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Open access Original research

Long-­term trends in the prescription

of antidiabetic drugs: real-­world
evidence from the Diabetes Registry
Tyrol 2012–2018
Clemens Engler,1 Marco Leo,2 Bernhard Pfeifer,2,3 Martin Juchum,4
Di Chen-­Koenig,5 Karin Poelzl,6 Hans Schoenherr,7 David Vill,8
Juliana Oberdanner,9 Egon Eisendle,10 Klaus Middeldorf,11 Bernhard Heindl,12
Hannes Gaenzer,13 Gerald Bode,14 Karl Kirchmeyr,15 Guenther Ladner,16
Lisa Rieger,17 Ursula Koellensperger,17 Andrea Schwaiger,18 Florian Stoeckl,14
Guenther Zangerl,19 Monika Lechleitner,5,6 Irmgard Delmarko,2
Wilhelm Oberaigner,20 Clemens Rissbacher,21 Herbert Tilg,1
Christoph Ebenbichler  ‍ ‍1

To cite: Engler C, Leo M, ABSTRACT

Pfeifer B, et al. Long-­term Introduction  Prescription patterns of antidiabetic
Significance of this study
trends in the prescription of drugs in the period from 2012 to 2018 were
antidiabetic drugs: real-­world
investigated based on the Diabetes Registry Tyrol. To
What is already known about this subject?
evidence from the Diabetes ►► Evidence-­based guidelines are key to improve treat-
validate the findings, we compared the numbers with
Registry Tyrol 2012–2018. ment of patients with type 2 diabetes mellitus.
BMJ Open Diab Res Care trends of different national registries conducted in a
comparable period of time. ►► Increasing knowledge results in more detailed
2020;8:e001279. doi:10.1136/
Research design and methods  Medication data, guidelines.
bmjdrc-2020-001279
prescription patterns, age groups, antidiabetic ►► Knowledge increases fast due to Food and Drug
therapies and quality parameters (hemoglobin A1c, Administration-­
required cardiovascular outcome
Received 18 February 2020 body mass index, complications) of 10 875 patients trials.
Revised 26 June 2020 with type 2 diabetes from 2012 to 2018 were
Accepted 6 July 2020 What are the new findings?
retrospectively assessed and descriptively analyzed. ►► In more than 10 000 patients over 7 years, metformin
The changes were assessed using a time series alone or in combination was the most frequent anti-
analysis with linear regression and prescription trends
diabetic drug, followed by insulin or insulin analogs,
were plotted over time.
gliptins, sodium/glucose cotransporter 2 inhibitors
Results  Sodium/glucose cotransporter 2 inhibitors
(SGLT-­2i), sulfonylureas, glitazones, glucagon-­
(SGLT-­2 i) showed a significant increase in prescription
like peptide-1 agonists (GLP-­1a) and glucosidase
from 2012 to 2018 (p<0.001), as well as metformin
inhibitors.
(p=0.002), gliptins (p=0.013) and glucagon-­like
►► Metformin, gliptin, SGLT-­2i and GLP-­1a prescriptions
peptide-1 agonists (GLP-­1 a) (p=0.017). Significant
increased, sulfonylureas decreased, and insulin and
reduction in sulfonylurea prescriptions (p<0.001)
analogs did not change as well as glitazones.
was observed. Metformin was the most frequently
prescribed antidiabetic drug (51.3%), followed by How might these results change the focus of
insulin/analogs (34.6%), gliptins (28.2%), SGLT-­2 i research or clinical practice?
(11.7%), sulfonylurea (9.1%), glitazones (3.7%), GLP-­ ►► The results of the observational cohort from the
1a (2.8%) and glucosidase inhibitors (0.4%). Diabetes Registry Tyrol should encourage physicians
Conclusions  In this long-­t erm, real-­w orld study to implement novel evidence-­based findings to en-
© Author(s) (or their on prescription changes in the Diabetes Registry
employer(s)) 2020. Re-­use sure timely and up-­to date, evidence-­based medi-
Tyrol, we observed significant increase in SGLT-­2 i,
permitted under CC BY-­NC. No cine for their patients even before new guidelines
commercial re-­use. See rights metformin, gliptins and GLP-­1 a prescriptions. In
can be published.
and permissions. Published contrast prescriptions for sulfonylureas declined
by BMJ. significantly. Changes were consistent over the
For numbered affiliations see years 2012–2018. Changes in prescription patterns
end of article. occurred even before the publication of international INTRODUCTION
and national guidelines. Thus, physicians change their Diabetes mellitus prevalence has nearly
Correspondence to prescription practice not only based on published
Dr Christoph Ebenbichler;
doubled since 1980, affecting 8.5% of the
guidelines, but even earlier on publication of
​christoph.​ebenbichler@​i-​med.​ cardiovascular outcome trials. adult population, with half of the cases esti-
ac.a​ t mated to be undiagnosed,1 and this accounts

BMJ Open Diab Res Care 2020;8:e001279. doi:10.1136/bmjdrc-2020-001279 1

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Clinical care/Education/Nutrition

for nearly 463 million worldwide.2 According to the Inter- is crucial for the improvement of therapies regardless
national Diabetes Federation (IDF), over four million of disciplines.27 Registries provide a powerful tool to
died of diabetes and its accompanied diseases in 2019, assess changes in treatment. Following large numbers
which resulted in global healthcare expenditures of of patients with detailed demographics for years gener-
US$760 billion.2 By 2045 nearly 700 million people will ates large amounts of long-­term repeated measurements.
suffer from diabetes, costing US$845 billion.2 These allow for observation of changes over time and
Europe has the second least number of adult patients monitoring of implementation and impact of evidence-­
with diabetes among the regions of the IDF (6.8%).2 based treatment and guidelines.
Ranging from 2.1% in Greenland to 11.1% in Turkey, Despite its importance, nationwide and regional epide-
the intracontinental differences are extensive.2 Over miological data on diabetes treatment in Austria and
600 000 (6.6%) Austrians suffer from diabetes mellitus, Europe are scarce. The Diabetes Registry Tyrol (DRT) is
thereof 85%–90% from type 2 diabetes mellitus.2 3 The the only Austrian diabetes registry for adults, representing
diabetes epidemic has led to constant development of one out of nine states. The aim was to analyze treatment
disease-­controlling drugs and treatment strategies,4 5 modalities and quality parameters in comparison with
generating rapid changes in national and international recent changes in the treatment of type 2 diabetes from
guidelines.6–9 In 2015 the American Diabetes Associa- 2012 to 2018 due to the extensive growth of knowledge
tion (ADA) and the European Association for the Study during this period. These data were compared with
of Diabetes (EASD) updated the existing position state- guidelines, published high-­impact studies and equivalent
ment from 2012.10 11 In 2018 the position statement was nationwide data from different countries arising from
updated again and a further update was added in 2019 by the same period of time.
the European Society of Cardiology (ESC) and EASD.6 9
The Austrian Diabetes Association also releases regular
position papers which are in accordance with the interna- RESEARCH DESIGN AND METHODS
tional guidelines and are adapted to the Austrian popu- Data are from the DRT, a region-­wide diabetes registry
lation and insurance system, thereby ensuring timely, containing inbound and outbound patients from ten Tyro-
evidence-­ based, high-­quality and international compa- lean hospitals and from nine private internal specialists.28
rable recommendations.8 Nearly 21 000 patients diagnosed with diabetes mellitus
The time between the updates was marked by rapid are included, of whom 15 980 have type 2 diabetes. The
changes in the treatment of type 2 diabetes. In 2008 present data set includes data from 10 875 patients with
the US Food and Drug Administration (FDA) changed type 2 diabetes who attended at least one type 2 diabetes-­
their requirements for cardiovascular (CV) safety when related inpatient or outpatient visit between January
approving new antidiabetic drugs.12 The FDA require- 1, 2012 and December 31, 2018. The registry records
ments led to the publication of numerous large CV the demographics, medical history and clinical data of
outcome trials (CVOT) since new treatments have entered patients with incident and chronic type 2 diabetes. Data
the market, sodium/glucose cotransporter 2 inhibitors contain information on age, sex, body mass index (BMI),
(SGLT-­2i), gliptins and glucagon-­like peptide-1 agonists HbA1c, long-­term complications (eg, diabetic nephrop-
(GLP-­1a). SGLT-­2i, first approved in 2011, showed CV athy, neuropathy, retinopathy, and macrovascular events)
safety and potential renal benefits, reduced CV events, and duration of disease. Since 2012 diabetes medica-
reduced all-­cause mortality, and decreased worsening of tions have been assessed, including substance class and
heart failure and risk of death from heart failure.4 5 13 14 In start and end date. For raw data generation a project-­
the same period GLP-­1a, first approved in 2005, proved oriented software was established. To guarantee the legal
to be CV safe, reduced CV events and showed potential and ethical standards of data privacy, the data sets are
renal benefits.15–22 Gliptins already showed CV safety in pseudonymized. Participating centers measure body
2013, and the evidence was strengthened from 2015 to weight in whole kilograms at every patient visit. Body
2019, and showed renal safety.23–26 This new evidence led height is measured in centimeters using a tapeline at
to significant changes in the guidelines. The 2018/2019 first patient visit. Nephropathy is defined as the pres-
guidelines aim to provide an algorithmic approach for ence of albuminuria twice or more and/or glomerular
decision making in antidiabetic treatment.7 9–11 If hemo- filtration rate <60 mL/min/1.73 m². Retinopathy is diag-
globin A1c (HbA1c) targets cannot be met, recommenda- nosed by an ophthalmologist. Neuropathy is diagnosed
tions for intensification of therapy by the 2015 guidelines using the microfilament test and diabetic feet are diag-
were vague. Increasing evidence from large CVOTs nosed by the presence of chronic ulcer and infections.
helped to specify diabetes guidelines. The 2018/2019 Amputation due to diabetes is defined as non-­traumatic
ADA and EASD guidelines provide a five-­column step amputation for a diabetic foot syndrome. Myocardial
scheme personalized to the needs of patients, associated infarction, stroke, bypass and percutaneous transluminal
comorbidities, treatment targets and even costs.7 9–11 angioplasty are recorded according to medical documen-
Providing guidelines is only a small step in changing tation of the said events. Peripheral artery disease (PAD)
treatment regimens. Guideline compliance varies and is defined as the presence of symptomatic PAD, an ankle-­
knowledge concerning adherence and implementation brachial index less than 0.80 or diminished foot pulses.

2 BMJ Open Diab Res Care 2020;8:e001279. doi:10.1136/bmjdrc-2020-001279

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Clinical care/Education/Nutrition

HbA1c values are measured at the participating hospital

Table 1  Number, age, duration of diabetes and diabetes-­
or at the private internal specialists at the time of visit associated complications of participants in the Diabetes
in per cent or mmol/mol. Information on medication Registry Tyrol
is collected in a digital form with the following available
Patients Age in years, Frequency
options: no medication, GLP-­1a, insulin, insulin analogs, (n) mean (±SD) (%)
insulin pump and bariatric surgery or oral medication.
Sex
For oral medication a separate field is available with the
options metformin, gliptin, glitazone, glucosidase inhib-  Female 4491 68.51 (±11.75) 41.30
itor, SGLT-­2i, sulfonylurea or other oral medication.  Male 6384 68.58 (±11.76) 58.70
Our findings were discussed and compared with the  Total 10 875 68.55 (±11.76) 100
latest published guidelines by national and international Age groups
diabetes associations.6 8 9 To assess if the results apply to an
 0–39 185 34.2 (±5.66) 1.70
international context, they were discussed using compa-
 40–59 2227 53.5 (±4.97) 20.48
rable publications with similar key outcomes which were
conducted in a similar period of time.  60–79 6083 70.4 (±5.71) 55.94
 80–99 2374 85.8 (±4.53) 21.83
Statistics Diabetes duration (years)
Relative numbers of prescribed drugs per year were calcu-  0–5 1550 3.23 (±1.33) 19.06
lated with the number of annual patient visits as basis. For
 6–10 2043 7.79 (±1.40) 25.13
calculation of the relative number of prescriptions, the
 11–20 3064 15.04 (±2.85) 37.68
total number of patient visits was the basis. Only the most
recent annual examination for each patient was used for  21–99 1447 28.31 (±7.78) 18.13
analysis. Demography of patients was summarized by sex,  Mean 13.4 (±9.2)
age group and diabetes duration. They were divided into Diabetes-­associated complications
four age groups (0–39, 40–59, 60–79, 80–99). Diabetes  Nephropathy 1298 11.94
duration is calculated from the year of initial diagnosis
 Revascularization 938 8.63
to the last visit. Duration is given in four duration groups
and as mean±SD. Diabetes-­associated complications are  Myocardial infarction 884 8.13
defined as mentioned and the relative share is calculated  Neuropathy 737 6.78
from the total population (table 1). Antidiabetic drugs  Apoplectic insults 502 4.62
and metformin-­based combination therapies used in the  Peripheral artery 420 3.86
treatment are summarized in table 2. Absolute and rela- disease
tive numbers of patients prescribed a specific therapy are  Diabetic foot 268 2.46
given, and a time series analysis using linear regression  Retinopathy 204 1.88
was conducted (table 2). Table 3 shows the absolute and
 Amputation 106 0.97
relative numbers of prescribed antidiabetic drugs in four
age groups. Distribution of parameters was estimated
using histogram, boxplot, skewness and kurtosis. Vari- (11.9%) was the most common associated late complica-
ables are given as mean±SD. P values <0.05 were consid- tion, followed by revascularization (8.6%) and myocar-
ered significant. Statistical analyses were performed with dial infarction (8.1%). Less common were neuropathy
R V.3.5.3 (R Core Team, 2019). (6.8%), apoplectic insults (4.6%), PAD (3.9%) and reti-
nopathy (1.9%) (table 1).

RESULTS Prescribed drug classes

Demography Of all the analyzed patients in the DRT, 68.1% were
We analyzed 10 875 patients from the DRT from 2012 treated with at least one oral antidiabetic drug from 2012
to 2018. Of the patients 41.3% were female and 58.7% to 2018. In this period, metformin was the most frequent
were male, with a mean age of 69±12 years. Of the DRT (51.3%), followed by gliptins (28.2%), SGLT-­2i (11.7%),
patients, 55.9% were between 60 and 79 years old, 21.8% sulfonylurea (9.1%) and glitazones (3.7%). The least
were older than 80, 20.5% were between 40 and 59 years prescribed oral antidiabetic drug was glucosidase inhib-
old, and 1.7% were between 18 and 39 years old. The itors (0.4%). Among the injectable therapies, the use
mean age of participants is given in table 1. The mean of insulin or analogs was the most frequent (34.6%),
HbA1c in our cohort was 7.6%±1.88 (60 mmol/mol±20.6) followed by GLP-­1a (2.8%) (table 2).
and the mean BMI was 30.2 kg/m²±5.83. Of the patients, Since 2012 the number of metformin prescriptions
37.7% had a diabetes duration of 11–20 years, followed increased (2012, 45.4%; 2018, 59%; p=0.002) (figure 1),
by 25.1% with duration of 6–10 years, 19.1% with 0–5 as well as gliptins (2012, 23.3%; 2018, 34.1%; p=0.013)
years and 18.1% with 21 or more years. The mean dura- and SGLT-­2i (2012, 0.06%; 2018, 23.4%; p<0.001). In
tion of diabetes was 13.4±9.2 years. Diabetic nephropathy the same period a strong decrease (2012, 17.3%; 2018,

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Clinical care/Education/Nutrition

metformin (29.1%). Gliptins were common in patients

Table 2  Absolute and relative values of single class
medication and metformin-­based combination therapies older than 40 years (40–59 years, 26.5%; 60–79 years,
in the treatment of type 2 diabetes mellitus in the Diabetes 30.5%; ≥80 years, 25.4%), but less common in patients
Registry Tyrol and change over time from 2012 to 2018 aged 18–39 years (11.4%). Patients aged 40–59 years
Change from
received the most SGLT-­2i (19.6%) and patients older
Class Total* (%) 2012 to 2018† than 80 the least (2.4%). Insulin or analogs were most
frequent in patients older than 80 years (53.4%), and
Oral medication
patients 18–79 years received less (18–39 years, 30.3%;
 Oral antidiabetic drugs 7408 (68.12) <0.001 40–59 years, 33.9%; 60–79 years, 43.1%) (table 3).
 Metformin or gliptins 6535 (60.09) 0.005
 Metformin 5583 (51.34) 0.002 Combination therapies
 Gliptins 3067 (28.20) 0.013 More than half (55.6%) of the patients received a
 SGLT-­2i 1270 (11.68) <0.001 metformin-­based combination therapy with at least one
other antidiabetic drug. The most prevalent combina-
 Sulfonylurea analogs 994 (9.14) <0.001
tion was metformin with gliptin (19.5%), followed by
 Glitazones 399 (3.67) 0.098 metformin in combination with insulin or an analog
 Glucosidase inhibitors 39 (0.36) 0.005 (17.1%). The third most prevalent antidiabetic combi-
Injectable medication nation was metformin with SGLT-­2i (9.7%), followed by
 Insulin or analogs 3765 (34.62) 0.073 metformin with sulfonylurea (4.6%). Therapy enhance-
 Insulin analogs 3656 (33.62) 0.101
ment to a triple therapy consisting of metformin, SGLT-­2i
and gliptins was more often seen (4.2%) than the dual
 Insulin 3180 (29.24) 0.065
combination therapy with metformin and glitazones
 GLP-­1a 301 (2.77) 0.017 (2.6%) and metformin and GLP-­1a (1.9%). The least
Metformin-­based combinations prescribed combination therapy was metformin, SGLT-­2i
 Metformin and gliptin 2115 (19.45) 0.024 and GLP-­1a (0.7%) (table 2).
 Metformin and (insulin/ 1858 (17.09) 0.003 Metformin in combination with gliptin (2012, 7.8%;
analogs) 2018, 17.5%; p=0.024) and metformin in combination with
 Metformin and SGLT-­2i 1049 (9.65) <0.001 insulin or analogs (2012, 18.6%; 2018, 23.9%; p=0.003)
increased significantly. Metformin in combination with
 Metformin and 503 (4.63) 0.001
sulfonylurea SGLT-­2i showed the steepest increase (2012, 0.3%; 2018,
15.8%; p<0.001). Combination of metformin, SGLT-­ 2i
 Metformin and SGLT-­2i 459 (4.22) 0.002
and gliptin and gliptin increased significantly (2012, 0%; 2018, 6.7%;
p=0.002). Metformin together with sulfonylurea decreased
 Metformin and glitazone 281 (2.58) 0.329
significantly (2012, 8.6%; 2018, 2.9%; p=0.001) and
 Metformin and GLP-­1a 210 (1.93) 0.006
metformin in combination with glitazone stayed the same
 Metformin and SGLT-­2i 75 (0.69) 0.002 (2012, 1.7%; 2018, 2.3%; p=0.329) (table 2).
and GLP-­1a Combination of metformin and gliptins was most
 Total number of patients 10 875 (100) frequent in patients aged 40–79 years (40–59 years, 22%;
*Data are absolute number of patients prescribed one of the 60–79 years, 22.1%) and almost the same in the youngest
drugs or combinations. and oldest patient groups (18–39 years, 10.9%; 80–99
†Time series analysis with a linear regression was used to years, 11%). Metformin in combination with insulin was
assess if drug prescription has changed in the time from 2012 most common in patients aged 40–79 years (40–59 years,
to 2018. P<0.05 was considered a significant change over the
7-­year period.
19.1%; 60–79 years, 19%), while the youngest and oldest
GLP-­1a, glucagon-­like peptide-1 agonist; SGLT-­2i, sodium/ groups received less (18–39 years, 14.6%; >80 years,
glucose cotransporter 2 inhibitor. 10.6%). Metformin combined with SGLT-­ 2i was most
often in patients 40–59 years (16.7%), almost the same
in patients 18–39 and 60–79 years (10.3% and 10.2%)
4.6%; p<0.001) was observed in the number of sulfony- and the least in patients older than 80 years (1.6%).
lurea prescriptions. Glitazones stayed stable at a low level Metformin and sulfonylureas were most common in
(2012, 3.72%; 2018, 5.34%; p=0.098) and glucosidase patients 60–79 years (5.3%), followed by patients 40–59
inhibitors decreased (2012, 0.74%; 2018, 0.27%; p<0.05). years and older than 80 years (3.9% and 3.8%) and the
Among injectable therapies insulin and analogs did not least in the youngest (18–39 years, 2.7%) (table 3).
change (2012, 50.8%; 2018, 47.5%; p=0.073), but GLP-­1a
(2012, 1%; 2018, 6.1%; p=0.017) prescriptions increased
(figure 1, table 2). DISCUSSION
Metformin was most frequent in patients younger Over 7 years metformin alone or in combination was
than 80 years (18–39 years, 54.1%; 40–59 years, 65.0%; the most frequent antidiabetic drug, followed by insulin
60–79 years, 55.0%). Patients older than 80 received less or insulin analogs, gliptins, SGLT-­ 2i, sulfonylurea,

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Clinical care/Education/Nutrition

Table 3  Absolute and relative values of oral medication, injectable medication and metformin-­based combination therapies
in the treatment of type 2 diabetes mellitus in the Diabetes Registry Tyrol by age groups
Class 18–39 years, n (%) 40–59 years, n (%) 60–79 years, n (%) 80–99 years, n (%)
Oral medication
 Oral antidiabetic drugs 108 (58.4) 1672 (75.1) 4297 (70.6) 1331 (56.1)
 Metformin or gliptins 101 (54.6) 1541 (69.2) 3859 (63.4) 1034 (43.6)
 Metformin 100 (54.1) 1446 (65.0) 3347 (55.0) 690 (29.1)
 Gliptins 21 (11.4) 590 (26.5) 1852 (30.5) 604 (25.4)
 SGLT-­2i 22 (11.9) 437 (19.6) 753 (12.4) 58 (2.4)
 Sulfonylurea analogs 7 (3.8) 136 (6.1) 528 (8.7) 323 (13.6)
 Glitazones 4 (2.2) 116 (5.2) 239 (3.9) 40 (1.7)
 Glucosidase inhibitors 0 (0) 4 (0.2) 21 (0.4) 14 (0.6)
Injectable medication
 Insulin or analogs 56 (30.3) 754 (33.9) 2623 (43.1) 1267 (53.4)
 Insulin analogs 42 (22.7) 578 (26.0) 2092 (34.4) 933 (39.3)
 Insulin 40 (21.6) 498 (22.4) 1822 (30.0) 818 (34.5)
 GLP-­1a 8 (4.3) 109 (4.9) 174 (2.9) 10 (0.4)
Metformin-­based combinations
 Metformin and gliptins 20 (10.8) 490 (22.0) 1343 (22.1) 262 (11.0)
 Metformin and (insulin/analogs) 27 (14.6) 426 (19.1) 1153 (19.0) 252 (10.6)
 Metformin and SGLT-­2i 19 (10.3) 372 (16.7) 619 (10.2) 39 (1.6)
 Metformin and sulfonylurea 5 (2.7) 87 (3.9) 320 (5.3) 91 (3.8)
 Metformin and SGLT-­2i and gliptin 4 (2.2) 154 (6.9) 283 (4.7) 18 (0.8)
 Metformin and glitazone 3 (1.6) 89 (4.0) 168 (2.8) 21 (0.9)
 Metformin and GLP-­1a 8 (4.3) 79 (3.6) 117 (1.9) 6 (0.3)
 Metformin and SGLT-­2i and GLP-­1a 5 (2.70) 27 (1.2) 41 (0.7) 2 (0.1)
 Total 185 (100) 2227 (100) 6083 (100) 2374 (100)
GLP-­1a, glucagon-­like peptide-1 agonist; SGLT-­2i, sodium/glucose cotransporter 2 inhibitor.

glitazones, GLP-­ 1a and glucosidase inhibitors. In the approval to patients with mild and moderate chronic
7-­year period metformin, gliptin, SGLT-­2i and GLP-­1a kidney disease (CKD), subsequently leading to an addi-
prescriptions increased, sulfonylureas decreased, and tional increase in metformin prescriptions.32 33 The
insulin and analogs did not change as well as glitazones. latest ADA, EASD and ESC guidelines showed a trend
The variety of available therapies and the constantly toward novel antidiabetic drugs in initial treatment.
evolving knowledge allow sophisticated and targeted Metformin remained the first-­ line recommendation,
therapies for patients with type 2 diabetes, but also more except for drug-­ naïve patients with arteriosclerotic
complex treatment regimens. Diabetes societies face cardiovascular disease (ASCVD) and a high or very high
this challenge with regular publications of guidelines to CV risk.6 7 11 These developments led to the current posi-
ensure evidence-­ based, standardized and cost-­ efficient tion of metformin in the treatment of type 2 diabetes.
treatment regimens. However, knowledge is constantly Since 2012, metformin has shown strong increases, is the
increasing and guidelines cannot change annually. Our most prevalent drug and is more often used in younger
data (figure 1) showed that changes occur after publi-
patients.34–38 Since the last DRT publication data have
cation of large-­ scale studies proving their benefits,
shown that metformin is now the most prevalent anti-
even before these novel findings are applied to guide-
diabetic medication throughout every age group.28
lines.13 15–17 23 24 29–31 This indicates that diabetologists
Approval in CKD, decreased CV mortality in mono-
react fast to published literature and thereby enable
therapy and combination therapy, same glycemic results
evidence-­based treatment for their patients.
as glitazones and sulfonylureas, higher effectiveness
Metformin than gliptins, increasing long-­term data and physician
The 2015 guidelines strengthened the first-­line therapy experience made metformin applicable to all age groups
position of metformin.10 11 In 2016 the European and and substantiated the increase in use of metformin in
American drug approval authorities enhanced its the treatment of type 2 diabetes.32 33 39

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Clinical care/Education/Nutrition

the last choice for treatment intensification. Sulfony-

lureas are still considered second line, if cost is a major
issue.6 7 10 11 Accordingly, the number of patients receiving
sulfonylureas was constantly decreasing, not only in our
cohort but internationally (figure 1).28 34 36–38 Sulfony-
lurea prescriptions were decreasing in the USA, but were
also the most prevalent second-­line therapy.34 42 43 Due
to a different insurance system, antidiabetic medica-
tion is significantly more expensive in the USA, making
affordable antidiabetics more important for patients.
Sulfonylureas reduce HbA1c, similar to metformin and
glitazones, but metformin monotherapy shows a better
CV long-­ term outcome. Furthermore, sulfonylureas
increase body weight and are associated with an increased
Figure 1  Proportion of antidiabetic drugs prescribed risk of hypoglycemia.39 These facts led to a persistent
per year from 2012 to 2018 in the Diabetes Registry Tyrol decreasing significance of sulfonylureas in recent guide-
and changes over time from 2012 to 2018. Time series lines.7 8 However, when cost is a major issue, sulfonylureas
analysis with a linear regression was used to assess if drug are still considered an option for intensification.7
prescription has changed in the time from 2012 to 2018.
***P<0.001, **P<0.01, *P<0.05. Overall n=10 875; metformin Insulin and analogs
n=5583; insulin or analogs n=3765; gliptin n=3067; SGLT-­
Novel antidiabetic drugs show enhanced CV benefits, are
2i n=1270; sulfonylurea n=994; glitazones n=399; GLP-­1a
easier to manage and show less severe side effects than
n=301. GLP-­1a, glucagon-­like peptide-1 agonist; SGLT-­2i,
sodium/glucose cotransporter inhibitor. insulin.39 In the 2016 guidelines, insulin was considered
earlier in therapy intensification, and since the 2019
guidelines it is now one of the latter steps.6 7 10 11 Despite
SGLT-2 inhibitors its consideration later in therapy, insulin is still common
The first SGLT-­2i was approved in 2012. Due to conflicting in the treatment of type 2 diabetes worldwide, ranging
data and lack of evidence, the authors of the 2015 and from 30% to 40%.37 42 Insulin showed no significant
2016 guidelines were neutral in SGLT-­2i recommenda- changes from 2012 to 2018 (figure 1), and insulin is still
tions.10 11 40 In 2015 Zinman et al4 published the first large the second most common antidiabetic drug (table 2)
CVOT proving significant CV benefits and a lower rate in the DRT.28 Although insulin and sulfonylureas share
of all-­cause death for one of the SGLT-­2is.4 Driven by the a higher risk for hypoglycemia, sulfonylurea prescrip-
CVOT, the 2019 guidelines recommended SGLT-­2i, espe- tions were decreasing while insulin remained stable
cially in the presence of cardiovascular disease (CVD) (figure 1).34 36 42 Insulin is an important cornerstone in
and heart failure.4–9 13 14 First increases in prescriptions the treatment of advanced and long-­term type 2 diabetes.
started between 2013 and 2014. At that time it was known Due to decreasing beta-­ cell and kidney function in
that SGLT-­2i promotes decrease in HbA1c, weight loss elderly patients with type 2 diabetes, many antidiabetic
and a slight decrease in blood pressure (figure 1).41 drugs fail to achieve glycemic targets or are contraindi-
After the publication of the first CVOT, a marked and cated.44 Therefore, insulin is prescribed more often to
steep increase started (figure 1). UK and US registries elderly patients (table 3).42 The risk of severe hypogly-
showed the same dynamics.36 42 43 Compared with the last cemia is higher in insulin-­treated patients, but modern
DRT evaluation, SGLT-­2i increased strongly from 3.7% insulin analogs decreased the risk of hypoglycemia
to 11.7%. This increase was very pronounced in patients and nocturnal hypoglycemia.38 45 The characteristics of
18–79 years and least in patients above 80 years,28 insulin in the treatment of long-­term type 2 diabetes and
although these patients would probably benefit the most the necessity for the treatment of type 1 diabetes have led
from CV advantages, such as lower rate of heart failure, to constant development of new insulins, justified their
all-­cause death and hypoglycemia. Nevertheless the side position in the guidelines and in the antidiabetic therapy
effects impose a bigger risk for this population. In non-­ which is directly reflected in the prescription patterns of
obese elderly patients, weight loss is undesirable, same as diabetologists.
the decrease in blood pressure and risk of dehydration
due to increased urinary excretion. Young patients are Gliptins
not as prone to develop these side effects.43 The 2015/2016 diabetes guidelines listed gliptins as
add-­on therapy to metformin without noting special pref-
Sulfonylureas erences.10 40 The 2019 guidelines recommend gliptins as
The ADA and EASD recommended sulfonylureas as add-­on to metformin in dual therapy or as triple therapy.
a second-­ line intensification option in the treatment Combination of gliptins and sulfonylureas was not
of type 2 diabetes in 2015 and 2016.10 11 In the current recommended. For patients without CKD or CVD, who
guidelines both societies considered sulfonylureas as cannot achieve HbA1c with a monotherapy, gliptins are

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Clinical care/Education/Nutrition

recommended if there is no need to lose weight.7 Gliptin but the numbers are overall low (figure 1).28 34 36 37 Treat-
prescriptions have been increasing since its approval ment with GLP-­1a is expensive.7 9 Some countries even
especially as first add-­on therapy of choice.34–36 42 In the recommend discontinuation of GLP-­1a if there was no
DRT gliptin prescriptions have significantly increased reduction in HbA1c of at least 1 percentage point and
since 2012; however, the curve has flattened out in the 3% in body weight after 6 months, and additionally due
last years (figure 1).28 Whereas increasing prescriptions to gastrointestinal side effects the discontinuation rate is
were an international trend, the proportion of prescribed high.17 34 50
gliptins showed large differences.35–37 42 Gliptins are
expensive, show intermediate efficacy and some of them Glucosidase inhibitors
need dose adjustment in patients with CKD, but the Already in the 2015 European and US guidelines, gluco-
negligible risk for hypoglycemia, easy and convenient sidase inhibitors were a minor matter which only ought
management, weight neutrality, and overall good accep- to be tried in specific situations, but were generally not
tance made them a beneficial add-­on therapy.7 23 24 The favored due to modest efficacy and side effects.11 Current
differences in the number of prescriptions were largely guidelines state the same.7 Overall the use of glucosidase
driven by economic factors, especially in the USA where inhibitors is low in Western countries.34 36 37 In Japan, for
the price for gliptins is noticeably higher than in Europe. example, glucosidase inhibitors were prescribed more
This also reflects in the current guidelines, where gliptins often.35 The larger the carbohydrate intake the more the
are considered last if cost is a major issue.7 9 blood glucose-­lowering effect, and the Japanese have a
distinctly higher carbohydrate intake than Western popu-
Glitazones lations.35 Glucosidase inhibitors and metformin have
In the 2015/2016 guidelines glitazones were recom- similar side effects, such as meteorism, nausea, diarrhea
mended when HbA1c targets were not achieved after and flatulence, but metformin shows better glycemic
monotherapy. The guidelines stated drug choice is based control, additional weight-­ lowering effects, evidence-­
on patient preferences as well as disease and drug charac- based CV benefits, and is the first-­line therapy in Europe
teristics.10 11 Current guidelines recommend glitazones as and the USA for type 2 diabetes.7 11 Therefore, metformin
first-­line intensification in two clearly defined situations. is probably preferred over glucosidase inhibitors.
They are recommended if targets cannot be achieved with Our study has some limitations. The participating
metformin monotherapy in a patient without ASCVD centers are specialized hospital outpatient depart-
or CKD and without the need to minimize weight gain ments or private internal specialists, so the study is not
or promote weight loss. Furthermore, they are recom- population-­based. This carries the possibility of potential
mended as first-­ line intensification if cost is a major bias, as diabetes specialists might intensify therapy more
issue.7 9 Glitazones are not recommended in patients with quickly than general practitioners. Additionally, due to
congestive heart failure, bladder cancer, obesity or oste- their specialization, diabetologists are more likely to read
oporosis.7 11 39 46 In the DRT prescriptions of glitazones novel study outcomes, and due to their experience in
stayed stable at a low level, and the same can be seen in antidiabetic treatment they might be more courageous in
the USA and in Europe.34 36 37 Good glycemic control implementing novel approaches. A potential bias could
and low risk for hypoglycemia led to extensive glitazone be in HbA1c evaluation. To ensure that per year each
prescriptions in the late 1990s and early 2000s. Troglita- patient is only assessed once, only data of the last annual
zone and rosiglitazone lost their approvals because they visit are considered for the registry. Patients with elevated
were associated with severe side effects, such as hepato- glycemic parameters visit their responsible doctor more
toxicity, higher CV risk, development of bone fractures often until optimal diabetes treatment and control are
and bladder cancer,46 47 which led to a steep decrease in achieved. At this time point HbA1c is most likely to be
prescriptions from then on.36 38 48 49 Nevertheless, piogl- lower than at treatment start. Beneficial study outcomes
itazone, the remaining approved glitazone, showed CV for drugs lead to extensive marketing efforts. These
benefits and is a low-­cost medication, but due to the can also lead—consciously or unconsciously—to more
previous findings and alternatives the numbers stayed prescriptions of the promoted drugs. The strengths of
low.7 9 our study are the real-­world set-­up and the size of the
cohort. The study contains data on 10 875 patients, an
GLP-1 agonists estimate of 20%–25% of patients with type 2 diabetes in
Since 2015 evidence on the safety and benefits of GLP-­1a Tyrol. It involves repeated measures over 7 years, an inter-
strengthened.15–22 The 2016 guidelines did not recom- esting period of time when several new antidiabetic drugs
mend GLP-­1a explicitly for use in patients with CVD.10 11 were introduced, two guidelines were published, and
In the current guidelines, GLP-­1a and SGLT-­2i are consid- numerous results of large-­scale studies and FDA-­required
ered first-­
line therapy intensification in patients with CVOTs were published.
CVD and obesity.7 Furthermore, GLP-­ 1a is the first In conclusion, we saw significant changes in prescrip-
recommended injectable therapy because it is easy to tion patterns of antidiabetic medications in the DRT and
manage, carries no risk for hypoglycemia and decreases also in other national registries. Interestingly the changes
weight. International GLP-­1a prescriptions were rising did occur in accordance with the guidelines often before

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 BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2020-001279 on 1 September 2020. Downloaded from http://drc.bmj.com/ on January 15, 2021 by guest. Protected by copyright.
Clinical care/Education/Nutrition

they were published, proving that diabetologists adapt University of Innsbruck in a general statement. Procedures involving patients, patient
their prescription patterns to large-­scale trials even before data collection, and handling and storage of personal data are in accordance with
national laws and the ethical standards of the seventh revision of the Declaration
guidelines can be adapted, highlighting the importance of Helsinki.
of up-­to-­date, evidence-­based medicine to ensure timely, Provenance and peer review  Not commissioned; externally peer reviewed.
modern and high-­quality treatment for patients and their
Data availability statement  Data that support the findings of this study are
successful implementation. Registries play an important available on reasonable request from the corresponding author. Data are not
role in monitoring the benefits of new treatments, iden- publicly available due to data and personal privacy rights of the participants.
tifying potential risks, developing modern and evidence-­ Open access  This is an open access article distributed in accordance with the
based guidelines, and ensuring a high level of treatment. Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
Author affiliations and license their derivative works on different terms, provided the original work is
1
Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, properly cited, appropriate credit is given, any changes made indicated, and the
Medical University Innsbruck, Innsbruck, Austria use is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/.
2
Department of Clinical Epidemiology, Tirol Kliniken, Innsbruck, Austria
3 ORCID iD
Center for Health and Bioresources, Digital Health Information Systems, Austrian
Christoph Ebenbichler http://​orcid.​org/​0000-​0001-​5025-​7929
Institute of Technology, Hall in Tyrol, Austria
4
Rehabilitation Center Muenster, Muenster, Austria
5
Department of Internal Medicine and Geriatrics, Hospital Hochzirl, Hochzirl, Austria
6
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