pharmacy

Article
Estimating Type 2 Diabetes Prevalence: A Model of Drug
Consumption Data
Rita Oliveira 1,2,3,4, * , Matilde Monteiro-Soares 5,6,7,8 , José Pedro Guerreiro 9 , Rúben Pereira 9 and
António Teixeira-Rodrigues 9,10,11

1 FP-BHS—Biomedical and Health Sciences Research Unit, FFP-I3ID—Instituto de Investigação, Inovação e

Desenvolvimento, Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Rua Carlos da Maia 296,
4200-150 Porto, Portugal
2 UCIBIO—Applied Molecular Biosciences Unit, MedTech, Laboratory of Pharmaceutical Technology,
Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo de Ferreira 228,
4050-313 Porto, Portugal
3 Associate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto,
Rua Jorge Viterbo de Ferreira 228, 4050-313 Porto, Portugal
4 Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
5 CINTESIS—Center for Health Technology and Services Research, Faculty of Medicine, University of Porto,
4050-313 Porto, Portugal; [email protected]
6 MEDCIDS—Departamento de Medicina da Comunidade Informação e Decisão em Saúde,
Faculty of Medicine, University of Porto, 4050-313 Porto, Portugal
7 Portuguese Red Cross Health School Lisbon, Avenida de Ceuta nº 1, 1300-125 Lisbon, Portugal
8 Cross I&D, Avenida de Ceuta nº 1, 1300-125 Lisbon, Portugal
9 Centre for Health Evaluation & Research/Infosaúde, National Association of Pharmacies,
1300-125 Lisbon, Portugal; [email protected] (J.P.G.); [email protected] (R.P.);
[email protected] (A.T.-R.)
10 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
11 ICVS/3Bs PT Government Associate Laboratory, Campus de Gualtar, 4710-057 Braga, Portugal
* Correspondence: [email protected]

Abstract: Observational, cross-sectional prevalence studies are costly and time-consuming. The
development of indirect methods estimating prevalence used to obtain faster, less-expensive, and
Citation: Oliveira, R.; Monteiro- more robust results would be an advantage for several healthcare applications. This study aimed
Soares, M.; Guerreiro, J.P.; Pereira, R.;
to use the drug dispensing data from community pharmacies to estimate the prevalence of Type
Teixeira-Rodrigues, A. Estimating
2 Diabetes mellitus (T2DM) in the Portuguese population. A cross-sectional study was conducted
Type 2 Diabetes Prevalence: A Model
using a database of dispensed medicines with an indication for Diabetes mellitus in 2018 and 2021,
of Drug Consumption Data. Pharmacy
stratified by geographic region. The methodology was based on a sequential method of acquiring
2024, 12, 18. https://doi.org/
10.3390/pharmacy12010018
prevalence estimates obtained through exposure to medicines using the daily doses defined per
thousand inhabitants per day and adjusted to the rate of adherence to therapy, prescription patterns,
Academic Editor: Jack E. Fincham
and concomitance of antidiabetic drugs. The estimated overall T2DM prevalence in 2018 was 13.9%,
Received: 27 November 2023 and it was 14.2% for 2021. The results show the increased consumption of antidiabetic drugs, with
Revised: 15 January 2024 fixed-dose combination antidiabetics and new antidiabetics being particularly important in 2021. This
Accepted: 19 January 2024 work allowed for the development of a model to obtain the estimated prevalence of T2DM based on
Published: 22 January 2024 drug consumption, using a simple, fast, and robust method that is in line with the available evidence.
However, with the recent expanding indications for new antidiabetics, the inclusion of further data
in the model needs to be studied.

Copyright: © 2024 by the authors.

Keywords: drug utilization data; prevalence; diabetes mellitus; antidiabetics
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
1. Introduction
creativecommons.org/licenses/by/ The knowledge of an accurate estimate of the prevalence of a disease or clinical
4.0/). condition has considerable clinical relevance, as it defines the a priori probability of a

Pharmacy 2024, 12, 18. https://doi.org/10.3390/pharmacy12010018 https://www.mdpi.com/journal/pharmacy

Pharmacy 2024, 12, 18 2 of 18

diagnosis, supports clinical decision making, enables an understanding of the burden of

diseases, and guides future research. An adequate prevalence estimate is also required for
health technology assessment (HTA) processes, like medicines, medical devices, therapeutic
procedures, or health-related interventions, and to provide information to improve clinical
practices or health policymaking [1]. The knowledge of the prevalence of a condition in
the HTA context is a central parameter, as its magnitude defines the importance of the
medicine/technology to be evaluated in societal, political, economic, and clinical terms [2].
The regulatory dynamics associated with these processes would benefit significantly from
the regular and dynamic updating of the prevalence value.
This continuous updating of the prevalence estimation through classical observational
studies on the primary data is not feasible as it becomes costly, challenging to implement,
and time-consuming [3–6]. Developing accurate, rapid, and validated methods would add
value for clinical and regulatory purposes.
While primary data collection may be onerous and expensive, secondary databases are
more easily accessible data sources if they are standardized and informatically compatible
between healthcare institutions [7,8]. Drug utilization data can be collected along the
drug chain (acquisition, storage, distribution, prescribing, treatment compliance, and
treatment outcome) from databases at the regional, national, or international levels. The
manufacturers, suppliers, regulatory agencies, inpatient and outpatient health institutions
(for prescribing data), and pharmacies (for dispensing data) are all data sources that
are commonly used for drug utilization research [9]. Drug consumption data have the
advantage of being readily available information. However, as this surrogate information
may not directly relate to diagnosis, a methodological challenge emerges [10,11]. The
research on drug utilization data is essential to improve the methods’ robustness.
In Portugal, ambulatory prescriptions, whether they come from the NHS or private
institutions, are reimbursed in the same way. The pharmacies collect all the dispensing
records, and the public reimbursement is then made by the Central Administration of the
Health System (ACSS). Additional reimbursements made by private insurance companies
can also be applicable. As this information is not always readily or freely available, the
resort to pharmacy databases is considered as a simpler option.
For the execution and validation of these methods, it is vital to find a clinical condition
with particular features, namely, a high prevalence in the population, chronic in nature, a
solid pharmacological relationship with the diagnosed and treated population, and one
for which we have excellent clinical and epidemiological knowledge to test the model. We
have selected Diabetes mellitus (DM), as this disease complies with these criteria.
As a long-known chronic disease, in 2019, the World Health Organization (WHO)
presented an updated classification of DM, excluding the subtypes of Type 1 Diabetes
mellitus (T1DM) and Type 2 Diabetes mellitus (T2DM), and adding new types of DM
(hybrid forms and unclassified DM) [12]. However, T2DM is the most common form,
accounting for 90% to 95% of the total diabetes disease cases [12,13]. As the onset of
T2DM is challenging to identify due to its asymptomatic characteristics, it is estimated that
one-third to one-half of the patients are undiagnosed [13].
The pharmacological therapy for DM comprises the administration of non-insulin
antidiabetic drugs (NADs)—therapeutic subgroups identified by their respective Anatom-
ical Therapeutic Chemical (ATC) classification [14]: biguanides, sulfonylureas, alpha-
glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors,
glucagon-like peptide-1 (GLP-1) analogues, sodium-glucose co-transporter 2 (SGLT2);
and insulins used for outpatient administration.
The clinical guidelines for T2DM management have been established and frequently
updated by several expert medical associations, such as the International Diabetes Federa-
tion, the American Diabetes Association, the European Association for the Study of Dia-
betes, public health national agencies, and the Portuguese Society of Diabetology [15–18].
The pharmacological approach usually starts with metformin and has evolved to include
other NADs in a monotherapy or combination therapy. When indicated, insulin can be
Pharmacy 2024, 12, 18 3 of 18

added to optimize glycemic control and prevent micro- and macrovascular complications
in the long term, avoiding hypoglycemic episodes [18,19]. Polytherapy is frequently used
when treating DM, resulting in concomitance, which is defined as administering two or
more drugs simultaneously for the same condition. The American Diabetes Association
and the European Association for the Study of Diabetes treatment guidelines advise up to
three NADs plus insulin until HbA1c control [17]. However, some recent studies, mainly
from Asia, aim for quadruple NAD therapy [20–22]. Ultimately, the decision is clinical and
patient-centered, based on the best available clinical evidence.
This study aimed to estimate the prevalence of T2DM in the Portuguese population.
Meanwhile, the evolution of antidiabetic drug (AD) consumption in 2018 and 2021 was
characterized according to the ATC code and stratified by region. The impact of off-label
use, therapeutic adherence, and concomitant AD prescription in the prevalence estimation
was also assessed.
This study was carried out on a representative sample of medicine-consuming people
in Portugal, enabling comparison with the existing literature data and providing a simple
implementation, allowing easy replication. The development of this type of model for
estimating prevalence can be applied to other diseases, and the robustness of the estimation
can be improved as the inputs of the model are updated.

2. Materials and Methods

A nationwide, descriptive study of drug dispensing data was conducted to allow the
estimation of T2DM prevalence in the Portuguese population. To assess the robustness of
the estimation, the model was used to estimate the prevalence of T2DM in two periods: the
full year 2018 and the full year 2021.

2.1. Data Source

ADs for outpatient use are dispensed in Portugal upon prescription only. Portuguese
data were retrieved from the Health Market Research® Pharmacy Sales Information System,
a national database of around 2400 pharmacies with drug dispensing data (including
sales by medicine ATC code, pharmaceutical form, number of units, and dosage) at the
regional level for ambulatory care. This database includes data from more than 82% of the
Portuguese community pharmacies.
Data collection was based on the ATC classification system, as recommended by the
WHO [14].
The data collected covered ATC classes A10A, insulins and analogues, and A10B (blood
glucose-lowering drugs, excluding insulins), which were commercialized in Portugal in
2018 and 2021.

2.2. Population
The quantification of the study population was retrieved from demographic data for
2018 and 2021 (Table 1), including the total national population by the residence district,
from the National Official Statistics Agency.

Table 1. Portugal’s population per district [23].

Region 2018 2021

Aveiro 695,702 700,957
Beja 141,178 144,465
Braga 828,650 846,418
Bragança 124,571 122,826
Castelo Branco 179,038 177,995
Coimbra 405,267 408,609
Évora 152,865 152,511
Faro 438,864 467,475
Pharmacy 2024, 12, 18 4 of 18

Table 1. Cont.

Region 2018 2021

Guarda 144,354 142,998
Leiria 454,592 458,672
Lisboa 2,271,772 2,275,846
Portalegre 105,479 104,930
Porto 1,778,146 1,785,627
Santarém 429,719 425,025
Setubal 852,328 874,926
Viana do Castelo 230,954 231,293
Vila Real 191,894 185,705
Viseu 354,453 351,315
Madeira 253,945 250,769
Açores 242,846 236,440
Total 10,276,617 10,344,802

The WHO recommends the unit of drug measurement, Defined Daily Dose (DDD),
for drug utilization monitoring and research [24]. According to their definition, the DDD is
the “assumed average daily dose of a drug when used in its main therapeutic indication in
adults” [14]. It is defined from the existing experience with the drug recommendations in
the literature and from its manufacturers. As measured by the DDD, drug consumption is
usually expressed as DDD per 1000 inhabitants per day (DID). The DID calculation allows
us to roughly determine the proportion of the population receiving, per day, the standard
treatment of a given drug.
The population’s exposure to AD was then assumed to correspond to the population’s
consumption and is expressed as DID.
Two outcomes were estimated:
1. The total DDD consumed per year was calculated as follows:

Total DDD consumed = No. of units consumed in one-year × dosage/DDD (1)

The DDD for each drug was based on the ATC Index 2022, regardless of the year the
consumption refers to. The drugs were classified according to the ATC Index 2022, level
5—active substance.
2. DID: This indicates the number of people per 1000 who receive antidiabetic drugs
daily and was calculated using the following equation.

DID = Total DDD consumed × 1000/(No. inhabitants × 365 days) (2)

2.3. Literature Data

The national and international literature data considered most relevant and chosen for
comparing the results are compiled in Table 2, along with the bibliographical references.

Table 2. Literature data.

2018 2021 References

Global 9.3% 10.5% [13]
Adult diabetes prevalence estimates Europe 8.9% 9.2% [13]
(20–79 years old) Portugal 14.2% 13% [13]
Portugal 13.6% [25]
Pharmacy 2024, 12, 18 5 of 18

Table 2. Cont.

2018 2021 References

Non-diagnosed DM Global 50.1% 44.7% [13]
Europe 40.7% 35.7% [13]
Portugal/TID 475.2 433.3 [13]
Portugal 44% [25]
T2DM treatment adherence 60% 60% [26,27]
T2DM concomitance factor 0.608 0.608 [28]
T2DM insulin users 7.5% 7.5% [29]
DM: Diabetes mellitus; T2DM: Type 2 Diabetes mellitus; TID: thousand inhabitants per day.

2.4. Prevalence Estimation Model

The estimation of the prevalence of T2DM was performed by applying the formula
proposed by Sartor and Walckiers [30]:
 
v
∑ik=1 cii
p̂ = (3)
N
where:
p̂—the estimated prevalence;
k—the classes of drugs;
vi —the total amount of NAD sold in Portugal for the years 2018 and 2021;
ci —the technical unit of drug consumption (DID);
N—the estimated resident population in Portugal for 2018 and 2021.
For the application of this methodology, the authors assumed the following assump-
tions:
• The treatment of the pathology is mainly pharmacological;
• The drugs used are specific for the pathology considered;
• The administration of the drugs is not seasonal.
The prevalence estimation model was processed using Microsoft Office Excel 2007
software and developed in 5 steps, as follows:
Step (1) The number of patients undergoing treatment for DM based on DID estimations.
Exposure to AD is expressed in DID, which reflects the number of DDDs dispensed to
1000 inhabitants per day. As the DDD is the assumed average daily dose of a drug when
used in its main therapeutic indication in adults, it is a rough estimation of the number of
patients undergoing treatment with ADs.
The calculations considered the ATC classification—level 4—chemical subgroup.
Step (2) The adjustment to treatment adherence.
Treatment adherence was assumed to be 60% for all the NADs (crude value) [26,27]. It
was considered 100% for the insulin AD.
Step (3) The adjustment to NADs in monotherapy or polytherapy.
The concomitance of different antidiabetic pharmacological regimens impacts the
prevalence estimation, i.e., two packages in a month may be used to treat one patient or
two patients, according to the therapeutic regimen.
Concomitance in NAD therapy was estimated according to Sartor and Walckiers,
1995 [30], by using the weighting factor (w), which was achieved as follows:

1
w= (4)
[1 + π2 + (2π3 ) + (3π4 )]
Pharmacy 2024, 12, 18 6 of 18
Pharmacy 2024, 11, x FOR PEER REVIEW 6 of 19

where π2 , π3 , and π4 represent the probability of patients taking two, three, or four drugs
We applied respectively.
simultaneously, a w value of 0.608 that corrects for the proportion of patients taking an
association of two,a three,
We applied or four
w value classes
of 0.608 thatofcorrects
NAD following an oral hypoglycemic
for the proportion drug use
of patients taking an
study [28]. of two, three, or four classes of NAD following an oral hypoglycemic drug use
association
study
Step (4)[28].
The exclusion of insulin AD users.
StepInsulin-only
(4) The exclusion
usersof insulin
were AD users.
excluded. Regarding the T2DM patients, it was considered
that 7.5% of them were insulin AD users [29].
Insulin-only users were excluded. Regarding the T2DM patients, it was considered
that (5)
Step 7.5% of prevalence
The them were insulin AD of
estimation users
T2DM[29].patients under pharmacological treatment
StepPrevalence
(5) The prevalence estimation
was obtained of T2DM
as a ratio patients
of the number under pharmacological
of patients treatment
undergoing treatment
for T2DM estimated in the previous steps per Portuguese patient [23].
Prevalence was obtained as a ratio of the number of patients undergoing treatment for
Step
T2DM(6)estimated
The prevalence estimation
in the previous of T2DM.
steps per Portuguese patient [23].
StepTo obtain
(6) The an overall
prevalence estimation
estimation of the prevalence of T2DM in Portugal, the
of T2DM.
percentages of non-diagnosed T2DM were considered:
To obtain an overall estimation of the prevalence 44% for
of T2DM 2018 [25] the
in Portugal, andpercentages
35.7% for
2021 [13] of non-diagnosed
of non-diagnosed T2DM werepatients.
considered: 44% for 2018 [25] and 35.7% for 2021 [13] of
non-diagnosed patients.
2.5. Sensitivity Analysis
2.5. Sensitivity
SensitivityAnalysis
analysis was performed by varying the crucial parameters used in base
case analysis. Each
Sensitivity of these
analysis wasassumptions
performed was changed,
by varying while
the all the
crucial other variables
parameters used inwere
base
held
case constant.
analysis. Each of these assumptions was changed, while all the other variables were
heldWe assessed the effect on T2DM estimated prevalence of changing the following
constant.
parameters for the the
We assessed extreme
effectvalues foundestimated
on T2DM in the literature:
prevalence of changing the following
parameters
• for the extreme values found in
Medication adherence: 50% and 92% [31–33]; the literature:
•• T2DM insulin
Medication users: 6%50%
adherence: and and
15.8%92%[29,34];
[31–33];
•• TheT2DMconcomitant factor:
insulin users: 6%wand= 0.596
15.8% [35];
[29,34];
•• Non-diagnosed
The concomitantT2DM w = 0.596
factor:patients: [35];
9.8% and 50% [13].
• Non-diagnosed T2DM patients: 9.8% and 50% [13].
3. Results
3. Results
3.1. Characterization of AD Consumption in Portugal
3.1. Characterization of AD Consumption in Portugal
Figure 1 shows the AD consumption rates measured in DID in Portugal and its
Figure
regions 1 shows
in 2018 the AD consumption rates measured in DID in Portugal and its regions
and 2021.
in 2018 and 2021.

Consumptionof
Figure1.1.Consumption
Figure ofantidiabetic
antidiabeticdrugs
drugsexpressed
expressedby
byDefined
DefinedDaily
DailyDose
Doseper
per1000
1000inhabitants
inhabitants
per day by region in 2018 and 2021.
per day by region in 2018 and 2021.
Pharmacy 2024, 12, 18 7 of 18

The consumption of ADs in Portugal in 2018 and 2021 increased from 91 DID to 104.9
DID, presenting an increase in all of the regions. The region of the lowest consumption rate
in 2018 was Lisbon, and in 2021, it was Faro, while the highest one occurred in Bragança in
both these periods.
The insulin consumption rate increased in 2018 and 2021 from 15.5 DID to 16.0 DID (%
change of +2.6%), while the NAD consumption rate experienced an increase from 75.4 DID
to 88.9 DID (% change of +17.9%), respectively (Table 3).

Table 3. Antidiabetic consumption in DID in 2018 and 2021.

DID (%) 1
ATC Code Description of the ATC Code 2018 2021 Variation 2 (2018–2021, %)
A10AB Fast-acting insulins 2.8 (3.1%) 3.3 (3.1%) 16.8
A10AC Intermediate-acting insulins 1.8 (2.0%) 1.3 (1.2%) −26.8
A10AD Combined-acting insulins 4.0 (4.3%) 3.3 (3.1%) −16.8
A10AE Long-acting insulins 7.0 (7.7%) 8.1 (7.7%) 15.3
A10A Insulins 15.5 (17.0%) 16.0 (15.2%) 2.6
A10BA Biguanides 24.2 26.6%) 24.5 (23.4%) 1.4
A10BB Sulphonylureas 14.5 (15.9%) 11.5 (11.0%) −20.5
A10BD Oral fixed-dose combinations 22.4 (24.6%) 28.3 (27.0%) 26.5
A10BF α-glucosidase inhibitors 0.7 (0.8%) 0.4 (0.4%) −45.7
A10BG Glitazones 0.4 (0.4%) 0.4 (0.4%) −11.7
A10BH DPP-4 inhibitors 7.0 (7.7%) 7.6 (7.2%) 8.9
A10BJ GLP-1 analogues 1.6 (1.8%) 4.9 (4.7%) 196.8
A10BK SGLT2 inhibitors 4.4 (4.8%) 11.2 (10.7%) 153.0
A10BX Other non-insulin antidiabetics 0.2 (0.2%) 0.1 (0.1%) −40.1
A10 B Non-insulin antidiabetics 75.4 (82.9%) 88.9 (84.8%) 17.9
Total A10 Antidiabetics 91.0 104.9 15.3
1 2
Shared DIDs of each drug in overall AD consumption; absolute variation in DID from 2018 to 2021. The raw
data was used in the computations. Results from calculations using the variables in Table 3 may vary slightly.

The regions with the highest NAD consumption rates in 2018 were Vila Real and
Bragança, and similar ranked positions were found in 2021. Lisbon and Faro were the
regions with the lowest NAD consumption rates in 2018 and 2021.
In 2018, insulins represented 17.0% of the total ADs consumed, and in 2021, this
decreased to 15.3%. NAD use increased from 82.9% to 84.8% from 2018 to 2021. Among
the NADs, sulphonylureas showed a more considerable decrease in consumption, and the
oral fixed-dose combinations, DPP-4 inhibitors, GLP-1 analogues, and SGLT2 inhibitors,
presented a growth in their consumption.
Table 3 shows that there was a change in the pattern of NAD consumption between
2018 and 2021. Biguanides and oral fixed-dose combinations are the most commonly
consumed subgroups in the two years analyzed. However, the consumption rate of sul-
fonylureas is decreasing, and the trend is increasing for the newest NADs: DPP-4 inhibitors,
GLP-1 analogues, and SGLT2 inhibitors.

3.2. Estimated Prevalence of Diabetes in Portugal

The number of patients undergoing treatment and the AD consumption rate for T2DM
increased for every region and national area between 2018 and 2021. The prevalence of
treated T2DM has also increased, but not in the case of overall prevalence when considering
the non-diagnosed patients. The Coimbra, Lisboa, and Setubal regions experienced no
variation in overall prevalence. For the regions of Beja, Évora, Faro, and Guarda e Portalegre,
this value has even reduced despite the growth at the national level (Table 4).
Pharmacy 2024, 12, 18 8 of 18

Table 4. Estimated prevalence of Type 2 Diabetes mellitus from antidiabetic consumption data.

N. Patients in Treatment N. Patients under Prevalence of Treated Overall Prevalence of

for DM 1 Treatment for T2DM 2 T2DM Patients (%) 3 T2DM (%) 4
Region 2018 2021 2018 2021 2018 2021 2018 2021
Aveiro 65,315 75,645 54,322 64,443 7.8 9.2 13.9 14.3
Beja 14,173 15,723 12,159 13,542 8.6 9.4 15.4 14.6
Braga 74,463 89,563 63,971 78,413 7.7 9.3 13.8 14.4
Bragança 14,678 16,368 12,379 14,070 9.9 11.5 17.7 17.8
Castelo Branco 17,882 20,991 14,429 17,555 8.1 9.9 14.4 15.3
Coimbra 41,017 45,944 32,594 37,924 8.0 9.3 14.4 14.4
Évora 16,286 18,073 14,000 15,766 9.2 10.3 16.4 16.1
Faro 34,275 40,214 28,303 34,120 6.4 7.3 11.5 11.4
Guarda 14,510 15,904 12,101 13,615 8.4 9.5 15.0 14.8
Leiria 45,654 54,204 38,138 46,200 8.4 10.1 15.0 15.7
Lisboa 181,282 205,529 153,755 177,216 6.8 7.8 12.1 12.1
Portalegre 11,007 12,126 9340 10,482 8.9 10.0 15.8 15.5
Porto 169,066 199,690 143,733 173,001 8.1 9.7 14.4 15.1
Santarém 47,601 54,357 40,418 46,830 9.4 11.0 16.8 17.1
Setúbal 74,195 85,955 62,095 73,303 7.3 8.4 13.0 13.0
Viana do Castelo 24,114 28,366 20,824 24,827 9.0 10.7 16.1 16.7
Vila Real 22,214 25,621 19,369 22,760 10.1 12.3 18.0 19.1
Viseu 33,572 40,745 28,179 35,033 7.9 10.0 14.2 15.5
Madeira 20,411 23,940 17,904 21,493 7.1 8.6 12.6 13.3
Açores 23,377 27,908 19,295 23,595 7.9 10.0 14.2 15.5
Total 945,090 1,096,864 797,307 944,187 7.8 9.1 13.9 14.2
1
DM—Diabetes mellitus; T2DM—Type 2 Diabetes mellitus. Based on DID estimation and adjustment to adherence
and therapeutic concomitance. 2 Exclusion of people with T2DM that are insulin users. 3 Estimated prevalence
of T2DM-treated patients based on AD consumption. 4 Overall estimated prevalence of T2DM considering
non-diagnosed patients.

Using an indirect method to estimate the prevalence based on AD consumption, that

of T2DM was 7.8% in 2018 and 9.1% in 2021 for the patients undergoing pharmacological
treatment.
The overall estimated prevalences considering the assumed proportion of non-diagnosed
patients described in the Methods were 13.9% and 14.2% in 2018 and 2021, respectively.

3.3. Sensitivity Analysis

Table 5 shows the prevalence estimates obtained by changing some parameters
through sensitivity analysis.

Table 5. Sensibility analysis of estimated prevalence of Type 2 Diabetes mellitus.

Prevalence of Treated T2DM

Overall Prevalence of T2DM (%)
Patients (%)
Parameters Scenario 2018 2021 2018 2021
Base estimated prevalence 1 7.8 9.1 13.9 14.2
50% 9.3 10.9
Medication adherence
92% 5.1 6.0
6.0% 7.9 9.3
T2DM insulin users
15.8% 7.7 9.1
Concomitance factor (w) 0.596 7.6 9.0
9.8% 8.6 10.1
Non-diagnosed T2DM patients
50% 15.5 18.3
T2DM—Type 2 Diabetes mellitus. 1 Base case scenario parameters: medication adherence 60%, and T2DM insulin
users 7.5%; w factor 0.608; non-diagnosed patients 44% (2018) and 35.7% (2021).
Pharmacy 2024, 12, 18 9 of 18

4. Discussion
This study obtained estimated overall prevalences of T2DM of 13.9% and 14.2% (2018
vs. 2021) and 7.8% and 9.1% (2018 vs. 2021) for the patients undergoing treatment, respec-
tively. An easy-to-implement-and-to-update method was used to estimate the prevalence
of clinical conditions without resorting to the primary data or databases that are difficult to
obtain and complex to compute.

4.1. Characterization of AD Consumption

The AD consumption rate increased between 2018 and 2021, with overall values of
91 DID and 104.9 DID, respectively. The NADs showed more pronounced growth than
the insulins, rising from 75.4 DID in 2018 to 88.9 DID in 2021, and the insulins maintained
their value at 15.5–16.0 DID. The pattern of NAD consumption changed between 2018 and
2021, with a decrease in sulphonylureas and a growth in combination ADs and DPP-4
inhibitors, GLP-1 analogues, and SGLT2 inhibitors. In 2018, the NADs that showed the
most consumed ones were biguanides (24.2 DID), followed by dose-fixed combinations
(22.4 DID).
The 2019 National Diabetes Observatory Annual Report reported an overall AD
consumption of 68.1 DID for 2017. The Organisation for Economic Co-operation and
Development (OECD) data for pharmaceutical consumption published DID rates of 70.2
(2018), 74.0 (2019), and 76.6 (2020) [36]. These differences may be explained by evaluating
different metrics (e.g., the calculation of DID of fixed-dose combinations) and databases
(population covered).
Although lifestyle can be a cause of T2DM, and its control may have a therapeutic
effect [37–39], there is still a lack of quality evidence for the most effective lifestyle pro-
grams [40,41] and the pharmacological approach required. No results were found about
an estimate for the patients treated only with a lifestyle approach, especially in real-world
clinical practice.
Regarding the growth in consumption of the most recent AD agents, the trend is
also increasing across Europe, as shown by a study of 11 European countries [42]. Some
reasons can explain the increase in AD consumption, such as the increased prevalence
of DM, increased longevity, increased early diagnosis and consequent increase in treated
patients, the possible treatment of situations classified as pre-diabetes, more aggressive
clinical approaches with higher doses, changes in prescribing patterns in line with new
guidelines, and the emergence of fixed-dose NAD combinations following the growing
scientific evidence. The increased prevalence of obesity in childhood and adolescence
also changes the epidemiological picture of T2DM, with its onset at increasingly earlier
ages [43].
It should be pointed out that in recent years, new ADs, such as GLP-1 agonists and
SGLT2 inhibitors, expanded their indications beyond T2DM. This is the case of semaglutide
for obesity [44,45], tirzepatide for obesity and its co-morbidities [46], and dapaglifozin and
empaglifozin for heart failure and chronic kidney disease [44]. However, most of them
were approved in Europe after 2021, and for this reason, were not considered as such in this
study. Nevertheless, dapaglifozin was approved by the EMA for heart failure in November
2020 and chronic kidney disease in the middle of 2021 [44]. In Portugal, the decision to
reimburse was authorized in 2022 [47]. These facts make their use other than for T2DM
considered residual at the time of data collection.
The geographical distribution of AD consumption remains constant across the Portugal
regions when comparing 2018 with 2021. The increasing trend was seen across the regions
and with similar distributions.

4.2. Prevalence Estimation

This study found an overall and treated estimated prevalence of T2DM of 13.9% and
7.8% for 2018 and 14.2% and 9.1% for 2021, respectively.
Pharmacy 2024, 12, 18 10 of 18

Between 2006 and 2007, the Epidemiological Study on the Prevalence of Metabolic
Syndrome in the Portuguese Population (VALSIM) was carried out [34]. This cross-sectional
study used a representative sample of adults living in mainland Portugal and the islands
followed up in primary healthcare facilities, and 16,856 individuals were evaluated, with
the registration of their previous diagnosis and the control of fasting glycemia and HbA1c,
out of several other parameters. Among the characterization of cardiovascular risks, the
prevalence, treatment, and control of DM were evaluated. The prevalence of DM in
the population using primary healthcare services, adjusted for sex and age, was 14.9%,
increasing progressively with age and being higher in men (men: 16.8%; women: 13.2%).
The limitations of this study are related to the sampling method, which was conducted by
convenience in primary healthcare facilities, not including the individuals who do not seek
public healthcare and may have undiagnosed DM.
The data from the General Practice Sentinel Network between 1992 and 2015 were
used to describe the evolution of DM incidence and to estimate the future incidence of DM
through Poisson regression models until 2024. The average increase in DM incidence rate
was 4.29% [confidence interval (CI) 95%: 3.80–4.80], and the study revealed an increase in
incidence projections similar to the observed data. The reasons were attributable to the
population ageing and the higher-risk groups [48].
The results from the First National Health Examination Survey (INSEF 2015) showed
an overall prevalence of diabetes of 9.9% (CI95%: 8.4; 11.5), again with a higher value in the
males when compared with that of the females (12.1% vs. 7.8%). This cross-sectional study
was performed on a sample of 4911 adults from Portuguese primary healthcare centers at
the national level through interviews, physical examination, and blood analysis (for HbA1c,
among others) [49].
The Portuguese National Diabetes Observatory publishes an annual report to generate
and disseminate reliable and scientifically credible information on diabetes in Portugal
using essentially registered and collected information on diabetes in the Portuguese NHS as
a data source. This is based on the first large epidemiological study on DM carried out in the
country, the PREVDIAB, with in-person data collection conducted in 2008 on a sample of
5167 individuals. It has been updated with population data from the national censuses [50].
The latest annual report of the national diabetes observatory published in 2019 estimated
a DM prevalence of 13.6%. However, its main limitation is the voluntary participation of
NHS patients and the fact that private healthcare entities were not considered.
The International Diabetes Federation performs frequent estimates of diabetes preva-
lence for several countries based on the highest-quality data available during analysis.
These estimates depend on the type of data sources, ranging from peer-reviewed publi-
cations to national survey data, or data from regulatory bodies. The data quality highly
depends on the diagnostic method chosen for DM, the sample size and representativeness,
the study’s date, the type of study, and the publication type. Predicted future estimates
are based only on the projected changes in age, sex, and rural/urban place of residence,
as defined by the United Nations [51]. The International Diabetes Federation prevalence
estimates for Portugal for 2018 and 2021 were 14.2% and 13%, respectively.
Compared to the European data, the prevalence of T2DM is much higher in Portugal
(Table 2). It is hypothesized that this may be due to the adoption of less-healthy lifestyles
inherent in a consumer society, but mainly to the countries’ demographics. Portugal is a
country with the fourth highest proportion of elderly people in Europe, with an aging index
(the ratio between the elderly population (over 65) and the young population (under 14)) of
169.4 in 2019 and 181.3 in 2021 [23]. Consequently, the overload on primary healthcare may
be becoming less effective in preventing the disease, together with a lack of health literacy
among this population segment.
This study reached a result that falls within the estimates considered for comparison.
However, this is not precisely the same trend since the International Diabetes Federation
predicts a decrease in prevalence in Portugal in 2021, contrary to the results obtained, which
probably reflect more complex prescription patterns.
Pharmacy 2024, 12, 18 11 of 18

4.3. Prevalence Estimation Model: Adherence to Medication in DM

Adherence to therapy is an important parameter reflected in drug consumption and
the consequent effectiveness of the prescribed therapy. Non-adherence can be defined as
the failure to follow the medical prescription, usually classified as primary (failure to fill a
new prescription) versus secondary non-adherence (failure on medication use upon filling
a prescription) [52].
It is challenging to assess adherence in DM, and several studies diverge in terms
and metrics to achieve a consensus. Pasina et al. obtained a non-adherence rate reported
(n = 100) in 55.1% of the patients at the first follow-up and 69.6% 3 months from hospital
discharge in elderly patients receiving polypharmacy, confirming that age is a predictor of
increased non-adherence [53,54]. A survey performed in 2016 in Slovakia (n = 117) found
adherence rates to pharmacological treatment of up to 83% in females and 79% in males
and over 70% for all the age categories up to 75 years old [33]. In Italy, a study conducted
in 2017 obtained rates of non-adherence ranging from 8% to 13% for AD [32]. According to
the WHO report of 2003, the average adherence to long-term therapy for chronic diseases in
developed countries is approximately 50%, and in developing countries, lower adherence
rates were encountered [26,31]. Some systematic reviews approached the adherence of
NAD and performed interesting comparisons between them, but none provided a crude
adherence estimate as a reference [55–57]. A recent cross-sectional study on adherence in
chronic diseases performed in Spain found that the proportion of patients adherent to their
treatment was 55.5% [27].
Regarding the study of primary adhesion, Raebel et al., in 2012, performed a retro-
spective, observational cohort study to identify primary non-adherence for hypertension,
diabetes, and hyperlipidemia patients. The proportion of primary non-adherent patients
varied by therapeutic class, and a value of 13% was found to be the primary non-adherence
rate for antidiabetic drugs [58].
The studies on adherence to ADs are limited, and none applied to the Portuguese
population were found. In this study, the knowledge of the primary adherence reflected
in dispensing the prescribed drugs is of paramount interest. Considering the range of
estimations published in the literature, a global treatment adherence rate (either primary or
secondary) of 60% was considered as the base case scenario, taking into consideration the
closest scenario found in a European country for chronic diseases [27].

4.4. Prevalence Estimation Model: Concomitant Use of AD Drugs

For the application of the model, it was also necessary to adjust for the concomitant
use of ADs, according to the most recent guidelines for DM treatment management, which
sometimes may reach two, three, or four medications.
Some studies about prescribing patterns have been performed in recent years, but
only a few reflect the usage of new NADs. Heintjes et al. conducted an observational study
analyzing the Electronic Health Records of antidiabetic drug prescription/dispensing
in four European countries (Netherlands, Spain, Italy, and the United Kingdom) from
2007 to 2012 (n = 295,923). The prescription patterns were categorized as first-line: oral
monotherapy (metformin, a sulphonylurea, a thiazolidinedione, DPP4 inhibitors, other oral
antidiabetic drugs, a GLP1, or insulin); second line: dual oral therapy (combined metformin
+ sulphonylurea, any oral combination treatment including a thiazolidinedione, and any
oral combination treatment, including a DPP4 inhibitor); third line: triple oral therapy
(oral/insulin or oral/GLP-1 combination therapy); fourth line: insulin only, a GLP-1 only,
or a combination of insulin + GLP-1. Combining all the countries, 47% initiated a first-line
treatment, 28% initiated a second-line treatment, 19% initiated a third-line treatment, and
7% progressed to a fourth-line treatment [35].
In Italy, a regional observational study was performed in 2016 (n = 14,679) of new
users of ADs, considering only first-line treatments (monotherapy, fixed-dose combination
and dual therapy). The results showed dispensing rates of 86.9% for the monotherapy,
9.7% for the fixed-dose combination therapy, and 3.4% for the dual therapy. However, this
Pharmacy 2024, 12, 18 12 of 18

study did not account for therapy intensification, that is, second-, third-, or fourth-line
treatments [59]. Another study conducted in Spain in 2013–2014 (n = 65,167) obtained
similar results [60]. Some other researchers are dedicated to assessing the same subject,
though not achieving a general prescription pattern for concomitance [60,61].
The prevalence of insulin monotherapy in T2DM in Europe is unknown, but a study
from 2018 estimated that the T2DM insulin users’ values in the United Kingdom, Sweden,
and Denmark were 12.5%, 11.7%, and 15.8%, respectively. An estimated 7.5% of T2DM
insulin users in Europe were reported [29]. In a study from the United States of America
conducted in 2014, 12% of patients with T2DM used insulin monotherapy and 14% used
insulin combined with an NAD [62]. Based on a study from the United Kingdom [63],
in 2010, 37% of T2DM patients were treated with insulin. From the VALSIM study, of
the 3215 people with diabetes, 90.2% were on a targeted treatment, meaning 9.8% of the
subjects were untreated. Among the treated patients, 89% were on oral antidiabetics alone,
6% were on insulin therapy, and 5% were on simultaneous oral antidiabetic and insulin
therapy [34]. The scenario has changed with the market authorization of new hypoglycemic
agents [64].
In this study, the weight factor (w) for medicine associations was used for the calcula-
tion methodology developed by Sartor et al., 1995 [30], based on a study by Duarte-Ramos
et al. [28]. The same methodology has been used by other authors [65]. The weight factor
used (w = 0.608) was obtained in a national cross-sectional survey from December 2003
until March 2004. Considering the study period, it is easy to notice that the prescribing
patterns do not correspond to the current ones, namely polytherapy. The mentioned study
by Heintjes et al. [35] obtained updated prescribing patterns, and their results were used to
recalculate the weight factor for the associations. The factor obtained (w = 0.596) yielded
estimated prevalence values for the treated T2DM patients of 7.6% for 2018 and 9.0% for
2021, proving to have a little influence on the final estimation. The weight factor of Duarte-
Ramos [28] obtained for the Portuguese population was then considered. It is important to
consider the periodic collection of primary data on prescription patterns for longitudinal
monitoring. This will allow for information acquisition to calculate the correction factor w
and adjust the estimates.
A proportion of non-treated DM patients (44%) was considered based on the National
Diabetes Observatory Annual Report for the Portuguese population in 2018 [25]. A value
of 35.7% was considered for 2021 based on the International Diabetes Federation for
Europe [13]. This estimate may not be accurate, considering that it was acquired from
in-person surveys.

4.5. Sensitivity Analysis

Sensitivity analysis was conducted based on the parameter values found in the lit-
erature. The choice of the base case scenario was based on the closest approximation to
the Portuguese population, the data origin (official sources and professional associations),
and the closeness to the years studied. Subsequently, the other scenarios were developed
by varying the parameters between the lowest and highest values found in the literature.
The results show that the parameters most affected the DM prevalence were medication
adherence and the undiagnosed T2DM patients due to their more significant variation.
These parameters became critical in the obtention of an accurate result.
Medication adherence is a parameter that influences AD consumption, and for which
there are no updated estimations for the Portuguese population. The existing information
shows a considerable variation between the studies. The adherence considered to be 60%
for all the NADs and 100% for the insulins indeed does not correspond to real-world since
there is some non-adherence in insulins, although this is not significant. On the other hand,
adherence among NAD users is not homogeneous, since it is directly linked to adverse
effects and costs, which are very different among the ATC subclasses.
Pharmacy 2024, 12, 18 13 of 18

4.6. Strengths and Limitations

As a limitation, this model can only estimate the prevalence of diagnosed and treated
DM due to the data’s origin.
Concerning the medications utilized on a continuous or chronic basis, such as an-
tidiabetics or antihypertensives, the DID is a rough estimation of the number of patients
undergoing chronic treatment since it is a technical unit of measurement of the exposure
of a given population to a particular drug to perform the aggregation of drug subgroups
and geographical comparisons [10,66]. The access to aggregate data requires parameter
adjustments with assumptions that are not always precise and appropriate to the study pop-
ulation, influencing their validity. Although the DID is an estimate of the actual use of the
drugs, it does not necessarily reflect the prescribed daily dose (which depends on the posol-
ogy) or the daily dose consumed (which is related to treatment compliance). For the same
reason, the outcome cannot be stratified by sex or age as clinically valuable information.
Therapeutic adherence, which reflects compliance to a prescription, is reflected in the
data on drug dispensing, the implementation of the correct treatment, and the persistence
of the same treatment that impacts the prevalence estimation, and high-quality adherence
studies should be considered [56,67]. Although they are not very suitable for identifying the
direct non-adherence cases, drug dispensing records are more accessible than prescription
and clinical records for the indirect calculation of adherence and its indicators.
The aggregate drug consumption data do not precisely reflect the prescription clinical
practice, which implies predicting dosing patterns and the concomitant use of drugs [21,68].
The prescribing patterns have changed over the years, and the concomitance factor used
will not be updated for the emergence of new NADs and combinations, with the increase
in polytherapy and the trend towards the introduction of increasingly earlier insulin use
for the control of hyperglycemia and the prevention of future complications.
The off-label use of medicines distorts the drug consumption data and their approved
indications, and in most cases, their alternative application is unknown. The off-label
use of a drug is defined as the prescription of a drug outside the scope of the therapeutic
indications approved in the respective marketing authorization [69]. This implies that it has
yet to be assessed, or at least validated, by the health authorities and, therefore, lacks the
same scientific evidence as the treatments approved for specific indications. Consequently,
the data about the off-label use of medicines are scarce, as it is often associated with a
practice with no legal framework [69]. The off-label use of ADs is not well documented,
but some studies suggested the use of NADs for T1DM [70–75], obesity [70,76], polycystic
ovarian syndrome [77–79], dermatological diseases [80,81], and as a senolytic [82–84].
Recently, the European Medicines Agency approved the SGLT inhibitors dapagliflozin and
sotagliflozin as adjuvant treatments to insulin for T1DM in adults [85], and insulins were
already recommended in T2DM in the previous guidelines. In this study, the off-label use
of NADs was not considered since no data metrics were found.
The recently expanded indications for GLP-1 agonists and SGLT2 inhibitors were not
reflected in this study, as it refers to data from up to 2021. However, the implementation of
the developed model at the current time requires the inclusion of prescription data for the
additional indications approved to date.
Although comprehensive research is conducted in robust sensitivity analysis, the
estimates used for several parameters were based on the available literature, which is only
sometimes updated, is related to other populations or does not use robust methods, biasing
the final estimated result.
The database used does not include inpatient consumption; however, it includes other
health subsystems that need to be identified in the NHS databases.
The indirect method of estimating the prevalence of drug utilization data has been
tested in several chronic diseases [86–89], such as ocular hypertension [90], inflammatory
bowel disease [65], thyroid disorders [91], and DM [28,92,93]. Compared with the other
studies using prescription data or data not covering the entire population, the dispensing
information obtained from a sample representing 82% of the pharmacies in Portugal with
Pharmacy 2024, 12, 18 14 of 18

a homogeneous geographical distribution is a strength of the study consolidating the

results presented.
This method allowed us to estimate DM prevalence simply. This will benefit from
evolving drug utilization research, especially studies on primary and secondary adherence,
prescribing patterns, and the off-label use of AD, to refine the assumed parameters.

5. Conclusions
An estimate of T2DM prevalence was achieved from aggregate AD drug consumption
data, with similar results to those obtained by the standard methodologies. Nevertheless,
the developed method operates on many assumptions and can be improved by more
precise estimates for the assumed parameters to substitute or complement the traditional
methods for estimating the prevalence of clinical conditions.
The developed method based on information collected from the pharmacy network
widely distributed throughout Portugal has the advantage of accessing a large and rep-
resentative population sample size, can be repeated periodically, and can be regionally
stratified, identifying and exploring the differences for this purpose.
This study contributes to the development of pharmacoepidemiology and drug uti-
lization data. Less-complex methods, even if not as accurate than classical methods, allow
for the fast updating of health policies, clinical guidelines, or pharmacoeconomic studies.

Author Contributions: Conceptualization, A.T.-R.; methodology, A.T.-R. and M.M.-S.; formal analy-
sis, investigation and data curation, R.O., J.P.G., R.P. and A.T.-R.; writing—original draft preparation,
R.O; writing—review and editing, R.O., M.M.-S. and A.T.-R.; supervision, M.M.-S. and A.T.-R. All
authors have read and agreed to the published version of the manuscript.
Funding: The APC were funded by the Faculty of Medicine of University of Oporto.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data supporting this study’s findings are available from the
authors, but restrictions apply to the availability of these data, which were used under license from
the National Association of Pharmacies for the current study and are not publicly available. The
data are, however, available from the authors upon reasonable request and with permission from the
National Association of Pharmacies.
Acknowledgments: The authors would like to thank the National Association of Pharmacies for
providing the database for research. The authors would also like to thank to the Faculty of Medicine
of University of Oporto for funding the publication.
Conflicts of Interest: Author A.T.R. is the Executive Director of the Centre for Health Evaluation
and Research (CEFAR), National Association of Pharmacies. J.P.G. and R.P. are staff members at
the Centre for Health Evaluation and Research (CEFAR), National Association of Pharmacies. The
authors R.S.O. and M.M.S. declare they have no conflicts of interests.

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