchasing at least one antidiabetic in the month decreased from 2689.33 DDD/TDD (95% CI: 2631.55; 2744.62) in 2013 to 2467.09 (95% CI: 2408.77; 2528.10) in 2022, indicating an 8.26% decrease (Figure 1 and Appendix I).

Analysis of monthly DDD/TID by antidiabetic medication class revealed varying evolution profiles depending on the prescribed drugs. Sales of GLP1 analogs increased from 1.52 DDD/TID (95% CI: 1.47; 1.57) in 2013 to 12.18 (95% CI: 11.43; 12.91) in 2022. SGLT2 inhibitors sales began in France only from 2020, with their consumption profile increasing from an average of 0.12 DDD/TID per month (95% CI: 0.04; 0.20) in 2020 to 3.87 (95% CI: 3.12; 4.61) in 2022, representing a 701.32% increase for GLP1 analogs over 10 years and a 3125.00% increase for SGLT2 inhibitors over 3 years. Insulin sales increased from a monthly average of 15.90 DDD/TID (95% CI: 15.40; 16.40) in 2013 to 20.00 (95% CI: 19.49; 20.52) in 2022, representing a 25.79% increase. Biguanides and DPP4 inhibitors monthly sales increased respectively from 28.08 DDD/TID (95% CI: 27.23; 28.91) and 10.89 (95% CI: 10.58; 11.20) in 2013 to 33.44 (95% CI: 32.53; 34.36) and 12.39 (95% CI: 12.04; 12.74) in 2022, representing increases of 19.09% and 13.77%. The monthly consumption of sulfonylureas and alpha-glucosidase inhibitors decreased respectively from 20.42 DDD/TID (95% CI: 19.76; 21.08) and 1.20 (95% CI: 1.15; 1.25) in 2013 to 15.39 (95% CI: 14.89; 15.90) and 0.36 (95% CI: 0.35; 0.38) in 2022, representing a decrease of 24.63% and 70%. Monthly consumption of other antidiabetics decreased from 4.60 DDD/TID (95% CI: 4.46; 4.73) in 2013 to 4.05 (95% CI: 3.93; 4.17) in 2022, representing a decrease of 11.96%. Glitazones were no longer sold since January 2015 (Figure 1 and Appendix I).

Analysis of DDD/TDD by individual antidiabetic drugs found some difference compared to DDD/TID analysis. There is a decrease in monthly consumption of biguanide and DPP4 inhibitors with respectively 909.33 DDD/TDD (95% CI = 894.89; 932.24) and 354.42 (95% CI = 347.56; 362.29) in 2013 and 812.08 DDD/TDD (95% CI = 791.24; 832.93) and 300.87 (95% CI = 921.73; 310.01) in 2022 (Figure 1).

Evolution of Expenditures

Average monthly expenditures for overall antidiabetic drugs represented €120.51 million over the study period. Expenditures per antidiabetic medication class strongly varied between drug classes. Insulin, DPP4 inhibitors, and GLP1 analogs were the leading expenditures for antidiabetics over the study period, with a monthly average of €40.24, €24.67, and €24.30 million, respectively (Table).

French health insurance expenditures associated with antidiabetic medication increased from a monthly average of €111.50 million (95% CI: 107.15; 115.85) in 2013 to €151.71 million (95% CI: 144.78; 158.65) in 2022. Monthly expenditures for insulin and GLP1 analogs have respectively increased from €35.84 (95% CI: 34.39; 37.30) and €11.07 million (95% CI: 10.59; 11.55) in 2013, to €45.47 (95% CI: 43.85; 47.08) and €47.51 million (95% CI: 45.01; 50.01) in 2022, representing a 26.87% and 329.17% increase. Monthly expenditures for DPP4 inhibitors decreased from €27.94 (95% CI: 26.89; 28.99) million in 2013 to €21.17 (95% CI: 20.21; 22.13) million in 2022. Thereby, expenditures for GLP1 analogs surpassed those of biguanides and DPP4 inhibitors in 2018 and of insulin in 2022. SGLT2 inhibitors were reimbursed by social security since 2020. Associated monthly expenditures represented €0.27 million (95% CI: 0.08; 0.47) in 2020 and increased by 3707.40% to €10.28 million (95% CI: 8.09; 12.46) in 2022. Expenditures related to the consumption of all other antidiabetics decreased between 2013 and 2022 (Figure 2 and Appendix I).

Discussion

Main Findings

This study demonstrated a notable rise in antidiabetic medication-treated patients within the French general population from January 2013 to December 2022. While this is correlated with an increase in total DDD/TID over the study period, we observed a concurrent decrease in DDD/TDD. French health insurance expenditures related to antidiabetic medications have shown an upward trend over the last decade, with a marked increase from 2020.

Throughout the study period, sales of biguanides have consistently been the highest among all antidiabetics, followed by insulin and sulfonylureas. The sales trend indicates that SGLT2 inhibitors and GLP1 analogs have experienced the most significant sales growth, while sulfonylureas have seen the most substantial decline in DDD/TID sold.

Insulin sales represent the primary expense for the French health insurance system throughout the study period, with a monthly average of €40.24 million over the study period. The expenditure trend demonstrates that costs associated with SGLT2 inhibitors and GLP1 analogs are increasing most rapidly, with GLP1 analogs surpassing biguanides and insulin expenditures in recent years. Meanwhile, expenditures linked to sales of other antidiabetic medication classes are decreasing, among
<figure><img src="image_4.png" /><figcaption>**Figure 1.** Evolution of antidiabetic drug sales. Overall, on the left, individual antidiabetic drugs, on the right, Shaded areas represent 95% confidence intervals.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 2.** Evolution of average monthly expenditures. Overall, on the left, individual antidiabetic drugs, on the right. Aeras in grey represent 95% confidence interval.</figcaption></figure>

which DPP4 inhibitors antidiabetic medication experienced the most important decrease.

## Results in Context

The rise in patients receiving antidiabetic medication treatment across the general population reflects the increasing prevalence of diabetes in France.² This has led to an overall rise in total antidiabetic consumption in DDD/TID like in other European country or in China.¹⁷⁻¹⁹ This increase is associated with a reduction in individual consumption in DDD/TDD among treated patients like in Denmark.¹⁷ This decline may be attributed to improved diabetes management, indicating potentially

earlier detection and intervention, resulting in less aggressive treatment approaches. It's also possible that use of newer SGLT2 inhibitors and GLP1 analogs may reduce the need for combination therapies due to their effectiveness. This is in accordance with the observed decrease of hospitalizations for diabetes complication in France.⁷ More research is needed to highlight whether the use of new treatments for diabetes is associated with less use of combination treatment.

Insulin and biguanides are the top-selling medications and have demonstrated efficacy in reducing mortality and diabetes-related complications.²⁰,²¹ They are recommended as first-line treatments for type 1 and type 2 diabetes, respectively. Insulin is also used in type 2 diabetes with insulinopenia in combination with biguanides.⁹ Sulfonylureas
lureas are among the most widely sold diabetes medications, compa-
rable in scale to insulin. This is likely because they have been rec-
ommended as a second-line treatment for type 2 diabetes in combina-
tion with biguanides since 2013 in France.⁸ However, sales of sulfony-
lureas have significantly declined, likely due to concerns about their
risk-benefit balance.²²,²³ Since May 2024, sulfonylureas are no longer
recommended except in cases of biguanides intolerance.

Consumption of GLP1 agonists has surged during the study pe-
riod. These newer drugs have shown effectiveness in reducing diabetes-
related complications.²⁴,²⁵ Since 2013, they were part of third-line
treatments for type 2 diabetes due to insufficient usage data and cost
concerns until May 2024, when they became a recommended second-
line treatment.²⁶,²⁸ The use of SGLT2 inhibitors has exponentially in-
creased since their market authorization in 2020. These novel drugs
have proven effective in managing type 2 diabetes, particularly in cases
of renal or heart failure.²⁷,²⁸ Until 2024, they were part of second-line
treatment for diabetes associated with renal or heart failure.⁸ Those
data are in accordance with other European or China studies showing
an increasing use of GLP1 analogs and SGLT2 inhibitors.¹⁷,¹⁸,²⁹ Impor-
tantly, the introduction of SGLT2 inhibitors and the increased use of
GLP1 analogs appears to have led to a particularly marked increase in
healthcare expenditures on antidiabetic medications from 2020.

The increase in sales of DPP4 inhibitors is surprising, considering their demonstrated low effectiveness in reducing mortality and diabetes-related complications.³⁰,³¹ This increase is also seen in another European country in association with biguanides.¹⁹ But their utilization decreases for individual treated patient. This increase in sales could be explained by the growing number of patients treated by antidiabetic drugs. Like sulfonylureas, DPP4 inhibitors became third-line treatment in diabetes in 2024.⁸ Noticeable declines in the consumption of other antidiabetic medications, alpha-glucosidase inhibitors, and glitazones are more pronounced due to their less favorable risk-benefit balance in diabetes management.³⁰,³² The rise in sales of insulin, biguanides, GLP1 analogs, and SGLT2 inhibitors is also seen in other European country or in China. These rises alongside the decline in sales of sulfonylureas, alpha-glucosidase inhibitors, glitazones, and other ADs indicate that prescribers may adapt their prescribing habits according to new evidence even before new recommendations are published like in Denmark. In contrast to our results, alpha-glucosidase inhibitors sales increase in China, but there is no data on individual consumption.¹⁷,¹⁸ Analyzing prescription habits based on the characteristics of prescribing physicians and patients would be interesting to understand the factors influencing these changes. Additionally, understanding the prescribing habits regarding DPP4 inhibitors could be insightful.

Despite the availability of many cheaper generics, expenditures asso-
ciated with antidiabetic medications continue to rise.³³ This may also af-
fect the healthcare budget and viability of the French social security sys-
tem in the longer term. While increased use of generics and biosimilars
should lead to decreasing healthcare expenditures, the adoption of such
drugs may be too slow or counteracted by growing disease burden and
innovation through new patented drugs. The French government's ini-
tiative to promote biosimilar insulin, which is effective in glycemic con-
trol but less expensive than traditional insulin analogs, has not curbed
the increase in insulin-related expenditures. This rise can be attributed
to the growing number of patients treated with insulin, leading to higher
quantities sold and associated costs.³⁴ Furthermore, increased consump-
tion of GLP1 analogs and SGLT2 inhibitors, which lack generic forms
and are among the most expensive antidiabetic drugs, are leading to in-
creased expenditures. Expenditures for GLP1 analogs exceeded expen-
ditures for insulin in 2022. DPP4 inhibitors also relevantly contributed
to the overall expenditures for antidiabetic medications, ranking sec-
ond over the full study period. Meanwhile, DPP4 inhibitors also showed
the most significant decrease in associated expenditures over the study
period despite a continued increase in sales. Negotiations on drug pric-
ing between the French National Agency for the Safety of Medicines and
Health Products (ANSM) and pharmaceutical enterprises both for gener-

ics and biosimilars and for new patented drugs play an important role in
containing drug costs for diabetes management. Further studies investi-
gating the impact of increasing genericization and such negotiations on
drug pricing and healthcare expenditures may provide valuable insights
into the dynamics of healthcare expenditures in diabetes management.

Strengths and Limitations

The main strength of this study lies in its comprehensive dataset,
derived from national routine databases in France, covering the entire
population under the general regime of French health insurance. It is the
first study to analyze monthly antidiabetic consumption data in outpa-
tient care and associated expenditures for French health insurance over
a 10-year period.

However, there are several limitations to consider. The use of DDD/TID or DDD/TDD may not fully represent antidiabetic medication consumption, as it reflects purchases rather than prescriptions or actual patient usage. Discrepancies between drug consumption and drug sales may arise due to unfilled prescriptions, nonadherence to treatments, or surplus medications that are not consumed. Additionally, the data do not allow for distinguishing medications used for off-label indications. Additionally, the estimates do not include those not covered by French health insurance, including immigrant populations or expatriate workers, as well as patients in hospitals or home hospitalization. Moreover, the number of patients purchasing at least one antidiabetic medication in a month may not represent the entire population of patients with diabetes in France, as it does not capture patients with diabetes managed through lifestyle and dietary measures and as some antidiabetic medication boxes last for several months while others last only one month.

GLP1 analog use for weight loss and the use of SGLT2 inhibitors for heart and kidney failure out of diabetes indication may lead to an overestimation of sales among people living with diabetes.³⁵⁻³⁷ GLP1 analogs were authorized for weight loss in obesity management in 2022, September in France. SGLT2 inhibitors were authorized for heart failure in 2021 December, and in kidney failure in 2023, July in France. The analysis of associated expenditures is further limited by dependent variables such as the genericization of drugs, which could potentially lower costs. These variables are challenging to evaluate, and data were unavailable for this study.

Conclusion

The increase in DDD/TID over time correlates with the growing num-
ber of people with diabetes within the general population. The concurrent decrease in DDD/TDD may be attributable to earlier diagnosis and improved diabetes management. The rise in costs for French health insurance is attributed to the increase in DDD/TID but also to the increasing use of high-cost antidiabetic medications, notably GLP1 analogs, which became the largest expenditure category in diabetes management in 2022, insulin, SGLT2 inhibitors, and DPP4 inhibitors. In addition, the sales of DPP4 inhibitors remain disproportionately high relative to their risk-benefit balance. The results of this study could help health policies to better anticipate changes in drugs consumption and associated costs, especially in the context of GLP1 analogs shortage. The results of this study could also help healthcare professionals to better understand diabetes management in France, guide practices, and improve patient care. Efforts should focus on optimizing prescriptions, particularly for GLP1 analogs, to balance clinical need and resource allocation.

Data Sharing

All data used for this study were extracted from the anonymized pub-
lic French health insurance data set and INSEE data set freely available
on their website.
Declaration of competing interest

DM received project and salary funding for an unrelated project by the Swiss Cancer Foundation (SCF), the Dr. Arnold U. und Susanne Huggenberger-Bischoff Stiftung, and one further, private, not-for-profit research foundation from Switzerland requesting anonymity via the University of Zurich. Pr Claire Carette has received consulting fees from Pfizer, Novo Nordisk, and Lilly, congress fees from Ipsen Pharma, Pfizer, AstraZeneca, Novo Nordisk, Lilly, Vitalaire, Boehringer, and Merck France, support for attending meetings/travel from AstraZeneca, Novo Nordisk, Lilly and participate on data safety monitoring for Bioproject. The other authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

CRediT authorship contribution statement

**De Bandt David:** Writing – review & editing, Writing – original draft, Validation, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Johanna Mezence:** Writing – original draft, Investigation, Conceptualization. **Claire Rives Lange:** Writing – review & editing, Validation, Conceptualization. **Dominik Menges:** Writing – review & editing, Validation, Methodology, Formal analysis, Conceptualization. **Claire Carette:** Writing – review & editing, Validation, Supervision, Project administration, Methodology, Formal analysis, Conceptualization.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.clinthera.2025.02.005.

References

1. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. *Diabetes Res Clin Pract.* 2019;157:107843. doi:10.1016/j.diabres.2019.107843.

2. Prévalence et incidence du diabète 2021. https://www.santepubliquefrance.fr/maladies-et-traumatismes/diabete/prevalence-et-incidence-du-diabete (accessed April 13, 2023).

3. Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. *Lancet Lond Engl.* 2017;389:2239–2251. doi:10.1016/S0140-6736(17)30058-2.

4. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. *Nature.* 2010;464:1293–1300. doi:10.1038/nature08933.

5. Lin K, Hsih W, Lin Y, et al. Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy. *J Diabetes Investig.* 2021;12:1322–1325. doi:10.1111/jdi.13480.

6. Wukich DK, Johnson MJ, Raspovic KM. Limb salvage in severe diabetic foot infection. *Foot Ankle Clin.* 2022;27:655–670. doi:10.1016/j.fcl.2022.02.004.

7. Le diabète en France : les chiffres 2020 n.d. https://www.santepubliquefrance.fr/les-actualites/2021/le-diabete-en-france-les-chiffres-2020 (accessed March 18, 2024).

8. Stratégie thérapeutique du patient vivant avec un diabète de type 2. Haute Aut Santé 2024. https://www.has-sante.fr/jcms/p_3191108/fr/strategie-therapeutique-du-patient-vivant-avec-un-diabete-de-type-2 (accessed June 9, 2024).

9. Chevalier N, Bachelot A. Endocrinologie, Diabétologie & Maladies Métaboliques. 5th ed. France: Elsevier Masson; 2021.

10. Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential. *Nat Rev Endocrinol.* 2023;19:460–476. doi:10.1038/s41574-023-00833-4.

11. Médicaments délivrés par les pharmacies de ville par classe ATC—Medic’AM—2012 à 2022 (série labellisée) | L’Assurance Maladie n.d. https://assurance-maladie.ameli.fr/etudes-et-donnees/medicaments-classe-atc-medicam (accessed January 5, 2023).

12. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association Consensus statement on inpatient glycemic control. *Diabetes Care.* 2009;32:1119–1131. doi:10.2337/dc09-9029.

13. Tuppin P, Rudant J, Constantinou P, et al. Value of a national administrative database to guide public decisions: from the système national d'information inter-

régimes de l'Assurance Maladie (SNIIRAM) to the système national des données de santé (SNDS) in France. *Rev DÉpidémiologie Santé Publique.* 2017;65:S149–S167. doi:10.1016/j.respe.2017.05.004.

14. Statistiques et études | Insee n.d. https://www.insee.fr/fr/statistiques (accessed April 19, 2022).

15. World Health Organization (WHO). ATC-DDD toolkit 2022. https://www.who.int/tools/atc-ddd-toolkit (accessed September 24, 2022).

16. ICP.M.F.R.N.000000.4.INX | ECB Data Portal n.d. https://data.ecb.europa.eu/data/datasets/ICP/ICP.M.F.R.N.000000.4.INX (accessed August 25, 2023).

17. Bang C, Mortensen MB, Lauridsen KG, Bruun JM. Trends in antidiabetic drug utilization and expenditure in Denmark: a 22-year nationwide study. *Diabetes Obes Metab.* 2020;22:167–172. doi:10.1111/dom.13877.

18. Cao W, Feng H, Yang Y, et al. Trends in antidiabetic drug use and expenditure in public hospitals in Northwest China, 2012-21: a case study of Gansu Province. *BMC Health Serv Res.* 2024;24:415. doi:10.1186/s12913-024-10917-0.

19. Moura AM, Martins SO, Raposo JF. Consumption of antidiabetic medicines in Portugal: results of a temporal data analysis of a thirteen-year study (2005-2017). *BMC Endocr Disord.* 2021;21:30. doi:10.1186/s12902-021-00686-w.

20. Turner RC, Holman RR, Stratton IM, Cull CA, Matthews DR, Manley SE, Frighi V, Wright D, Neil A, Kohner A, McElroy H, Fox C, Hadden D. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. *Lancet Lond Engl.* 1998;352:854–865.

21. Gubitosi-Klug RA, Lachin JM, Backlund J-YC, Lorenzi GM, Brillon DJ, Orchard TJDiabetes control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and complications (EDIC) Study research group. Intensive Diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC study 30-year follow-up. *Diabetes Care.* 2016;39:686–693. doi:10.2337/dc15-1990.

22. Xie Y, Bowe B, Xian H, et al. Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records. *Lancet Diabetes Endocrinol.* 2023;11:644–656. doi:10.1016/S2213-8587(23)00171-7.

23. Madsen KS, Kähler P, Kähler LKA, et al. Metformin and second- or third-generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus. *Cochrane Database Syst Rev.* 2019;4:CD012368. doi:10.1002/14651858.CD012368.pub2.

24. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. *The Lancet.* 2019;394:121–130. doi:10.1016/S0140-6736(19)31149-3.

25. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. *Lancet Diabetes Endocrinol.* 2021;9:653–662. doi:10.1016/S2213-8587(21)00203-5.

26. Association mieux prescrireDiabète de type 2 chez un adulte. Paris Union Régionale Assoc Form Médicale Contin.* 2023;43:595.

27. Association mieux prescrireDiabète de type 2, quand la metformine ne suffit pas. Paris Union Régionale Assoc Form Médicale Contin.* 2023;43:603.

28. Toyama T, Neuen BL, Jun M, et al. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and meta-analysis. *Diabetes Obes Metab.* 2019;21:1237–1250. doi:10.1111/dom.13648.

29. Heald AH, Livingston M, Bien Z, et al. The pattern of prescribing of glucose modulating agents for type 2 diabetes in general practices in England 2016/17. *Int J Clin Pract.* 2018;72:e13080. doi:10.1111/ijcp.13080.

30. Shi Q, Nong K, Vandvik PO, et al. Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. *BMJ.* 2023;381:e074068. doi:10.1136/bmj-2022-074068.

31. Kanie T, Mizuno A, Takaoka Y, et al. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. *Cochrane Database Syst Rev.* 2021;10:CD013650. doi:10.1002/14651858.CD013650.pub2.

32. Green JB, Everett BM, Ghosh A, et al. Cardiovascular outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: a Comparative Effectiveness Study). *Circulation.* 2024;149:993–1003. doi:10.1161/CIRCULATIONAHA.123.066604.

33. Evaluation de la politique française des médicaments génériques n.d. https://igas.gouv.fr/Evaluation-de-la-politique-francaise-des-medicaments-generiques.html (accessed May 16, 2024).

34. Prescription des biosimilaires n.d. https://www.ameli.fr/yvelines/medecin/exercice-liberal/facturation-remuneration/dispositif-interessement-prescription-biosimilaires (accessed May 16, 2024).

35. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. *N Engl J Med.* 2019;380:347–357. doi:10.1056/NEJMoa1812389.

36. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. *N Engl J Med.* 2020;383:1413–1424. doi:10.1056/NEJMoa2022190.

37. Vokinger KN, Nussli E, Dusetzina SB. Access to GLP-1 weight loss drugs in the US, Canada, Switzerland, and Germany. *JAMA Intern Med.* 2024;184(9):1002–1004. doi:10.1001/jamainternmed.2024.2559.