Factors Associated with Type 2 Diabetes Mellitus Treatment Choice Across Four European Countries

doi:10.1016/j.clinthera.2017.09.016

Clinical Therapeutics

Volume 39, Issue 11, November 2017, Pages 2296-2310.e14

https://doi.org/10.1016/j.clinthera.2017.09.016 Get rights and content

Abstract

Purpose

The aim of this analysis was to identify factors associated with the choice of type 2 diabetes mellitus (T2DM) therapy at the time of intensification of antidiabetic treatment across 4 European countries.

Methods

Antidiabetic drug prescription/dispensing records and patients' characteristics were obtained from the electronic health care records of patients with T2DM from the Netherlands (NL), Italy, and Spain (ES) (all, 2007–2011); and the United Kingdom (UK; 2008–2012). Oral monotherapy was defined as first-line; oral dual therapy, as second-line; >2 oral treatments or oral combined with an injectable, as third-line; and injectables only, as fourth-line treatment. Treatment intensification was defined as the start of a higher line of treatment. Comedication, comorbidities, clinical parameters, and other factors associated with treatment choice were identified using multivariate relative risk estimation by Poisson regression with robust error variance.

Findings

In the 5-year study period, 485,120 patients (79% of the treated T2DM population) underwent treatment intensification. Changes in treatment choice were clearly visible over the study period, such as a decline in the use of thiazolidinediones (NL, ES, UK) and increases in the use of dipeptidyl peptidase-4 inhibitors (DPP4i) (NL, ES, UK) and glucagon-like peptide-1 receptor agonists (UK). With first-line treatment, advanced age and renal comorbidity were associated with the use of sulfonylureas (SUs; all countries), whereas high body mass index (BMI) was inversely associated with SU use in the United Kingdom and Spain. With second-line treatment, advanced age was associated with metformin + SU use (all countries); and renal comorbidity with SU + DPP4i use in the United Kingdom and the Netherlands. High BMI was associated with metformin + thiazolidinedione (TZD) use in the United Kingdom and Spain, and with metformin + DPP4i in the United Kingdom. With third-line treatment, advanced age and renal comorbidity were associated with the use of SU + insulin (NL, ES, UK). Hemoglobin A_1c >8.5% was positively associated, and high BMI was inversely associated, with the use of any third-line combination containing insulin. Across treatment lines TZD and metformin were negatively associated with renal and cardiac morbidity. Second and third line treatment choices strongly depended on prior treatments. With fourth-line treatment, women were more likely to receive glucagon-like peptide-1 receptor agonists than were men in the United Kingdom and Spain.

Implications

The results suggest that the main factors driving treatment choice at any stage of intensification were age, hemoglobin A_1c, BMI, renal and cardiac morbidity, and treatment history. These drivers were consistent with guidelines on, and contraindications of, specific medications. Differences between countries were generally consistent with, but not solely attributable to, differences in local guidelines and reimbursement policies.

Introduction

Type 2 diabetes mellitus (T2DM) is a progressive disease of epidemic proportions. The estimated prevalence of T2DM in Europe is expected to rise from ~9.1% (59.8 million patients) in 2015 to 10.7% (71.1 million patients) in 2040. In Western Europe, the estimated prevalence in 2015 ranges from <5% to >9%.¹ Cardiovascular and other complications may be prevented by close monitoring of blood glucose levels and intensification of treatment if glycemic targets are not met.

The increasing complexity and recognized importance of glucose-lowering treatment have led to the development of guidelines to help physicians to make treatment decisions. Despite the American Diabetes Association/European Association for the Study of Diabetes international consensus statement on the T2DM treatment algorithm of 2006² and subsequent position statements,3, 4 European countries have developed local guidelines as well,5, 6, 7, 8 each weighing cost considerations and the evidence of effectiveness and risk differently, resulting in slightly different recommendations. The general consensus at the time of this study was that the intensification of treatment based on failure to reach glycemic targets should take place along the following lines: Start with oral monotherapy, preferably metformin. If that is no longer effective, subsequent treatment steps are adding a second oral drug, and subsequently adding a third oral drug, basal insulin, or a glucagon-like peptide-1 receptor agonist (GLP-1ra). Guidelines2, 3, 4, 5, 6, 7, 8, 9 allow skipping steps in this algorithm when hemoglobin (Hb) A_1c levels are far from the target of 7% (53 mmol/mol). Insulin or GLP-1ra monotherapy may be considered if a patient does not tolerate, or seem to benefit from, a combination with oral drugs, but it is not recommended in the guidelines,2, 3, 4, 5, 6, 7, 8, 9 as oral drugs may help to keep insulin doses low.

There is variation in local guidelines, which could result in different treatment choices across countries. Published treatment-pattern studies9, 10 mainly describe cross-sectional distributions of prescribed T2DM treatments rather than factors associated with treatment choice. In a previous study,¹¹ we described individual switching patterns in the period 2007 to 2012 in 5 European countries (France, Italy [IT], the Netherlands [NL], Spain [ES], and the United Kingdom [UK]). The present study aimed to identify factors associated with the choice of treatment at the time of intensification of treatment.

Section snippets

Setting

The data in this observational cohort study were obtained from population-based databases containing electronic health records from routine primary care in 4 European countries: the Pharmo Database Network¹² (NL), the Health Search Longitudinal Patient Database (IT), the Sistema d' Informació per al Desenvolupament de la Investigació en Atenció Primària13, 14 (ES), and The Health Improvement Network (UK).¹⁵ Additional information regarding the different data sources is described elsewhere.¹¹ No

Patients and Treatment Characteristics

Overall, 617,346 patients received T2DM treatment during the study period, 485,120 (79%) of whom were included in the present study cohort as they initiated or intensified treatment within the study period. Spain contributed 61% to the study cohort; United Kingdom, 22%; Italy, 9%; and the Netherlands, 7%. Combining all countries, 47% initiated first-line treatment, 28% intensified to second-line treatment, 19% intensified to third-line treatment, and 7% intensified to fourth-line treatment. A

Discussion

Our study included all patients with T2DM who underwent treatment intensifications in 4 European countries, which affected 79% of all patients treated with antidiabetic drugs in the 5-year study period. This suggests that diabetes screening, monitoring, and treatment modification are an ongoing process affecting the majority of patients. The fact that 47% of the study population consisted of patients who were initiated on first-line treatment is testimony to the growing epidemic of T2DM.

Conclusions

The results suggest that the main factors driving treatment choice at any stage of intensification across these 4 European countries are age, HbA_1c level, renal comorbidity, macrovascular complications, and BMI. These drivers are consistent with guidelines and contraindications for specific medications. Differences between countries can be explained at least in part by differences in freedom of choice of treatment, based on guidelines and reimbursement policies.

Conflicts of Interest

This work was supported by a grant from AstraZeneca Pharmaceuticals LP. No limitations were set with regard to the conduct of the study and the writing of the manuscript by the study sponsors.

E.M. Heintjes, J.A. Overbeek and I.D. Bezemer are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related health care authorities and several pharmaceutical companies. G.C. Hall has been a member of

Acknowledgments

The authors thank all of the health care providers who contributed information to the different databases included in this study.

All of the authors contributed substantially to study conception and design, acquisition of the data, and/or analysis and interpretation of the data. E. Bianchini, A. Roso, F. Hill and G. Lucrezi contributed to the analysis of the data. E.M. Heintjes, J.A. Overbeek, and I.D. Bezemer drafted the manuscript, and D. Prieto-Alhambra, G.C. Hall, F. Lapi, and N. Hammar

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Cited by (13)

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2021, Health Policy
International literature suggests that co-payment increases are associated with decreased medicine use, although the effects depend on context. We examined the impact of a co-payment increase on the consumption of type 2 antidiabetics in Finland, a country with a comprehensive health and social security system including ceiling mechanisms aiming to protect patients from high co-payment expenditures.
We used administrative register data on all reimbursed purchases of antidiabetics during 2014−2018. An interrupted time series design with segmented regression was used to examine the mean monthly purchase per person, measured as Defined Daily Doses (DDDs), before and after the co-payment increase.
At baseline, the mean monthly purchase per person of type 2 antidiabetics was 105 DDDs (95% CI 103.8; 106.0;p<0.001) and there was a decreasing trend of 0.2 DDDs per month (95% CI -0.23;-0.13;p<0.001). A statistically significant decrease of 5.6 DDDs (95% CI -7.3;-3.8;p<0.001) was detected after the reform; however, no significant change in the trend was observed. No significant increase was detected in the mean monthly per person purchase of insulins.
The results suggest that a co-payment increase decreases consumption of necessary medicines despite the presence of a medicine co-payment ceiling mechanism. Whether the decrease was associated with negative health effects remains to be further investigated.
Determinants of treatment modification before and after implementation of the updated 2015 NICE guideline on type 2 diabetes: A retrospective cohort study
2021, Diabetes Research and Clinical Practice
Citation Excerpt :
While sulphonylureas were the preferred second-line therapy in the 2009 guideline [2], the new guideline (published in December 2015) recommends to choose the second-line treatment based on patient characteristics, risk factors, treatment efficacy, safety and tolerability, costs and patient preferences [3]. Recent studies have shown that patient characteristics and risk factors are associated with treatment choices [4,5]. In particular, body mass index (BMI), HbA1c, age, cardiovascular risk and renal function have been identified as significant determinants of general practitioners’ prescribing [4,5].
To identify patient-specific factors associated with early metformin treatment modification among type 2 diabetes patients before and after implementation of the updated 2015 NICE (National Institute for Health and Care Excellence) guideline.
We conducted a population-based cohort study using data from the Clinical Practice Research Datalink GOLD database (2009–2016). Patients ≥ 18 years, newly treated with metformin only, during the period of valid data collection were included. The first prescription defined start of follow-up. Determinants of treatment modification in two cohorts (before and after implementation of the updated guideline) were studied by time-dependent Cox proportional hazards regression.
After implementation of the updated guideline, patients were less likely to receive sulphonylureas (62.3% vs 41.3%) or thiazolidediones (4.7% vs 2.2%) and more likely to receive dipeptidyl peptidase-4 inhibitors (15.8% vs 27.1%) or sodium-glucose cotransporter-2 inhibitors (0.8% vs 9.9%). Some determinants influenced general practitioners’ prescribing differently after implementation of the updated guideline compared to before, including a high body mass index and heart failure.
Our results indicate that a first step towards tailored prescribing has been made. However, not all determinants that are important to consider when prescribing second-line glucose-lowering agents were of influence on general practitioners’ prescribing.
Patterns and preferences of antidiabetic drug use in Turkish patients with type 2 diabetes – A nationwide cross-sectional study (TEMD treatment study)
2021, Diabetes Research and Clinical Practice
Citation Excerpt :
The model explained 24.4% (Nagelkerke R2) of variance in the complexity of the treatment and correctly classified 73.1% of cases. The choice of antidiabetic regimens not only depends on the patient characteristics but also other factors such as the physicians’ level of experience, drug availability and the reimbursement strategies in different countries [5]. It is therefore important to understand the local factors related to the treatment decisions.
The treatment preferences in type 2 diabetes (T2DM) are affected by multiple factors. This survey aims to find out the profiles of the utilization of antidiabetics and their determinants.
The nationwide, multicenter TEMD survey consecutively enrolled patients with T2DM (n = 4678). Medications including oral antidiabetics (OAD) and injectable regimens were recorded. Multiple injectable regimens with or without OADs were defined as complex treatments.
A total of 4678 patients with T2DM (mean age: 58.5 ± 10.4 years, 59% female) were enrolled. More than half of patients (n = 2372; 50.7%) were using injectable regimens with or without OADs, and others (n = 2306, 49.3%) were using only OADs. The most common OADs were metformin (93.5%), secretagogues (40.1%), and DPP-4 inhibitors (37.2%). The rates of the use of basal, basal-bolus and premix insulin were 26.5%, 39.5% and 22.4%, respectively. Patients using OADs achieved better glycemia, blood pressure and weight control (p < 0.001 for all) but poorer LDL-C control (p < 0.001). The independent associates of complex treatments were diabetes duration, obesity, eGFR, glycated haemoglobin, macro and microvascular complications, education level, and self-reported hypoglycemia.
This study is the first nationwide report to show that almost half of the patients with T2DM are using injectable regimens in Turkey.
A view on the quality of diabetes care in Italy and the role of Diabetes Clinics from the 2018 ARNO Diabetes Observatory
2020, Nutrition, Metabolism and Cardiovascular Diseases
To investigate relevant indicators of quality of care in a large population-based sample of people with diabetes representative of clinical practice in Italy in 2018.
We analyzed data from 11,300,750 subjects. All administrative healthcare claims collected in 2018 were scrutinized to identify subjects with diabetes and investigate several indicators of quality of care. Subjects with diabetes were identified by anti-hyperglycemic drug prescriptions, disease-specific co-payment exemption and hospital discharge codes. Indicators of quality of care pertained to monitoring (HbA1c, creatinine, lipid profile, microalbuminuria, eye examination, ECG, ultrasonography of carotid and lower limb arteries) and diabetes treatment (anti-hyperglycemic agents in subjects with cardiovascular disease, CVD). Subjects attending and nonattending Diabetes Clinics were compared.
We identified 697,208 individuals with diabetes. HbA1c was assessed at least once in the year in 62.7%, creatinine in 62.3%, total cholesterol in 59.6%, microalbuminuria in 34.3%. Frequency of eye examination was 8.2%, ECG 23.5%, carotid ultrasonography 14.3%, lower limb ultrasonography 7.6%. Among anti-hyperglycemic drugs, SGLT-2 inhibitors were prescribed to ~5% and GLP-1 receptor agonists to ~5% although the proportion of subjects with CVD was ~45%. Subjects attending Diabetes Clinics had higher figures for all these monitoring and treatment indicators.
The implementation of national and international guidelines regarding disease monitoring and treatment is far from being satisfactory, especially among subjects nonattending Diabetes Clinics. Further efforts and investments are needed for better disseminating guidelines, more efficaciously engaging healthcare professionals and more strongly empowering the healthcare system to improve diabetes care.
Metformin was associated with lower all-cause mortality in type 2 diabetes with acute coronary syndrome: A Nationwide registry with propensity score-matched analysis
2019, International Journal of Cardiology
Citation Excerpt :
The prescription rate for metformin in our cohort was only 58%, even with the exclusion of patients with advanced kidney disease and of lean stature (BMI <18.5 kg/m2). In contrast, 67% of the ACS population had received metformin therapy in recent clinical trials, [5,6] while a high metformin prescription rate ranging from 75% to 90% has been reported in real-world cohort studies [27,28]. The disparity in metformin prescription rates between the general population with type 2 DM and an ACS cohort might reflect the unconfirmed beneficial effects and safety concerns regarding metformin therapy in this very high-risk population.
No randomized controlled trials evaluating metformin therapy efficacy in patients with type 2 diabetes mellitus (DM) and acute coronary syndrome (ACS) have been reported. We aimed to examine the mortality benefit of metformin therapy in patients with type 2 DM and ACS, compared with non-metformin anti-diabetes agents users.
Data were extracted from the prospective nationwide ACS-DM Taiwan Society of Cardiology registry. Propensity score (PS) matching on baseline characteristics and treatment measures was performed for metformin versus non-metformin users. The Cox proportional hazards model was used to compare mortality outcomes among the PS-matched cohort as the primary analysis. The Cox proportional hazards models adjusting for all pre-determined covariates and quintiles of the PS among the overall population were performed as the secondary analyses.
Of 1157 patients with type 2 DM and ACS receiving anti-diabetes agents, 78 patients (6.7%) died over the 2-year follow-up period. After PS matching, 318 metformin users were matched with 318 non-metformin users. Metformin users had a lower all-cause mortality rate (adjusted hazard ratio [aHR] 0.50, 95% confidence interval [CI] 0.26–0.95) in the primary analysis. The survival benefit of metformin therapy was consistent in the secondary analyses (aHR 0.30, 95% CI 0.17–0.54 while adjusting for all pre-determined covariates, and aHR 0.34, 95% CI 0.19–0.59 while adjusting for quintiles of the PS).
Among patients with type 2 DM and ACS, metformin was associated with lower all-cause mortality. However, a detrimental effect of any of the comparators could not be excluded.
Meta-analysis of factors associated with antidiabetic drug prescribing for type 2 diabetes mellitus
2023, European Journal of Clinical Investigation

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Factors Associated with Type 2 Diabetes Mellitus Treatment Choice Across Four European Countries

Abstract

Purpose

Methods

Findings

Implications

Introduction

Section snippets

Setting

Patients and Treatment Characteristics

Discussion

Conclusions

Conflicts of Interest

Acknowledgments

The American journal of medicine

Diabetes Res Clin Pract

Clin Ther

Value health

Curr Atheroscler Rep

IDF Diabetes Atlas

Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes

Diabetologia

Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes

Diabetes care

NHG-Standaard Diabetes mellitus type 2 (Tweede herziening)

Huisarts Wet

National Collaborating Centre for Chronic Conditions and the Centre for Clinical Practice at NICE

NICE guideline Type 2 diabetes: The management of type 2 diabetes

Glycaemic control and implementation of the ADA/EASD-2006 consensus algorithm in type 2 diabetes mellitus patients in primary care in Spain

Int J Clin Pract