Number of type 2 diabetes patients achieving HbA1c goal and Related Factors in Brazil: A real world evidence study

Despite the clinical advances in the management of type 2 diabetes mellitus (T2DM) over the past decades, in the US, nearly 48% of patients do not achieve the ADA recommended glycemic goal of glycated hemoglobin (HbA1c) below 7.0% 1 . The Brazilian Guidelines for the Treatment of T2DM has established the same goal of HbA1c below 7.0% 2 , but the data for the rate of glycemic goal achievement in Brazil is lacking. The aim of this study was to determine the rate of HbA1c goal achievement among Brazilian patients receiving antidiabetic therapy and investigate its relation to other clinical and demographic covariates.


Abstract Background
Despite the clinical advances in the management of type 2 diabetes mellitus (T2DM) over the past decades, in the US, nearly 48% of patients do not achieve the ADA recommended glycemic goal of glycated hemoglobin (HbA1c) below 7.0% 1 . The Brazilian Guidelines for the Treatment of T2DM has established the same goal of HbA1c below 7.0% 2 , but the data for the rate of glycemic goal achievement in Brazil is lacking. The aim of this study was to determine the rate of HbA1c goal achievement among Brazilian patients receiving antidiabetic therapy and investigate its relation to other clinical and demographic covariates.

Methods
Using a cross-sectional database analysis from a group of private clinics in São Paulo, Brazil, this Real Word Evidence study evaluated 1034 patients with T2DM, which were being treated with at least one antidiabetic agent for a minimum of three months and had a basal level of Glycated Hemoglobin (HbA1c) above 7.0%. The number of patients that did not achieve the therapeutic target of HbA1c below 7% was calculated. Demographic and clinical characteristics were collected and a correlation analysis with the treatment target achievement was performed.

Results
The average age of the population was 60.5 years and gender were equally distributed. A total of 60.3% of the patients did not achieve the target of HbA1c below 7% after a minimum of three months treatment with one or more antidiabetic agents. The average time between HbA1c basal to nal was 9.9 months.
The average basal level of HbA1c was 9.9% ± 2.2 and the nal level was 7.8% ± 1.9. In the univariate analysis a statistically signi cant difference was observed in the following clinical variables: age, total cholesterol level, LDL level, basal and nal HbA1c, time to HbA1c nal measure, treatment time, and number of antidiabetic agents.

Conclusion
In this retrospective real-world study, only 40% of patients achieved the glycemic target of HbA1c below 7% after at least 3 months of treatment with one or more antidiabetic agent. The average initial HbA1c was 9.9% and the nal level was 7.8%. Patients not at goal were older and had more comorbidities, which highlight the challenge that represents the management of diabetes in Brazil. This study con rms previous published data that T2DM glycemic targets are di cult to achieve and the reasons for this are complex and multifactorial Page 3/16 Background According to the latest estimates of the International Diabetes Federation (IDF), in 2019, Brazil had 16.8 million people between 20 and 79 years with type 2 diabetes mellitus (T2DM), ranking the country as the fth nation in number of patients with diabetes worldwide 3 . It is estimated that the number of people with diabetes in Brazil will increase to 23.5 million in 2040. The overall prevalence of diabetes in Brazil is 8.5% for this age group, but this prevalence can reach approximately 20% in older patients with more than 65 years 3 . Another important problem to consider is the fact that 40 to 50% of these patients have not been diagnosed, and therefore are not being treated 3 .
The main goal of diabetes treatment is to achieve and maintain sustained glycemic control, along with managing the microvascular and macrovascular complications associated with the disease; these complications which result from long term hyperglycemia represent the main cause of morbidity and mortality in patients with T2DM 4 . To achieve and maintain optimal glycemic control, prompt treatment intensi cation is recommended for patients who do not achieve their glycemic goals and consistent monitoring is necessary to evaluate changes in glycemic control over time. Despite the clinical advances in the management of type 2 diabetes over the past few decades, nearly 48% of the patients with type 2 diabetes do not achieve the ADA recommended glycemic goal of glycated hemoglobin (HbA1c) < 7.0% in the US 4 . The Brazilian Guidelines for the Treatment of Type 2 Diabetes has established the same goal for HbA1c < 7% 2 , but there is a lack of local data for the rate of glycemic goal achievement in Brazil. Clinical Inertia has been reported to be one of the reasons for inadequate blood glucose control in patients with type 2 diabetes, and it has been reported that clinical inertia occurs in > 50% of patients with type T2DM in the US 4 .
This study aimed to determine the rate of HbA1c goal achievement among Brazilian patients receiving antidiabetic therapy and investigate its relation to clinical and demographic covariates.

Study Design and Population
This was a retrospective, population-based, cross-sectional non interventional study that utilized data collected from the "Dr. Consulta" group of private clinics in São Paulo, Brazil, from December 1 st , 2013 to October 1 st , 2018. Patients diagnosed with T2DM aged ≥18 years undergoing antidiabetic therapy for at least 90 days were considered for analysis. Patients with initial HbA1c <7.0%, and patients with second HbA1c assessment <90 days were excluded from the analysis. For patients with consecutive HbA1c assessments, only the latest measurement was considered. Other clinical and demographic characteristics such as age, BMI, systolic and diastolic blood pressure, serum cholesterol, serum LDL, serum creatinine and comorbidities were also collected.

Study Objectives
The primary objective of this study was to describe the number of patients with type 2 diabetes mellitus on antidiabetic therapy for at least 3 months who were not at the HbA1c goal of less than 7.0% The secondary objectives were to analyze these populations and describe their association according to (1) Demographic and clinical characteristics; (2) presence of comorbidities; and (3) number antidiabetic agents used.

Statistical Analysis
For the primary objective, the prevalence of patients on antidiabetic therapy for a minimum of 3 months who did not achieve HbA1c goal of <7.0% were described as simple proportion.
Descriptive analyses were performed for all relevant demographic and clinical characteristics. For inferential analysis, comparison through parametric tests (Student t, ANOVA, ANCOVA) for normal distribution samples, or through non-parametric tests (Wilcoxon-Mann-Whitney, Kruskall-Wallis) for nonnormal distribution samples were performed.
Categorical variables were characterized by frequency and proportion (%). Comparisons were made using chi-square or Fisher's exact tests.

Patient demographics and clinical characteristics
A total of 1946 patients diagnosed with T2DM were identi ed in the database. Following study criteria, 582 of these patients had a basal HbA1c measurement <7.0% and were not included in the analysis; 330 patients also did not have a second HbA1c measurement ≥90 days after the rst, probably due to clinical inertia, and were also not included in the analysis, consequently, a total of 1034 patients were analyzed for the primary and secondary objectives, as shown in Figure 1. Details on the demographic and clinical characteristics of the study patients are presented in Table 1. A total of 49.9% of the patients were male; mean age of study participants was 60.5 years old. Mean body mass index (BMI) was 29.1 kg/m²; mean systolic and diastolic blood pressure were 136.1 and 78.9 mmHg, respectively; mean serum cholesterol was 180.7 mg/dl; mean LDL-C was 105.4 mg/dl; and mean serum creatinine was 0.9mg/dl.

Number of patients achieving HbA1c Goal
In the study population, the average basal HbA1c was 9.9% ±2.2, and the average nal HbA1c was 7.8% ± 1.9. Patients had a minimum of two HbA1c assessments, spaced by at least 90 days; mean interval between baseline and nal HbA1c measurement was 14.1±10.0 months.
In total, 624 patients did not achieve glycemic target (HbA1c <7%), while the remaining 410 patients did achieve the treatment target, as shown in Figure 2.  A total of 941/1034 (91.0%) of patients presented with at least one comorbidity. The number of comorbidities varied from zero to seven. The prevalence of all registered comorbidities in this patient population are described in Table 2. Antidiabetic therapy and number of agents prescribed.
The mean antidiabetic treatment time was 11.1± 6.4 months for the study population. The number of antidiabetic agents prescribed varied from 1 to 5, including oral medications and insulin.
Patients were classi ed as: Oral Monotherapy (without insulin); Oral Dual therapy (without insulin); Oral Triple or more (without insulin); Insulin (as monotherapy) or Insulin in combination with one or more oral agents. The proportion of patients in each category is shown on Figure 3. Clinical and demographic variables, as well as comorbidities and number of antidiabetic agents were compared between the groups of patients that achieved and didn't achieve the HbA1c goal of <7.0%, as shown in Table 3, Table 4 and Table 5. Discussion: This was a retrospective, cross-sectional population-based real world study to determine the percentage of patients with T2DM achieving HbA1c goal < 7% after treatment with one or more antidiabetic agent for at least 90 days in a network of private clinics in São Paulo, Brazil. A total of 1034 patients were included in a retrospective database analysis. A total of 624 (60.3%) patients did not achieve the target (HbA1c < 7%), while the remaining 410 patients (39.7%) achieved the treatment goal. The average initial HbA1c was 9.9 ± 2.2% and the average nal HbA1c was 7.8 ± 1.9%. These two results highlight the great challenge that represents the management of T2DM in Brazil. Actually, the percentage of patients that achieved glycemic control is similar to other previous published studies (approximately 40 to 50%) 8,9 . It is also interesting to note that although all these patients were being treated with at least one antidiabetic agent for a period of at least 3 months, the nal average HbA1c for the total population evaluated was 7.8%, which is above the recommended treatment target of HbA1c < 7%. Probably one of the reasons for this nding could be related to clinical inertia.
Another important result observed in this study is the percentage of patients that are above the WHO recommended weight and BMI. Only 22% of the patients were considered normal and had a BMI < 25 kg/m 2 . Considering that T2DM is a complex metabolic disease and that its adequate control depends, among other factors on adequate weight control, these results should be viewed as an alert to all professionals who deals with this increasingly prevalent and serious disease 11,12 .
Concerning the analysis of the number of antidiabetic agents prescribed and the relation with the achievement of diabetes control, it is interesting to mention that there is an inverse relation, which means that the higher the number of prescribed agents the lower the chance to achieve the glycemic control (HbA1c < 7%). This nding could be interpreted as that in order to achieve effective glycemic control in patients with T2DM involves more than just prescribing medications. Many other factors are involved in the management of these very complex patients such as understanding the prescription and adherence to treatment, the individual metabolic response to therapy or patients with multiple agents may have a more severe disease, adherence to the recommended lifestyle changes including diet restrictions, physical activity and adequate weight management. Other important factor involves the presence of other comorbidities, that are amazingly frequent in these patients [13][14][15] .
In the population studied, a total of 91% had at least one additional clinical condition. The most prevalent associated conditions were being overweight and obese (77%), followed by hypertension (34.7%), elevated cholesterol (28.7%), elevated LDL (21.2%), retinopathy (5,2%). It's worth to mention the relative low prevalence of chronic renal disease in the population studied (3.0%).
An additional important factor in the management of T2DM is clinical inertia or delay of treatment intensi cation which has been reported to be one of the main causes of inadequate glycemic control in patients with T2DM. Clinical inertia has been de ned as failure by health care professionals to initiate or intensify treatment when glycemic targets have not been met. The ADA guidelines recommend addition of a second oral or injectable agent if metformin monotherapy fails to achieve or sustain the desired glycemic goals after 2 to 3 months. It has been reported that clinical inertia occurs in > 50% of patients with T2DM in the United States 3 .
The average treatment time (treatment initiation with antidiabetic agents until last HbA1c assessment) for patients was 11.1 months, while the interval between baseline and nal HbA1c assessments was 14.1 months. Although this cannot be considered as a measure of treatment inertia, it somehow shows that the decision to start the pharmacological treatment in this group of patients should be reviewed, since a correct timing for treatment intensi cation is an important factor for T2DM management 29 .
In the univariate statistical analysis, the following variables were found to be statistically different among the two groups: a) gender, b) age, c) cholesterol level, d) LDL level, e) basal HbA1c, f) nal HbA1c, g) time period between HbA1c basal to nal h) treatment time, i) Dr. Consulta`s follow up time, j) number of antidiabetic agents prescribed, and k) the number of associated comorbidities. Despite the fact that the variables of age, cholesterol, LDL levels, and the HbA1c initial and nal levels demonstrated a statistical signi cant difference between the two groups, the clinical relevance of these ndings does not seem to be very important since the data are very similar and are also within a range that could not really be considered as a major medical issue. A possible explanation for this is the large number of patients evaluated, and the statistical possibility that small numerical differences between groups may have statistical differences, without real clinical relevance. However, gender, number of antidiabetic agents prescribed, number of comorbidities and the three different evaluations of treatment periods demonstrated an inverse relation with the achievement of the treatment goal and this seems to have an important clinical signi cance since they might represent an estimation of the severity of the T2DM or, eventually, the real world di culties in managing these more complex patients as discussed above.

Conclusion
In this real world study, which analyzed 1034 patients with type 2 diabetes, only 40% of patients achieved the glycemic target of HbA1c < 7% after at least 3 months of treatment with one or more antidiabetic agent; the remaining 60% did not achieve the target of HbA1c < 7%. The average initial HbA1c was 9.9% and the nal level was 7.8%. Patients not at goal were older and had more comorbidities, which highlight the challenge that represents the management of diabetes in Brazil. This study con rms previous published data that type 2 diabetes glycemic targets are di cult to achieve and the reasons for this are complex and multifactorial Further observational and randomized studies should be conducted in order to better understand the complex and multifactorial aspects of T2DM management. Availability of data and materials The data that support the ndings of this study are available from "Dr. Consulta Centro Médico LTDA" but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of "Dr. Consulta Centro Médico LTDA".

Figure 2
Proportion of patients with HbA1c <7% after minimum 3 months treatment