Adequate treatment of risk factors, including glycosylated hemoglobin A1c (HbA1c) and systolic blood pressure (SBP), is important for people with type 2 diabetes mellitus (T2DM) to lower the risk of micro- and macrovascular complications (American Diabetes Association, 2021; Cosentino et al., 2019). When patients do not achieve recommended HbA1c and SBP target levels with lifestyle changes, medication treatment should be initiated. Timely initiation of medication treatment is important in order to achieve optimal targets and better outcomes (Martono et al., 2015; Martono et al., 2016; Khunti et al., 2019). Optimal targets, however, may differ between patients. In the last decade, treatment guidelines have incorporated more personalized recommendations based on patient factors such as age, frailty, cardiovascular risk, and patient preferences (Warnes et al., 2008; Nederlands Huisartsen Genootschap, 2011; Verenso, 2011; Mancia et al., 2013; Rydén et al., 2013; American Diabetes Assocation, 2015; Whelton et al., 2017; Federatie Medisch Specialisten, 2018; Nederlandse Internisten Vereniging, 2018; Williams et al., 2018; Cosentino et al., 2019; Nederlands Huisartsen Genootschap, 2019; American Diabetes Assocation, 2020; Barents et al., 2021). Older and more frail patients may require and prefer less aggressive treatment, given the shift in benefit-risk balance of tight risk factor control due to ageing (de Vries et al., 2015; Benetos et al., 2016; Sinclair et al., 2019; Ambrož et al., 2021a). Females with T2DM, on the other hand, may need more intensive treatment given their higher relative risks of cardiovascular and renal disease (Peters et al., 2014a; Peters et al., 2014b; Shen et al., 2017). Currently, it is unknown to what extent have these changes in treatment recommendations been applied in clinical practice. It is known that dissemination of new recommendations may need additional interventions targeting clinicians to be effective at changing practice patterns (Cliff et al., 2021).

To facilitate the effective and safe use of medication treatment, it is relevant to study drug utilization trends in the whole population as well as among specific subpopulations. A study looking at trends among Dutch T2DM patients showed that mean HbA1c and blood pressure levels decreased between 1998 and 2008 and were similar for different age categories (van Hateren et al., 2012). Another study showed a slight decrease in the proportion of patients treated with glucose-lowering medication between 1998 and 2013, with no significant sex differences in treatment or achieving targets in the later years (Hendriks et al., 2016). These studies also showed that treatment with blood pressure-lowering medication increased particularly in the early years, with only small differences between the sexes and age groups. Focusing on the initiation of medication, we previously observed little change in the mean HbA1c threshold at initiation of glucose-lowering medication between the years 2008–2014. Despite the changed recommendations towards more personalized treatment, we did not observe higher thresholds among older or frail patients over the years (Ambrož et al., 2021b). Furthermore, we observed that SBP thresholds at initiation of blood pressure-lowering treatment among T2DM patients decreased in the period 2009–2014, regardless of age or frailty (Ambrož et al., 2020).

Little is known about these treatment trends in the recent years. Our aim was to 1) assess trends in HbA1c and SBP thresholds at initiation of glucose- and of blood pressure-lowering treatment between the years 2015 and 2020, and 2) assess the influence of patients’ age and sex on these trends.

There were 2,671 and 2,128 patients who met our in- and exclusion criteria included in the analyses of HbA1c and SBP thresholds, respectively (Supplementary Figures S1, S2). The number of included general practices ranged from 72 in 2015, 78 in 2016–2018, 76 in 2019 to 59 in 2020. The variance explained by the general practices was 6.9% and 5.5%, respectively.

This study shows that the HbA1c thresholds at initiation of glucose-lowering medication increased over the years 2015–2020. This increase was particularly seen in younger age groups and in both males and females. Females generally initiated medication at lower HbA1c thresholds than males. Patients aged 60–69 years initiated medication at lower levels in the first years and at similar levels in the later years compared to patients aged 80 years or older. Patients under 60 years and between 70–79 years initiated medication at similar levels as patients of 80 years and older. The SBP thresholds at initiation of blood pressure-lowering medication remained relatively stable over the study period regardless of age or sex.

We previously observed a rising trend in HbA1c thresholds for medication initiation between 2011 and 2014 (Ambrož et al., 2021b). The current study adds to this knowledge that this upward trend continued up to the year 2020. Furthermore, the decreasing trend observed in SBP thresholds between 2009 and 2014 (Ambrož et al., 2021b) appears to have stabilized after 2014. Looking at studies conducted in other countries, a mixed picture emerges. One study conducted in Denmark showed a decrease in mean pre-treatment HbA1c level between 2000 (9.2%) and 2011 (7.3%) followed by an increase to 7.9% in 2017 (Knudsen et al., 2020). These results suggest that prescribers in both Denmark and Netherlands became less strict regarding the initiation of glucose-lowering medication in recent years. In contrast, a study in the United Kingdom (UK) observed no changes in HbA1c level at initiation of medication from 2010 to 2017 (Dennis et al., 2019). The HbA1c threshold in 2017, however, was 8.6% in this UK study, which is much higher than the levels observed in Denmark or Netherlands. Differences in diabetes care between countries have been observed before and could be linked to organizational differences of healthcare systems (Si et al., 2010; Stone et al., 2013).

Most guidelines recommend initiating glucose-lowering medication at HbA1c levels above 6.5% or 7% in younger patients and above 8% or 8.5% in older patients (Verenso, 2011; Rydén et al., 2013; American Diabetes Association, 2015; Nederlandse Internisten Vereniging, 2018; American Diabetes Assocation, 2020; Barents et al., 2021). Surprisingly, we did not observe significant differentiation regarding the HbA1c levels at initiation of medication based on age. In particular, we observed similar HbA1c thresholds in patients under 60 years and those aged 80 years or older. These findings indicate potential undertreatment of hyperglycemia in younger patients, who initiated at mean HbA1c thresholds higher than 7.5% or even 8% in 2020. The recommended SBP threshold for initiation of blood pressure-lowering medication is 130 mmHg or 140 mmHg in younger patients and 150 mmHg or 160 mmHg in older patients (Mancia et al., 2013; Rydén et al., 2013; Whelton et al., 2017; Williams et al., 2018; Nederlands Huisartsen Genootschap, 2019). We observed mean SBP thresholds in all age groups ranging between 140 and 150 mmHg. These results indicate potential undertreatment of younger patients and potential overtreatment of older patients. Undertreatment of diabetes in younger or male patients has also been shown in Norway and Spain and could be caused by barriers at clinician, patient, and/or healthcare system level (Khunti et al., 2019; Andreozzi et al., 2020). Undertreatment of both hyperglycemia and hypertension in this population is of concern since this can lead to more complications (Holman et al., 2008a; Holman et al., 2008b; Hayward et al., 2015). Although therapeutic inertia in T2DM has been a well-known problem for many years, it seems that this lack of timely initiation did not change much over the last decade (Khunti et al., 2018). More emphasis and involvement of other healthcare professionals, such as pharmacists, might help reduce clinical inertia (Fazel et al., 2017; Meredith et al., 2021). On the other hand, overtreatment among older T2DM patients has received a lot of attention in the past decade (Oktora et al., 2021) and our study suggests that potential overtreatment at initiation of glucose-lowering medication has decreased over time. That was, however, not the case at initiation of blood pressure-lowering medication, which is of concern, since older patients are more vulnerable for hypotension-related adverse events (Ambrož et al., 2021a).

Throughout the study period, we observed higher HbA1c thresholds at initiation of glucose-lowering medication in males compared to females. A post-hoc analysis of sex differences in the years 2008–2014 showed the same differences (Supplementary Figure S3A). Differences in screening rates are an unlikely explanation, since a recent systematic review observed no clear sex differences in the assessment of cardiovascular risk factors, such as SBP and HbA1c levels, in type 2 diabetes patients (de Jong et al., 2021). However, it could partly be due to later diabetes diagnosis among males. A previous study showed higher HbA1c levels in males than females at diagnosis of diabetes (Wright et al., 2020). Earlier initiation of glucose-lowering medication in females could also be a consequence of their increased relative risk for cardiovascular and renal disease (Peters et al., 2014a; Peters et al., 2014b; Shen et al., 2017). Additionally, no sex differences in SBP thresholds were observed between 2015 and 2020, but between 2007 and 2009 females initiated blood pressure-lowering treatment at higher SBP thresholds than males (Supplementary Figure S3B). This could indicate that some previously identified sex- or gender-related issues leading to undertreatment of cardiovascular diseases among females are diminishing (Vogel et al., 2021).

An intriguing finding was that both mean HbA1c and mean SBP thresholds were highest in 2020. For the HbA1c threshold this could be a continuation of the rising trend over the years, but this is not the case for the SBP threshold. There are indications that the COVID-19 pandemic influenced diabetes care in the year 2020 in Netherlands (InEen, 2020). Other studies have shown decreases in screening rates, consultations and patient use of healthcare services due to fear of COVID-19 infection, as well as worse glycemic and blood pressure control after the beginning of COVID-19 pandemic (Endo et al., 2022). The impact of this could differ per age group, driven by differences in fear, comorbidity, and frailty. More evidence is needed to assess whether our observations in 2020 were due to the COVID-19 pandemic.

A strength of our study is the use of a large database of real world data from electronic medical records, representing a range of Dutch general practices from urban and rural areas. Data undergo data entry error checks before being imported in the GIANTT database, increasing the internal validity. Using medical record data also brings some limitations. First, this is a dynamic cohort and the variation between years could in part be due to a variation between the participating general practices. We conducted additional analyses of trends in HbA1c and SBP thresholds including only the 59 general practices that were present in the whole period up to the year 2020, which showed similar results (data not shown). Secondly, some patients may not be true initiators but people who moved to a general practice participating in GIANTT while already using medication. Although we included only patients with a medical history of 1 year, this may not prevent the inclusion of some patients that have been treated with glucose-lowering or blood pressure-lowering medication by other healthcare professionals in the past. We used an arbitrary cutoff of 10 years to exclude patients that were unlikely to be initiators. A previous study conducted in Netherlands showed that around 20% of patients have not yet started medication treatment 3 years after their diagnosis (Spoelstra et al., 2004). Since it is not known what the maximum time to initiation is in our study population, we conducted a post-hoc analysis of the HbA1c thresholds including only patients with a maximum duration of diabetes at medication initiation of 5 years, which showed similar results (data not shown). A post-hoc analysis of SBP thresholds excluding all patients with a history of cardiovascular disease also did not change the results (data not shown). Another limitation of using medical record data is that we had missing data for some potential confounders, but we used multiple imputation for confounders with less than 20% missing data to reduce possible bias. Additionally, we conducted a post-hoc analysis also imputing the albuminuria values with more than 20% missing data, which did not change the results (data not shown). Finally, the study was conducted in Dutch primary care and the results may be more generalizable to countries with similar diabetes care systems.

To conclude, the rising trend in the HbA1c threshold for initiating glucose-lowering medication in the lower age groups was unexpected and requires further investigation. The lack of lower thresholds for the youngest age group and higher thresholds for the oldest age group at initiation of glucose- and blood pressure-lowering drugs calls for interventions to support age-related personalized diabetes treatment. Multicomponent interventions targeting clinicians are seen as effective type of interventions (Harvey and Kitson, 2015; Cliff et al., 2021). This could include educational programs, implementation of decision support tools with specific alerts, feedback reports and other health system interventions. Our finding that males received less timely initiation of glucose-lowering medication than females also need attention. Studies are needed to explore the reasons for as well as the implications of this sex difference. The results of our trend study provide valuable insight into the translation of guideline recommendations into clinical practice, shows areas with room for improvement and can help policy makers to tailor future interventions enhancing appropriate treatment for all patients.