Therapeutic Inertia in the Management of Proteinuria Among Type 2 Diabetes Patients in Hong Kong Primary Care Setting: Prevalence and Associated Risk Factors

Background: Proteinuria is a well-known predictor of poor renal and cardiovascular outcomes in T2DM patients Methods: Objectives: To explore the prevalence of Therapeutic inertia (TI) on proteinuria management among T2DM patients in primary care and possible patients’ and doctors’ factors. Study design: Cross-sectional study Subjects: T2DM patients with microalbuminuria and macroalbuminuria from 1/1/2014 to 31/12/2015. Outcome assessments: The prevalence of TI on proteinuria management and its association patients’ factors and the working prole of the attending doctors. Results: 5, 163 (26.4%) patients had diabetic nephropathy (DMN) with micro- or macroalbuminuria. Among the sampled 385 patients with DMN, TI was found to be 40.3%. Doctor factors for higher TI rate include male sex and doctors with longer duration of clinical practice and who have never received any form of Family Medicine training. Patients factors include lower average systolic (SBP) and diastolic blood pressure reading. Patients’ SBP reading and microalbuminuria were negative association factor whereas doctor’s year of clinical practice being over 21 years and patients being treated with submaximal dose of medication were positive association factors to TI. Conclusions: TI is commonly present on proteinuria management among T2DM patients managed in the primary care. Patient’s systolic blood pressure reading, microalbuminuria level, Dr’s year of clinical practice and dose of ACEI/ARB were found to be associated with the presence of TI. Further study on the barriers and strategies to combat TI is needed to improve the clinical outcome among T2DM patients. if latest urine ACR 2.5mmol/L 3.5 Consultation notes follow up urine ACR (CMS). TI considered to

Conclusions: TI is commonly present on proteinuria management among T2DM patients managed in the primary care. Patient's systolic blood pressure reading, microalbuminuria level, Dr's year of clinical practice and dose of ACEI/ARB were found to be associated with the presence of TI. Further study on the barriers and strategies to combat TI is needed to improve the clinical outcome among T2DM patients.

Background
Type 2 diabetes mellitus (T2DM) is one of the most common chronic conditions encountered in primary care and affects up to 10% of the Hong Kong population (1). Proteinuria, including microalbuminuria and macroalbuminuria, is well-known predictor of poor renal outcomes in T2DM patients and more recently, to be a predictor of cardiovascular outcomes in these populations (2,3). There is emerging data that reduction of albuminuria leads to reduced risk of adverse renal and cardiovascular events (4,5).
Effective treatments for preventing development and progression for diabetic kidney diseases are available. Angiotensin-converting enzyme inhibitors (ACEI) reduced the risk of new-onset of microalbuminuria, macroalbuminuria or both and death when compared to placebo for T2DM patient with or without hypertension (6,7). Although similar effects were not observed in Angiotensin II receptor blockers (ARB), meta-regression suggested possible bene ts from ARB for preventing kidney disease in high risk patients (8,9). Based on these evidences, the American Diabetes Association (ADA) guidelines currently state that all patients with diabetes mellitus and micro-or macroalbuminuria should be prescribed an ACEI or ARB to mitigate nephropathy (10).
Despite all these evidences, proteinuria control among diabetic patients has been inadequate in the primary care settings both internationally and locally. Studies from the United States have shown that the overall prevalence of micro-, and macroalbuminuria was 39% and 10% respectively among T2DM patients (11). However, among T2DM patients diagnosed with nephropathy, only 25% were receiving ACEI/ARB as per ADA guidelines has suggested (12). Similar studies carried out at local primary care settings have reported that the prevalence of microalbuminuria among T2DM patients was 13.4% and the condition was signi cantly associated with advanced age, female sex, poor glycaemic control, and coexisting hypertension (13). In addition, as shown by another study looking at the complications among Chinese T2DM patients in urban primary care clinics, only about half of diabetic patients with micro-or macroalbuminuria were treated with ACEI, or ARB (14).
Like other chronic conditions, reasons for poor proteinuria control are multifactorial and may include patient-, physician-and care delivery factors. Among them, suboptimal medication augmentation has been identi ed as an important physician factor. This is known as therapeutic inertia (TI). It is de ned as whenever the health-care provider does not initiate or intensify therapy appropriately when therapeutic goals are not reached: "recognition of the problem, but failure to act" (15)(16). TI has become increasingly acknowledged as a major impediment for CVD risk factor control. Indeed, in another study carried out by the author's research team, TI has been present in lipid management in over 60% of diabetes patients with dyslipidemia (17).
Locally, signi cant proportions of T2DM patients are managed in primary care and followed up at government General Out-patient Clinics (GOPCs) of the Hospital Authority. Up to now, there was no study exploring the prevalence of TI in proteinuria management among diabetes patients managed in the primary care setting both internationally and locally. To ll this knowledge gap, our study tried to explore the prevalence of TI in proteinuria management among T2DM patients and to explore possible associating factors. By overcoming these barriers, it was expected that the progression of renal complications and the cardiovascular outcome of T2DM patients could be improved in the long run.
Aim of the study: 1. To explore the prevalence of therapeutic inertia (TI) on proteinuria management among T2DM patients managed in the primary care. 2. To explore possible associating factors in both patients' and doctors' perspective.

Methods
Study design: Cross-sectional study Page 4/25 Subjects: Inclusion criteria: All T2DM patients having the International Classi cation of Primary Care (ICPC) code T90 (Non-insulin Dependent Diabetes Mellitus), who had been regularly followed up in all GOPCs of KCC from 1 Jan 2014 to 31 Dec 2015, and had regular blood and urine checked at least once during this period were identi ed from the Clinical Data Analysis and Reporting System (CDARS). In our clinics, T2DM patients were usually provided with blood and urine check-ups at least annually to every 18 months. This 2-year retrieval period was therefore likely to cover all such patients regularly followed up in our cluster. The diagnosis of diabetes was based on the "De nition and description of diabetes mellitus" from American Diabetes Association in 2013 (10).

Diabetes patients followed up in Specialist Outpatient Clinic
De nition of proteinuria (microalbuminuria, macroalbuminuria and high risk proteinuria) among T2DM patients According to American Diabetes Association (ADA) guideline 2015, all T2DM patients should have urine albumin/creatinine ratio (ACR) check to screening for microalbuminuria (10).
Microalbuminuria was de ned as albumin secretion of 30 to 300 mg/24 h and macroalbuminuria or overt proteinuria as a value of >300 mg/24 h. Screening for microalbuminuria can be performed by measurement of urine ACR in a random spot collection (10). Normo-albuminuria was de ned as a urine ACR of <2.5 mg/mmol in males and <3.5 mg/mmol in females. Corresponding values for microalbuminuria were de ned as 2.5 to 30 mg/mmol for males and 3.5 to 30 mg/mmol for females, and for macroalbuminuria they were >30 mg/mmol for both genders (18). An elevated urine ACR needed to be con rmed in the absence of urinary tract infection with additional rst-void specimens collected during the next 3 to 6 months.
De nition of therapeutic inertia in management of proteinuria among T2DM patients: In this study, management of microalbuminuria or macroalbuminuria is de ned as inadequate and escalation treatment is indicated if latest urine ACR level is ≥ 2.5mmol/L in male patients and ≥ 3.5 mmol/L in female patients. Consultation notes of the follow up immediately after the latest urine ACR test being available were reviewed through the computer management system (CMS). TI is considered to be present when attending doctors failed to initiate or intensify ACEI/ARB treatment. On the other hand, if there are valid reasons documented in the medical notes justifying that escalating treatment is not feasible despite clinical indications, it will not be counted as TI. , a sample size of 385 would provide 95% con dence level and 5% con dence interval. Therefore totally 400 cases were sampled to ensure adequate statistical power and allow room for case exclusion.
A list of random numbers was then generated from the research randomizer (http://www.randomizer.org/form.htm), from which the 400 patients to be included were selected. Details of the visit with latest urine ACR result seen were recorded. Data were collected by reviewing the consultation notes in CMS record of selected patients using a standard data collection form (please refer to Appendix) by the principle investigator and counter checked by another experienced doctor in the research team.

Determination of variables
The recruited patients' age, gender, smoking status, body mass index (BMI), latest blood pressure, hemoglobin A1c (HbA1c), serum creatinine levels, lipid pro le and urine ACR were retrieved from the CMS. The most recent blood or urine test was used for analysis if more than one test had been performed during the study period. The BMI was calculated as body weight/body height 2 (kg/m 2 ). The patient was considered a smoker if he/she currently smoked or was in the rst 6 months of stopping. Abbreviated Modi cation of Diet in Renal Disease (MDRD) formula was used to calculate the estimated Glomerular Filtration Rate (eGFR). Among the 400 randomly sampled diabetic nephropathy patients, 15 cases were excluded including 14 cases being FU regularly by Specialist SOPD and 1 case with wrong diagnosis. The remaining 385 patients were included for data analysis (Figure 1).     (Table 3), only doctors' year of clinical practice was entered into the logistic regression analysis. Logistic regression study revealed that the systolic blood pressure reading and microalbuminuria range of proteinuria were negatively associated with the presence of TI, whereas doctors' year of clinical practice being over 21 years and patients being treated with submaximal dose of ACEI/ARB were positively associated with the presence of TI.

Discussion
This was the rst clinical analysis of TI in proteinuria management among T2DM patients managed locally in the primary care setting. It has provided important background information about the prevalence of TI in this group of patients. It also explored possible underlying factors from both the doctor's and patient's perspective.
Microalbuminuria is the earliest sign of diabetic nephropathy and predicts increased cardiovascular mortality and morbidity and end stage renal failure. Our study revealed that the prevalence of microalbuminuria and macroalbuminuria among T2DM patients from primary care was 21.1% and 5.3% respectively. These gures are higher than those reported from similar studies done in a primary civil servant clinic in Hong Kong which showed that the prevalence of microalbuminuria was 13.4% among T2DM patients (13). It is noted that the average age of patients in their study was 58 yrs old, which is much younger than the average age of T2DM patients recruited in this study (70.0 yrs). Since advanced age is an independent risk for the development of microalbuminuria, a higher prevalence rate of microalbuminuria in our study is expected. In addition, multiple studies conducted overseas have demonstrated that the prevalence of microalbuminuria varies among races, even within the same community (19). For example, cross-sectional studies have reported marked variation in the prevalence of microalbuminuria, ranging from 14.2% in Singapore (20), around 30% in the United States (11) and over 40% in China (21). These variations in prevalence can be attributed to factors such as differences in populations, in the de nitions of microalbuminuria, method of urine collection, etc. However, this could also re ect true differences in the ethnic susceptibility to nephropathy.
Among T2DM patients included in the data analysis, 360 cases (93.5%) were found to have concomitant HT, whereas only 66.5% of them were treated with ACEI or ARB. Based on our set criteria, therapeutic inertia was found present in 40.3% cases, meaning that in over 40% of diabetic patients with proteinuria, appropriate drug treatment including drug initiation or dose augmentation were not provided. As there were no similar studies carried out internationally or locally, direct comparisons with other studies are not possible. However, this TI rate was much higher than the TI in glycaemic control (29-33%) among T2DM patients (22,23), although lower than the TI rate in blood pressure (63.3-68%) (24)  Indeed, some evidence suggests that Physicians who have been in practice for more years may be less likely to deliver high-quality care or comply with treatment guideline (25,26). Medical advances occur frequently, and the explicit knowledge that physicians possess may easily become out of date. Therefore, although it is generally assumed that the knowledge and skills accumulated by physicians during years of practice lead to superior clinical abilities; it is plausible that physicians with more experience may paradoxically be less likely to provide technically appropriate care. This has been con rmed by a systematic review performed on the relationship between clinical experience and quality of health care. It showed that, among 62 published studies that measured physician knowledge or quality of care and described time since medical school graduation or age, more than half suggested that physician performance declined over time for all outcomes measured (27). Therefore, these ndings raise concerns about the adequacy of continuing professional education in medicine and alert us the need to provide quality improvement interventions to this subgroup of doctors, particularly in the primary care setting.
With regards to patient's pro le, we found that TI was more prominent in patients with microalbuminuria group (85.2% of all TI patients). This could be explained by the threshold effect which is, the closer the urine ACR level is to target level, the less likely and the doctor to intensify the treatment. This threshold effect has been commonly observed in other similar studies. Other factors that contribute to the threshold effect could be "overestimation of current care" or "complacency with borderline values", leading to the physician's subjective misperception that the care provided is su cient.
Indeed, this threshold effect was also found to be related to the inertia of treating hyperglycemia and hyperlipidaemia in T2DM patients (22,17).
Our study also revealed that TI positive T2DM patient had a much lower average systolic and diastolic blood pressure reading compared with TI negative group. In TI positive group, a lower proportion of T2DM cases have concomitant HT (90.3% versus 95.7%, P = 0.037). In addition, 65.8% of TI positive group has satisfactory blood pressure control (< 130/80mmhg) at the clinical visit compared with TI negative group (47.8%, P = 0.0005). These data revealed that doctors are less likely to initiate or intensify ACEI or ARB treatment in normotensive albuminuria cases despite the evidence that ACEIs and ARBs reduce the risk of progression to macroalbuminuria in normotensive T2DM patients with microalbuminuria. The possible reasons might be the concerns about the development of hypotension if ACEI/ARB is initiated or the dose is augmented. The side effects of ACEI or ARB, such as hyperkalemia and persistent throat discomfort and dry cough, are other common concerns. Although these concerns sound reasonable, lots of studies have proven that albuminuria control may slow the progression of CKD and improve the clinical outcomes among T2DM patients even in the absence of hypertension (28). In addition, normalization of microalbuminuria is associated with a reduction in the rate of decline in glomerular ltration rate. In line with these ndings, international guidelines recommended that ACEIs or ARBs should be initiated in T2DM cases with microalbuminuria unless contraindicated to slow progression of diabetic nephropathy (29). Therefore, clinicians should be more proactive in initiating proteinuria control treatment to prevent the disease progression and improve the cardiac vascular outcome in the long run. At the same time, we should also strike a balance between the bene t of proteinuria control and the risk of possible hypotension and closely monitor the blood pressure level during follow up consultations.
Multiple variable logistic regression analysis revealed that systolic blood pressure reading and microalbuminuria range of proteinuria were negatively associated with the presence of TI, whereas doctor's year of clinical practice being over 20 years and patients being treated with submaximal dose of ACEI/ARB were positively associated with the presence of TI.

Strength And Limitations Of This Study
This is the rst clinical analysis of TI in proteinuria management among diabetic patients managed locally in the primary care setting. It has provided important background information about the prevalence of TI in proteinuria management among diabetic patients and explored the possible underlying factors from both the doctor's and patient's perspective. These ndings will help improve strategies to overcome TI in proteinuria control for these patients.
There are some limitations in this study. First, the study was carried out in one single cluster of HA and therefore selection bias might exist. These results from the public primary health care sector might not be applicable to the private sector or secondary care. Nevertheless, the present results may lay the groundwork for similar studies in the future, both locally and internationally. Second, patients with diabetes who had not had any blood testing performed during the study period were excluded (n = 3061, 13.5% of all diabetic cases). The urine ACR status of this group of diabetic patients remained unknown.
This might bias the accurate measurement of TI among our target population. Third, this study relied heavily on review of consultation notes to identify justi cation for submaximal therapy and to determine the presence of TI. Insu cient justi cation for a certain treatment may have resulted in an overestimation of the prevalence of TI.

Implications To Primary Care
Our study found that TI was common in proteinuria management among diabetic patients managed in the primary care, with a prevalence of 40.3%. Doctors with a longer duration of clinical practice and who had not received formal FM training had a higher rate of TI. Patients' systolic BP reading and microalbuminuria range of urine ACR were negatively associated with the presence of TI. Considering that a large volume of T2DM patients are managed in the primary care setting and the importance of proteinuria control to prevent the progression to CKD, comprehensive strategies with a more proactive approach should be devised to combat TI so that the cardiovascular outcome of diabetic patients can be improved. As only anonymous data were analysed and there was no patient involvement in the study, no written or verbal was obtained.

Consent for publication
The manuscript contains no individual person's data in any form

Competing interests
All authors have disclosed no con icts of interest.
Funding/support Data are shown as mean ± standard deviation or number (n) of cases