Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus

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Review

Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus G. Reach a,*, V. Pechtner b, R. Gentilella c, A. Corcos c, A. Ceriello d a

Department of Endocrinology, Diabetes and Metabolic Diseases, Avicenne Hospital APHP and EA 3412, CRNH-IdF, Paris 13 University, 93017 Bobigny, France Lilly Diabetes, Eli Lilly & Company, 92521 Neuilly-sur-Seine, France c Eli Lilly Italia, Sesto Fiorentino, 50019 Florence, Italy d U.O. Diabetologia e Malattie Metaboliche, Multimedica IRCCS Sesto San Giovanni, 20099 Milan, Italy b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 22 March 2017 Received in revised form 24 May 2017 Accepted 14 June 2017 Available online xxx

Many people with type 2 diabetes mellitus (T2DM) fail to achieve glycaemic control promptly after diagnosis and do not receive timely treatment intensification. This may be in part due to ‘clinical inertia’, defined as the failure of healthcare providers to initiate or intensify therapy when indicated. Physician-, patient- and healthcare-system-related factors all contribute to clinical inertia. However, decisions that appear to be clinical inertia may, in fact, be only ‘apparent’ clinical inertia and may reflect good clinical practice on behalf of the physician for a specific patient. Delay in treatment intensification can happen at all stages of treatment for people with T2DM, including prescription of lifestyle changes after diagnosis, introduction of pharmacological therapy, use of combination therapy where needed and initiation of insulin. Clinical inertia may contribute to people with T2DM living with suboptimal glycaemic control for many years, with dramatic consequences for the patient in terms of quality of life, morbidity and mortality, and for public health because of the huge costs associated with uncontrolled T2DM. Because multiple factors can lead to clinical inertia, potential solutions most likely require a combination of approaches involving fundamental changes in medical care. These could include the adoption of a person-centred model of care to account for the complex considerations influencing treatment decisions by patients and physicians. Better patient education about the progressive nature of T2DM and the risks inherent in long-term poor glycaemic control may also reinforce the need for regular treatment reviews, with intensification when required.

C 2017 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: Clinical inertia Physician-related factors Patient-related factors System-related factors Treatment outcomes Type 2 diabetes mellitus

Introduction Type 2 diabetes mellitus (T2DM) is a progressive disease involving a decline in b-cell function and increase in insulin resistance, meaning that most patients ultimately require intensification of treatment to maintain adequate glycaemic control [1]. Current practice guidelines recommend lifestyle and dietary modifications, usually followed by metformin monotherapy and the further addition of an increasingly complex array of therapies, including oral and injectable medications [2,3]. This treatment algorithm, which includes a recommended delay of 3 months before treatment intensification, has been endorsed by several professional organizations [4,5]. Indeed, patients whose glycaemia is not well controlled, according to guideline targets, may be at increased risk of the long-term micro- and macrovascular complications of diabetes [6–8]. As T2DM progresses, the need * Corresponding author. E-mail address: [email protected] (G. Reach).

for treatment intensification represents a point of transition, where there is a need for good communication between physician and patient, and sufficient understanding by the patient of the goals of therapy to facilitate adherence to treatment [9]. Indeed, it has been reported that patients appear most comfortable with the idea of adding new medicines when they have experienced few problems with their current medications and trust their healthcare provider [10]. However, such times of transition, during which treatment is modified and management becomes more complex, can generate a burden for both physicians and patients. Thus, many patients with poor glycaemic control despite treatment do not receive timely and appropriate intensification of therapy. This failure of physicians to initiate or intensify therapy in a timely manner, despite recognition of the problem, has become known as ‘clinical inertia’ [11,12]. Failure to initiate or intensify treatment, or taking treatment steps that do not follow evidence-based guidelines, is a frequent phenomenon and is most evident in chronic asymptomatic diseases, although it may influence the management of any

http://dx.doi.org/10.1016/j.diabet.2017.06.003 C 2017 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc1262-3636/ nd/4.0/).

Please cite this article in press as: Reach G, et al. Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.06.003

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medical condition [11–13]. As it is known to lead to poor control of the risks for secondary complications of the primary disease, clinical inertia has important implications for the health of individual patients, the public health and overall healthcare expenditures [11,14–16]. While the clinical and economic impact of clinical inertia is still uncertain, it has been implicated in suboptimal management of diabetes, hypertension and lipid disorders, and as a contributing factor in a large proportion of the myocardial infarctions and strokes that arise in patients with such conditions [16,17]. Therefore, specific strategies are required to avoid clinical inertia and patient non-adherence [9,18,19]. Thus, the present review explores the factors that contribute to clinical inertia in the management of T2DM, its impact on patient management and the associated clinical consequences. It also describes strategies for overcoming the obstacles that lead to clinical inertia and the role of education in reducing the impact of clinical inertia on patient care. Literature search strategy In our pragmatic review of the literature, searches were made for the terms ‘clinical inertia’, ‘therapeutic inertia’, ‘diagnostic inertia’ and ‘diabetes’. The databases used (limited to publication dates from January 2011 to January 2016) included PubMed, Embase, BIOSIS and SciSearch. In total, 241 references were retrieved, and those included in this review were selected by the authors following a review of the full text and complemented by citations from previous years where appropriate (retrieved from personal collections). Definition: is clinical inertia real or apparent? According to the definition used by Phillips et al. [11], the term ‘clinical inertia’ may be used interchangeably with ‘therapeutic inertia’. In the present review, the term ‘clinical inertia’ is used throughout [11,14,20]. It has been argued that three conditions must be present for clinical inertia to be identified:  clinical goals or targets are recognized;  there is a recommended therapy that can be used to achieve the clinical goals;  the time frame is appropriate for initiation or intensification of therapy [16,20]. However, standard definitions may not be sufficient to determine whether a decision to modify therapy is appropriate for a given patient. With no additional information of the treating physician’s rationale, the clinical results or intermediate steps leading to specific treatment decisions, any therapeutic decisionmaking that seems to represent clinical inertia may only be ‘apparent’ clinical inertia and may, in fact, reflect good clinical practice for the specific patient or clinical situation [14,21–23]. Thus, the following strict definition of clinical inertia has been proposed [12]: ‘‘Physician behaviour falls under clinical inertia if and only if:     

there is an implicit or explicit guideline; the physician is aware of the guideline; the physician believes the guideline applies to the patient; the physician has the resources to apply the guideline; all these conditions have been met, but the physician does not follow the guideline in the case of the patient.’’

Nevertheless, it has been suggested that clinical inertia may represent a ‘clinical safeguard’ in some situations, especially if the guidelines do not provide definitive answers for specific patients,

although this concept has been challenged [24,25]. Because clinical practice involves inherent uncertainties and complexities when determining the most appropriate course of management for a given patient, it is important to separate true clinical inertia from apparent clinical inertia. Indeed, the importance of individualized treatment targets and strategies, with an emphasis on a patientcentred approach to care, has been included in practice guidelines [3]. Consequently, understanding the factors that underlie true clinical inertia in any specific patient will help to establish how they may be modified so that these barriers to optimal disease control can be overcome [12,15]. The scale of the problem Clinical inertia can affect all disease stages for people with T2DM Many publications relating to management of T2DM focus on delays in initiation of insulin therapy. Indeed, treatment intensification with oral antidiabetic drugs (OADs) is done more frequently than intensification involving the initiation of insulin [26]. However, it is important to recognize that therapeutic delay may be evident at all stages of treatment, including the prescription of lifestyle changes and of metformin at the early stage of prediabetes, initiation of pharmacological therapy after diagnosis, and initiation of combinations of OADs and glucagon-like peptide1 receptor agonist (GLP-1RA) therapy [26–33]. Several studies have demonstrated clinical inertia at early stages of the disease: in a study involving primary-care physicians in the US, Marrett et al. [28] found that one-third of older people with T2DM, who were not receiving pharmacological therapy at least 6 months after diagnosis, had poor glycaemic control [HbA1c  7.0% (53 mmol/mol)], with HbA1c levels  8.0% (64 mmol/mol) in 4% of the cohort. In the same vein, in a study of Spanish primary-care practitioners, clinical inertia affected onethird of those with T2DM and poor glycaemic control [HbA1c > 7.0% (53 mmol/mol)], and was greater in patients treated with only lifestyle changes or OAD monotherapy than in those receiving more complex therapy [27]. Finally, in a more recent study, Pantalone et al. [34] evaluated intensification of diabetes therapy and HbA1c goal attainment in people with newly diagnosed T2DM when metformin monotherapy failed. Treatment was intensified early (within 6 months of metformin failure) in 62, 69 and 72% of patients with poor glycaemic control, defined as HbA1c > 7.0% (53 mmol/mol), > 7.5% (58 mmol/mol) and > 8.0% (64 mmol/mol), respectively. This had consequences, as the time required for HbA1c goal attainment was shorter in patients who received early treatment intensification [34]. Clinical inertia is a frequent phenomenon A note of caution in the interpretation of clinical inertia Several studies suggest that clinical inertia is a frequent phenomenon, observed sometimes in half of patient–physician encounters. However, as highlighted earlier in this review, it is important to distinguish between real clinical inertia and ‘appropriate inaction’. Outcomes from the French DIAttitude Study suggest that clinical inertia in people with T2DM is common in general practice in France. In that retrospective analysis of electronic records from general practitioners (GPs), 41% of patients with two HbA1c values above the recommended threshold still had not had their treatment intensified a year after the second high HbA1c value was recorded [35]. Also, clinical inertia in this study was more frequently observed in older patients and when HbA1c was not particularly high [36,37]. Similarly, another study reported that, for people with newly diagnosed T2DM, the median time to initiation of OAD therapy was significantly longer in those

Please cite this article in press as: Reach G, et al. Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.06.003

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aged > 65 years (therapy initiated > 2 years after diagnosis) than in those who were younger (approximately 1 year after diagnosis) [38]. As a more cautious approach is currently advised in older patients and in those with multiple complications [3], the lack of treatment intensification may represent ‘appropriate inaction’ in such cases. However, clinical inertia may be evident even when a range of HbA1c targets is set, including individualized targets based on comorbidities and micro- or macrovascular complications. In a study conducted in a managed-care setting in the US, in which the mean time to treatment intensification over the entire study was > 700 days, > 70% of patients still had no treatment escalation (addition of an OAD, GLP-1RA or insulin) 6 months after their HbA1c target was exceeded, irrespective of the target being used [39]. Nevertheless, the potential differentiation between real and apparent clinical inertia should be considered carefully when interpreting the significance of data on treatment intensification. Evidence for clinical inertia Significant delays in treatment intensification have been observed in several studies in addition to the French DiAttitude

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Study [35–37]. The multinational Study of Once Daily Levemir (SOLVE) documented a substantial delay in the initiation of insulin. In that observational study involving > 17,000 people with T2DM, the average HbA1c was 8.9% (74 mmol/mol) before insulin therapy was initiated, and nearly half the patients had HbA1c  9.0% (75 mmol/mol) despite treatment with combinations of OADs [40]. Findings from the UK cohort of SOLVE showed that, compared with the global SOLVE population, patients had higher baseline HbA1c before insulin initiation [9.8% (84 mmol/mol) vs 8.9% (74 mmol/mol)] despite a shorter duration of disease [41]. Khunti et al. [42] published a retrospective cohort study based on 81,573 people with T2DM in the UK Clinical Practice Research Datalink (CPRD). In patients taking one, two or three OADs, the median time from treatment initiation to intensification using an OAD or insulin was greater than the maximum follow-up time of 7.2 years, indicating that many patients had poor glycaemic control for many years before their treatment was intensified (Fig. 1) [42]. The same group has also published a more recent analysis of time to treatment intensification in patients treated with basal insulin, and confirmed that clinical inertia is also found with intensification of insulin. Overall, the median time from

Fig. 1. Time from HbA1c levels > 7.0% (53 mmol/mol), > 7.5% (58 mmol/mol) and > 8.0% (64 mmol/mol) to treatment intensification with: (A) one oral antidiabetic drug (OAD; n = 35,988, 31,375 and 25,096, respectively); (B) two OADs (n = 21,858, 20,164 and 16,991, respectively); and (C) three OADs (n = 5050, 4733 and 4112, respectively; no regimen was intensified with an additional OAD). Note: for OADs, probability is estimated as 1 minus cumulative incidence function for intensification; for insulin, it is estimated as 1 minus cumulative incidence function for intensification; and for either OAD or insulin, it is estimated as 1 minus sum of cumulative incidence function for OAD and insulin. Reproduced with permission from Khunti et al. [42].

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initiation of basal insulin to intensification was > 4 years, and less than one-third of eligible patients [HbA1c  7.5% (58 mmol/mol)] had their treatment regimen intensified (median time: 3.7 years) [43]. In Italy, the Associazione Medici Diabetologi (AMD) has documented progress in the quality of diabetes care by extracting data from the electronic medical records of 300 diabetes clinics [44,45]. Its database report from 2012 showed evidence of clinical inertia, with > 40% of patients not receiving insulin despite HbA1c values > 9.0% (75 mmol/mol) in 2011 [44]. Clinical inertia was also evident at earlier stages of disease: 18.1% of patients treated only with metformin had HbA1c values > 8.0% (64 mmol/mol) for 1 year before treatment intensification, and 14.0% of patients had this level of glycaemic control for 2 years before intensification [45]. During the time-period 2004–2011, there was a reduction in the number of patients not receiving insulin despite HbA1c levels > 9.0% (75 mmol/mol), and 40.5% of these patients were still not using insulin in 2011 (down from 54.6% in 2004, a 14.1% absolute reduction) [44,45]. Clinical inertia was also observed in the 2-year retrospective INERTIA study conducted in Spain [46]. Clinical inertia was defined as the failure to intensify treatment with OADs despite a physician visit at which an HbA1c  7.0% (53 mmol/mol) was recorded. Clinical inertia was recorded in half of all patients following visits during the 2-year study period, and approximately 13% had no treatment intensification even when HbA1c exceeded the target at every visit. Finally, a study of primary-care practitioners in Croatia examined levels of clinical inertia based on the number of consultations in which treatment intensification was indicated, based on HbA1c levels, yet did not happen. Clinical inertia was found in an average of 55.6% of consultations, and was demonstrated by all practitioners with some patients and by 9% of practitioners with all patients [47]. Clinical inertia may also apply to failure to discontinue or reduce therapy if it is no longer beneficial [24]. This phenomenon is evident through the low withdrawal rate of sulphonylureas documented in the quality-improvement programme conducted by the Italian AMD. In their 2011 report in which older patients were divided into different age classes, there was a reduction over time in metformin use and an increase in the use of secretagogues (sulphonylureas or glinides) as age increased [48]. The increased use of sulphonylureas in older patients is even more evident with older drugs, such as glibenclamide, but it is questionable whether

this should be considered an example of clinical inertia in adapting treatment appropriately with increasing age, when the risks of hypoglycaemia may be higher [2,3,49]. On the other hand, in their most recent report from 2012, over the course of 8 years, there was a trend in the overall population for an increase in the proportion of patients treated with metformin, while the use of sulphonylureas remained stable [44]. Among older patients ( 75 years), one-fifth were treated with a combination of metformin and a sulphonylurea, with an observed trend towards an increase in the proportion of those treated with metformin, a slight reduction in the use of sulphonylureas and an increase in the use of glinides [49]. Conversely, in France, metformin use increased between 2001 and 2007, while the use of sulphonylureas decreased proportionally during the same period [50]. What are the clinical consequences of clinical inertia? Clinical inertia may contribute to the large percentage of people with T2DM who live with suboptimal glycaemic control for years, and this can lead to adverse long-term outcomes in some patients [34,42,43]. Because T2DM is an inherently progressive condition, glycaemic control deteriorates over time and, as a consequence, there is an increased risk of complications. Delays in treatment intensification can mean that patients are exposed to long-term elevations of HbA1c that can negatively impact their prognosis [6,51]. Thus, Brown et al. [52] defined the ‘‘avoidable glycaemic burden’’ as that which occurs after the first HbA1c measurement showing that a patient has exceeded target levels. Fig. 2 (modified from their publication) illustrates how clinical inertia exposes patients to an avoidable risk of complications. Clinical inertia related to insulin initiation in real-world practice may also be behind the unexpectedly poor cardiovascular outcomes associated with insulin therapy reported in observational studies: such therapy is frequently initiated too late in patients who have experienced chronic hyperglycaemia and who therefore already have a poor and irreversible glycaemic legacy [53,54]. The consequences of clinical inertia may be dramatic for both the patient in terms of quality of life, morbidity and mortality, and for public health because of the huge costs resulting from uncontrolled T2DM [13]. A large study using data from the UK CPRD showed that 22% of people with newly diagnosed T2DM had poor glycaemic control for 2 years, and 26% never had their treatment intensified during this time. When compared with patients whose treatment was

Fig. 2. The concept of avoidable glycaemic burden, as defined by Brown et al. [52]. HbA1c: glycated haemoglobin.

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intensified within 1 year of diagnosis, delayed intensification together with poor glycaemic control [HbA1c  7.0% (53 mmol/ mol)] significantly increased the risks of myocardial infarction (67%; P < 0.01), heart failure (64%; P < 0.01), stroke (51%; P < 0.01) and their composite (62%; P < 0.01) [55]. A delay of 1 year in treatment intensification along with HbA1c levels  7.5% (58 mmol/mol) was associated with a comparable increase in risk for cardiovascular events. A recent study of 1206 records in Thailand identified 98 patients with a mean HbA1c of 10.3%. Clinical inertia was associated with a significantly shorter median time for progression to diabetic retinopathy (adjusted incidence rate ratio: 4.92; 95% confidence interval [CI]: 1.11–21.77; P = 0.036) [56]. Based on these effects of clinical inertia on complications, it has been suggested that ‘‘clinical inertia in diabetes care may lead to several hundred thousand serious adverse events, billions of dollars of excess health-care charges for these events, and tens of thousands of excess deaths per year in the United States alone’’ [16].

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non-JDS-affiliated physicians [57]. Whereas both specialists and non-specialists appeared to delay insulin use, the biggest differences in physicians’ concerns regarding initiation of insulin therapy were between JDS-certified specialists and non-JDSaffiliated physicians, and were related to a lack of staff (such as nurses, pharmacists) who could advise patients prescribed insulin and the use of insulin in elderly patients [57]. There have also been differences reported among medical specialists in response to poor HbA1c control. In a study in Taiwan, the odds ratio for cardiologists choosing to intensify therapy was 0.71 (95% CI: 0.68–0.74) times that of endocrinologists. Furthermore, patients cared for in specialist facilities were 1.08 times more likely (95% CI: 1.06–1.10) to be prescribed intensified treatment than patients in primary-care clinics [31]. More important, while there may be differences in approach between specialists and primary-care physicians and among physicians working in the different specialities, it should be possible to overcome these differences through focused collaboration, potentially involving nurse practitioners and other members of the wider healthcare team [9,58,59].

Determinants of clinical inertia Factors involved in clinical inertia Influence of medical speciality on clinical inertia in people with T2DM Differences in the prevalence of clinical inertia between specialists and primary-care physicians [29,30], and between endocrinologists and cardiologists [31], have been identified in the management of T2DM. When Reach et al. [29] studied factors influencing the use of insulin within 5 years of diagnosis (early use) among practitioners in France, it was found that specialists were 9.9 times more likely than primary-care practitioners to prescribe early vs late insulin (P < 0.0001). Furthermore, such differences in treatment intensification between specialists and primary-care physicians may be especially evident with initiation of insulin. Shah et al. [30] reported that, while fewer than half of 2502 patients with high HbA1c levels had their medications intensified, in general, specialists were significantly more likely than primary-care physicians to intensify treatment (45.1% vs 37.4% of patients, respectively; P = 0.009) and to initiate insulin therapy (8.6% vs 1.7%; P < 0.0001). However, specialists were no more likely to add a new oral drug (21.7% vs 20.7%, respectively; P = 0.7) or to increase the dose of a currently used oral drug (21.7% vs 18.6%; P = 0.2) [30]. There may also be differences between specialists and nonspecialists in the factors that underlie clinical inertia. In a study of perceived barriers to insulin initiation in Japan, physicians were categorized according to levels of speciality as Japan Diabetes Society (JDS)-certified specialists, JDS-affiliated physicians and

Indeed, it is important that healthcare professionals learn to overcome clinical inertia because it affects their ability to delay the onset of diabetic complications [60,61]. However, this can only be done when there is an understanding of the mechanisms leading to clinical inertia. Currently, the evidence for factors driving clinical inertia is weak because well-conducted studies are lacking [15]. Phillips et al. [11] originally attributed clinical inertia to a variety of factors, including overestimation of the therapeutic intervention provided, reliance on ‘soft reasoning’ to justify failure to escalate therapy and a need for better education, training or organization of healthcare systems focused on achieving therapeutic goals. Several authors have suggested that the principal factors contributing to clinical inertia can be classified into those related to the physician (50% relative contribution), the patient (30%) and the healthcare delivery system (20%). The specific factors identified are presented in Table 1 [9,14,16]. Also, a thorough analysis of the causes of the phenomenon was published by Cabana et al. [62] in 1999, before the term ‘clinical inertia’ was coined by Phillips et al. [11]. Physician-related factors These factors, as initially defined by Phillips et al. [11], are still assumed to be the most common factors contributing to clinical inertia [16,20], and include time and resource constraints, concerns relating to avoidance of treatment side-effects, underestimation of

Table 1 Physician-, patient- and healthcare-system-related factors contributing to clinical inertia. Physician-related factors (50% contribution)

Patient-related factors (30% contribution)

Healthcare-related factors (20% contribution)

Failure to set clear goals Failure to initiate treatment Failure to titrate treatment to achieve goals Failure to identify and manage comorbidities (e.g. depression) Patient ‘highjacks’ the clinical encounter Insufficient time Reactive rather than proactive care Underestimation of patient’s need

Denial of having the disease Denial that the disease is serious Low health literacy High cost of medication Too many medications Medication side-effects Poor communication between physician and patient Lack of trust in physician Depression or substance abuse Lifestyle Absence of symptoms

No clinical guidelines No disease registry No visit planning No active outreach to patients No decision support No team approach to care Poor communication between physician and staff

Adapted from O’Connor et al. [16], Allen et al. [14] and Ross [9].

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the patient’s need for therapy and a failure to set and/or monitor progress towards treatment goals [9]. Competing demands during a primary-care appointment can also lower the likelihood of changes in medication. Parchman et al. [63] observed 211 primarycare appointments for people with T2DM and reported that, as the number of patients’ concerns during the appointment increased, the likelihood of a change in treatment decreased. This effect was independent of how long the appointment lasted, the most recent HbA1c level, the time since the previous HbA1c measurement, the trend in HbA1c assessment and the number of discussion points raised by the physician. Finally, another important factor to consider in the genesis of clinical inertia is the uncertainty faced by physicians regarding the reality of poor disease control and the need to intervene [64]. Whatever the factors underlying clinical inertia, it is important to understand and offer support to physicians rather than to apportion blame, particularly when such blame may not be appropriate. A recent questionnaire survey conducted in Belgium established that clinical inertia may be apparent, rather than real, when inaction or delayed action follows the engagement of primary-care practitioners with their patients and a process of clinical reasoning that takes into account patients’ preferences in treatment decisions [65]. According to this survey, true clinical inertia seemed to arise when primary-care practitioners were overwhelmed and felt a sense of disempowerment due to patient or healthcare-system factors. Other important factors also identified included inconsistencies between guidelines and reimbursement policies. Patient-related factors Studies carried out within managed-care settings in the US have found that patient characteristics (but not healthcare-provider characteristics) predicted glycaemic control and therapy intensification. This led the authors to conclude that improving systems of care might be more effective than directing efforts towards modifying the clinical practices of individual providers [66]. Patient-related factors contributing to clinical inertia include sideeffects from medications, inability to follow complex treatment regimens, lack of acknowledgment of disease severity, poor physician–patient communication and low health literacy [9]. Insights from the PANORAMA study in France showed that the HbA1c targets set by French physicians for their patients indicated good awareness of the guidelines for diabetes care in France. However, more than two-thirds of patients failed to achieve their targets, and 40% of patients had HbA1c levels  7.0% (53 mmol/ mol). The main reason identified for this was patients’ reluctance to have their treatments intensified [67]. In fact, it has been reported that approximately 25% of patients prescribed insulin may refuse the treatment due to a phenomenon described as ‘psychological insulin resistance’ [68,69]. There is a variety of possible reasons why patients may want to avoid insulin treatment. However, the common factor that distinguished willing from unwilling patients was the perception that the need for insulin meant failure of diabetes self-management [69]. More important, psychological insulin resistance does not concern just patients, as physicians are also often reluctant to prescribe insulin when needed, so this phenomenon seems to represent a perfect example of a barrier affecting both patients and physicians [70]. Ratanawongsa et al. [71] reported that primary-care practitioners in the US perceive that patient resistance and poor selfmanagement are significant barriers to initiating insulin. In a study of T2DM management by primary-care practitioners in Spain, the prevalence of poor glycaemic control increased with the complexity of treatment, with the least controlled patients being those using a combination of OADs and insulin [72]. It has been

hypothesized that the likelihood of successful insulin initiation may be increased by interventions that improve patient–provider communication, thereby promoting better treatment adherence and improving provider perceptions of their patient’s ability to manage their condition [71]. The perception of patient non-adherence may also contribute to clinical inertia in intensifying OADs. This has been revealed by claims database evidence in a managed-care study in the US, which suggested that physicians are more likely to prescribe OAD dose escalation in patients adherent to therapy than in those who are not [73,74]. It is also feasible that the association between delayed treatment intensification and poor adherence reported by Grant et al. [73] may represent good clinical practice, with the aim to first address the adherence issue and then treatment intensification. However, that study also confirmed an overall slower rate of treatment intensification; even in the cohort with the best adherence, intensification was delayed for 2 years in most patients [73]. Nevertheless, in situations where the physician believes the patient is non-adherent, this must be addressed at the same time as treatment intensification. Indeed, studies in patients with hypertension have concluded that a patient’s prior adherence was not associated with a physician’s decision to intensify treatment, whereas attempts to simultaneously address poor adherence and treatment intensification by the physician were more likely to achieve better control of blood pressure [75]. Factors inherent in specific treatments used in T2DM may also contribute to clinical inertia through effects on adherence. Such factors include treatment side-effects (hypoglycaemia, weight gain, oedema, gastrointestinal symptoms), perceived complexity of treatment administration or poor ability of the treatment to maintain glycaemic control [74]. Healthcare-system-related factors Practical challenges inherent in healthcare delivery systems can also contribute to delays in treatment intensification or failure to intensify therapy appropriately. Examples include poor planning coordination and exchanges of data between members of the healthcare team, inadequate supportive technologies, the need for copayments, insurance coverage and formulary status, and differing regional or county-specific standards affecting access to care [9,14,16]. Resource constraints that limit time and availability of staff to develop care plans for individual patients can also mean less time to provide thorough diabetes education. The lack of a proper care plan, including adequate instruction on the use of medicines, can lead to delays in treatment intensification [9]. In situations where changes in healthcare systems may be required to improve care, system inertia can make reforms difficult. Clinical inertia may then be exacerbated by the inherent resistance to change within systems faced with competing complexities and demands [76]. Clinical inertia as a gap between principles of evidence-based medicine and how doctors reason An important concept that should be acknowledged in any assessment of the causes of clinical inertia and solutions to minimize the phenomenon is the gap between the principles of evidence-based medicine and the reasoning used by physicians when treating patients [18,19]. Current medical practice is influenced extensively by evidence-based medicine, but the principles it applies introduce simplifications of decision-making that do not accord with the complex considerations of physicians and patients. This issue was well recognized in a qualitative study on the care of people with T2DM by GPs [77], which showed that

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doctors are aware of the guidelines, but don’t always follow them because they fail to reflect the complexity of real-life situations. More fundamental changes, such as to a person-centred model of care, may help to find ways to address the challenges of both patient non-adherence and clinical inertia. The merits of such a model of care, and the ethical considerations associated with its implementation, have recently been described in depth elsewhere [18,19]. Strategies to overcome barriers related to patients, physicians and healthcare systems In many countries, people with T2DM are most frequently managed in primary care. However, when insulin initiation is required, it often fails to happen in this setting or in a timely manner. Coordination between primary and secondary care, and between medical and nursing personnel, may be important for achieving increased insulin initiation in primary care [78]. Open communication between physicians and patients may improve the effectiveness of education and enhance long-term patient self-management [9,18]. Telemonitoring may also be useful for addressing clinical inertia in chronic diseases, including diabetes [79]. In fact, the complexity of the interactions between physicians, patients and healthcare-system factors were explored in a qualitative study involving semi-structured interviews with primary-care physicians [80], who admitted to some responsibility for clinical inertia, but also cited barriers related to patients and the healthcare system. This suggests that primary-care physicians may be receptive to training to help them overcome barriers such as limited expertise. The misconceptions of some participants related to achieving their own targets suggest that feedback and data availability may also have an impact on their motivation to make improvements [80]. Communication and collaboration Steps to combat clinical inertia include management of the risk of side-effects of therapy and reducing patients’ fear of injectable therapy (‘needle phobia’), which may be achieved by good communication and patient education [9,68,69,74]. Ensuring that patients understand the progressive nature of T2DM, and the inherent need to review and adjust treatments in a timely fashion, may also reduce patients’ concerns over intensification that may ultimately discourage physicians from intensifying treatments [9]. The French Society of Hypertension guidelines recommend consulting with the patient to explain hypertension and the principles of its treatment as soon as the diagnosis is confirmed [81], and a similar approach may be useful in diabetes care. Equally, even though the approach to treatment intensification may differ between specialists and primary-care physicians, their collaboration may be key to avoiding clinical inertia [58]. Physician education Despite organizational barriers, physician education is perceived as a key strategy to facilitate early intensification of therapy in T2DM [82]. In their description of clinical inertia, Phillips et al. [11] identified physicians’ denial as a cause of the phenomenon. The first step in the fight against clinical inertia should therefore be the dissemination of information on clinical inertia into the medical community suggesting that any physician may be vulnerable to such behaviour at any time in their current practice. Accordingly, efforts to combat clinical inertia through improved and alternative methods of delivering physician education have been developed. ‘InsuOnLine’, for example, was developed from problem-based learning principles to help primary-care physicians

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learn and practise optimal insulin prescription via gaming elements [83]. The educational objectives of the game cover a wide range of topics related to the use of insulin in T2DM, including barriers to its use. In one pilot study, users reported they learned more from the game than they would have from a lecture and that the knowledge would influence their treatment of people with diabetes [83]. Educational initiatives using simulated case-management interventions have also been shown to improve diabetes management skills, knowledge and confidence in physicians [84]. Overall, however, improving clinical inertia through physician education is challenging. Billue et al. [85] reported that a wide-reaching, lowintensity, web-based continuing medical education (CME) programme had no significant incremental effect on medication intensification in a primary-care study conducted in rural North America, suggesting that more intensive education with efforts to improve physician engagement may be necessary. Patient preference, education and training It is especially important to understand and overcome barriers to good glycaemic control, including factors leading to poor patient adherence [9]. Strategies to improve the latter include minimizing the incidence of adverse events such as hypoglycaemia, weight gain and gastrointestinal symptoms through treatment choices, combating feelings of guilt and fear of needles or painful injections, improving convenience and providing effective diabetes education [9]. Improvements in delivery devices can help to improve patient adherence to injectable therapy [86–88]. The new pen injection devices can help to overcome barriers associated with fear of needles, especially compared with vials and syringes, and can also help physicians and/or other healthcare providers train patients on proper injection technique [88]. There is evidence that insulin pen devices can also lead to better clinical outcomes for HbA1c control, hypoglycaemia rates, adherence and persistence compared with vial and syringe injections [89]. More recently, an optimalized auto-injector device developed for a GLP-1RA (weekly dulaglutide) with the needle already attached and hidden seemed to help to overcome patients’ fear of injections and facilitate training by healthcare professionals [90]. Dosage frequency, formulation and other factors can also influence adherence. In a study using insurance claims data from > 22,000 people with T2DM initiating GLP-1RA therapy (exenatide twice daily or once weekly, or liraglutide once daily), patients were more likely to achieve  80% adherence if treated with exenatide once a week than with more frequently administered formulations [91]. Another recent retrospective database study found similar results on comparing dulaglutide (weekly) and liraglutide (daily) injections. In the same study, adherence and persistence with weekly dulaglutide were also superior to weekly exenatide, results that might be explained by the differing degrees of complexity required for preparing the injections [92]. Finally, a study of the effect of patients’ preferences on the choice of injectable GLP-1RA found that dosing frequency (weekly vs daily) and type of delivery system were the most important factors, followed by frequency of nausea, weight changes, HbA1c changes and frequency of hypoglycaemia [93]. Involvement of a wider healthcare team As time and resources may be limited, the development and monitoring of a comprehensive care plan for each patient that can be implemented by a wider healthcare team may be of benefit [9]. In Australia, the Step-Up programme is evaluating whether a primary-care-physician-/nurse-led model of care, supported by

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endocrinologists and a qualified specialist nurse educator, can improve glycaemic control [59,94,95]. Hospitalization has been proposed as an opportunity to improve glycaemic control by breaking clinical inertia [96]. However, a retrospective study of poorly controlled diabetics who had been hospitalized at least once found evidence to support widespread clinical inertia in such cases. Less than one-quarter of patients had their diabetes therapy changed upon discharge from hospital, and approximately onethird had no change in therapy, no follow-up appointment within 30 days or no follow-up HbA1c scheduled within 60 days [97]. Other approaches currently being investigated in randomized controlled trials include the contributions of clinical pharmacists towards efforts to intensify treatment in people with poorly controlled T2DM [98]. Previously, the AIM@GP study in Ontario, Canada, found that an initiative in which retail pharmacists collaborated with diabetes specialists was not successful in supporting primary-care practitioners to enhance insulin prescribing [99]. Thus, a CME programme involving an interdisciplinary team aiming for quality improvement has been suggested as an approach to improve diabetes care. This would provide support for practice improvements based on self-assessments of the entire system of care rather than just teaching new information. Early evidence indicates some success with this approach, with a large proportion of participants developing performance-improvement action plans and improvements of glycaemic control for their patients [100]. In addition, the REMEDIES 4D study is currently ongoing in the US to explore whether certified diabetes educators can improve intensification of therapy and offer a more costeffective approach to diabetes management [101]. Telemonitoring and computed decision support based on clinical data and performance Several studies have indicated that telemonitoring or computer-assisted decision support may also be useful for addressing clinical inertia in chronic diseases, including T2DM, and in patients with comorbidities that increase the risk of cardiovascular events [79,102–105]. A systematic review by Cleveringa et al. [103] found that computer-based decision support systems could be used to offer clinical-performance feedback for primary-care providers that could lead to better patient outcomes in T2DM. Other attempts to improve access to the clinical information needed by physicians to make treatment decisions include improved glucosemonitoring technology and diabetes ‘dashboards’ or ‘scorecards’, although these are not always effective [104,105]. It has also been shown that remote telemonitoring incorporating glucose-testing feedback directly to patients can break a major link in the chain of clinical inertia, thereby promoting self-management in noninsulin-dependent patients by reinforcing the idea that changes in medication can lead to lower levels of HbA1c [79]. Role of patient education and shared medical decision-making in the fight against clinical inertia and patient non-adherence Strategies to increase levels of patient education have been proposed based on the observation that clinical inertia does not arise in clinical trials, perhaps due to the increased time and resources available to improve patients’ understanding and engagement with the goals of the treatments [106]. One of the key barriers to treatment intensification appears to be the lack of open communication between patients and physicians that would allow patients to better understand the gravity of their diagnosis and become engaged in their treatment options. Good communication might also facilitate regular patient education and, more important, help the patient to better understand that regular reviews and therapy adjustments are not a sign of failure.

Approaches to enhance patients’ education in the context of a person-centred model of care have recently been suggested, as this may offer a potential solution to patient non-adherence by considering the complexity of patient and physician reasoning, while creating a mutual patient–physician trust that ethically allows patients to make autonomous treatment choices while avoiding accusations of manipulation [18,19]. A consensus study based on the Delphi approach showed that patient adherence to treatment can be improved by education, providing information to partners/family members/caregivers, increasing patients’ motivation and allowing physicians to share their decision-making with patients [107]. The study also found that clinical inertia can be challenged by greater motivation of healthcare professionals and clear recognition of cardiovascular risk [107]. Conclusion Achieving effective glycaemic control is often delayed because of a combination of clinical inertia and the use of treatment algorithms based on the sequential addition of OADs and noninsulin injectables before insulin initiation, while not forgetting that intensification steps should be taken at 3-month intervals. Incidentally, the early use of combination therapy [108] may represent one way to accelerate the achievement of glycaemic control. The importance of a multifactorial approach for managing clinical inertia in T2DM patients cannot be overstated, as unnecessarily exposing patients to the risks of complications is unacceptable. Clinical inertia may arise at any stage in the treatment algorithm, although it appears to be particularly evident when initiating injectable therapies. While there are differences between primary-care physicians and specialist diabetologists when it comes to intensifying therapy, solutions are more likely to involve offering support rather than apportioning blame. Multidisciplinary team collaboration, physician education and performance feedback may provide such support. More important, adopting a person-centred model of care that accounts for the complex considerations of both patients and physicians as individuals may prove fundamental for improving patient adherence and reducing the tendency towards clinical inertia. Patient education focusing on a better understanding of the progressive nature of T2DM and the risks inherent in long-term poor glycaemic control is also key for reinforcing the need for regular reviews of treatment effects and intensification when necessary. It is particularly important to allay concerns about sideeffects, ‘needle phobia’ and the reluctance of patients to begin insulin treatment based on the misperception that it means failure to self-manage their condition. New therapies with fewer of the side-effects feared by both patients and physicians (weight gain, hypoglycaemia) that also decrease the burden of injections (weekly instead of daily) may also help to overcome both patient and physician barriers to finally achieving better glycaemic control. Funding This research did not receive any specific grant from funding agencies in either the public or not-for-profit sectors. Disclosure of interest Ge´rard Reach:  advisory board membership: Abbott, Bayer-Diagnostics, Lifescan, Lilly, Novo-Nordisk, Sanofi-Aventis;

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 lectures: Abbott-Diagnostics, Abbott-Pharma, Abbvie, BayerDiagnostics, Beckton-Dickinson, BMS, Dexcom, GSK, Ipsen, Janssen, Lifescan, Lilly, Merck-Serono, Pfizer, Novartis, Novo-Nordisk, Roche-Diagnostics, Roche-Pharma, Sanofi-Aventis, Servier. Valeria Pechtner: full-time Lilly employee and owns stock options in Eli Lilly and Company Raffaella Gentilella: full-time Lilly employee and owns stock options in Eli Lilly and Company. Antonella Corcos: full-time Lilly employee and owns stock options in Eli Lilly and Company Antonio Ceriello:  advisory board membership: Astra Zeneca, Boehringer Ingelheim, DOC Generici, Eli Lilly, Janssen, Novo Nordisk, OM Pharma;  consultancy: Eli Lilly, Mendor;  lectures: Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Sanofi, Servier and Takeda;  research grants: Mitsubishi, Novartis and Novo Nordisk.

Acknowledgements Editorial support for development of this review was provided by Mark O’Connor and Dr Janet Douglas (Rx Communications, Mold, UK) and sponsored by Eli Lilly and Company.

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Please cite this article in press as: Reach G, et al. Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.06.003