Therapeutic Inertia: Still a Long Way to Go That Cannot Be Postponed

Abstract

In the context of type 2 diabetes, the definition of therapeutic inertia should include the failure not only to intensify therapy, but also to deintensify treatment when appropriate and should be distinguished from appropriate inaction in cases justified by particular circumstances. Therapy should be intensified when glycemic control deteriorates to prevent long periods of hyperglycemia, which increase the risk of complications. Strategic plans to overcome therapeutic inertia must include actions focused on patients, prescribers, health systems, and payers. Therapeutic inertia affects the management of glycemia, hypertension, and lipid disorders, all of which increase the risk for cardiovascular diseases. Thus, multifactorial interventions that act on additional therapeutic goals beyond glycemia are needed.

Clinical or Therapeutic Inertia? When Semantics Matter

Questions remain as to whether the lack of or delay in treatment intensification for patients not reaching therapeutic targets represents true inappropriate care or whether it is an acceptable decision to prevent the risks of overtreatment. The latter has been termed “appropriate inaction”—in opposition to “inappropriate inertia”—and is considered to be a factor contributing to the low treatment intensification rates observed in clinical practice (1,2). In type 2 diabetes, where clinical guidelines advocate a patient-centered approach (3–5), appropriate inaction could be exemplified by providers’ decisions regarding complex patients (e.g., the elderly or individuals with impaired awareness of hypoglycemia) who are either near their goal or for whom the “best” blood glucose level has already been achieved at a particular intensification step (e.g., the elderly, those for whom polypharmacy is an issue, and individuals with comorbidities). Despite being widely accepted as a source of confusion when quantifying inertia, appropriate inaction is an aspect rarely assessed in clinical studies (6). Additionally, some authors postulate that therapeutic inertia should also include the failure to withhold or reduce therapy when further prescription is not needed or not supported by evidence, a circumstance termed “therapeutic momentum,” or “reverse clinical inertia” (7–9).

Within this broader definition of therapeutic inertia, the failure to advance treatment results in failure to achieve a goal and may have both short- and long-term consequences (e.g., missed opportunities to prevent complications at early stages or increased risk of end-stage micro- and macrovascular complications) (10). Conversely, the failure to deintensify therapy, albeit largely neglected in therapeutic guidelines (11,12), raises safety concerns and may contribute to overtreatment and in turn to avoidable direct and indirect health care costs. For example, overmedication to achieve tight glycemic levels could be detrimental in older patients, particularly those with complications and serious comorbidities, because of their high likelihood of severe hypoglycemia. Such episodes in the elderly have implications for both short-term (e.g., risk of falls, accidents, hospitalizations, and death) and long-term (e.g., lower quality of life, decreased cognitive function, and increased risk of cardiovascular [CV] mortality) negative outcomes (13,14).

Outcomes of Sustained Glycemic Targets and Why Intensification Is Important

Persistent elevated glycemic levels remain a major public health problem, with about 40–60% of patients worldwide not at A1C goal (15,16). In the United States, recent data showed that 36% of patients with diabetes are not able to achieve individualized targets, and up to 16% have an A1C >9% (17).

Several long-term studies have shown that intensifying therapy at the first sign of deteriorating glycemic levels may be crucially important. In people with newly diagnosed type 2 diabetes, the U.K. Prospective Diabetes Study showed that early intensive glycemic management (i.e., mean A1C ≤7%) had long-lasting benefits; when A1C values converged between subjects on conventional therapy and subjects on intensive therapy 10 years after the completion of the trial, those who received intensive therapy still showed persisting reductions in microvascular events, CV events, and mortality (18,19). This phenomenon was called the “legacy effect” (18,19) and had been previously observed in patients with type 1 diabetes on intensive therapy after 6.5 years of follow-up in the Diabetes Control and Complications Trial and was termed “metabolic memory” (20–22). Of note, the legacy effect has also been reported in a recent real-world study in people with newly diagnosed type 2 diabetes (23).

However, in high-risk patients (i.e., those with either established CV disease [CVD] or additional CV risk factors) with a long duration of type 2 diabetes, two large independent trials (ACCORD [Action to Control Cardiovascular Risk in Diabetes] and ADVANCE [Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation]) reported that the risk of CV events was similar between those on 5 years of intensive therapy and those on conventional therapy, although intensive therapy prevented microvascular complications (24,25). Of note, the intensive blood glucose–lowering treatment arm of the ACCORD trial was terminated early because of increased CV mortality among participants in this group compared with those in the standard treatment arm after an average of 4 years of treatment, although the reasons for this higher risk remain unclear (26). Finally, a meta-analysis corroborated that this beneficial effect was not detectable regarding CVD rates in patients with a long duration of diabetes (27).

Therapeutic inertia is a barrier to effective treatment intensification and a common and widespread problem; it typically affects the care of 30–50% of people with uncontrolled type 2 diabetes worldwide (15) and even up to 30% of individuals with personalized A1C goals (28). The lack of or delay in intensification results in the accumulation of several years of hyperglycemia before treatment is intensified (i.e., “avoidable glycemic burden”), which has been documented at every stage in the natural history of type 2 diabetes (29–31). For example, as shown in Figure 1, if we sum up delays from all treatment steps, patients may spend up to 10 years with an A1C >7% and about 10 years with an A1C >8% from diagnosis until starting insulin (29–31). Moreover, in the 12 months after the A1C level rises above a target threshold, the proportion of patients receiving intensification is in most cases <50% (29). As a result, the median time patients spend above their target A1C level is unnecessarily long, in many cases over several years, increasing in parallel with the number of oral antidiabetic drugs (OADs) added and decreasing as the A1C level increases. In summary, failure to intensify treatment leads to avoidable delays, which in turn result in increased “bad” metabolic memory or dysglycemic legacy from excessively long periods of hyperglycemia, eventually increasing the risk of micro- and macrovascular diabetes-related complications (32,33).

FIGURE 1.

Schematic of therapeutic inertia showing the proportion of patients above target receiving intensification within 12 months (in green); the median time to intensification from the time at which the A1C level is above the threshold (in red); and the glycemic burden (i.e., the length of time with A1C level above target [≥7, 7.5, or 8%]) during a given period of time (in blue) (29). *Estimated in patients with two OADs and three OADs after 14 months. **Estimated in patients with three OADs. GLP-1RA, glucagon-like peptide 1 receptor agonist.

The Need for Multifaceted Implementation Strategies to Overcome Therapeutic Inertia

There is a growing interest in implementing active measures to promote the timely escalation of treatment for patients with type 2 diabetes (34–36). Primary Care Diabetes Europe in 2018 issued a call to action against inertia (37). Similarly, the American Diabetes Association recently launched a new initiative focused on overcoming therapeutic inertia (38).

What is indisputable is that strategic plans to overcome therapeutic inertia must be comprehensive and fully multifaceted, including actions focused on patients, prescribers, health systems, and payers (39–42). Approaches at these different levels and available evidence of their implementation in diabetes are summarized in Table 1.

TABLE 1.

Potentially Useful Approaches to Overcome Therapeutic Inertia in Type 2 Diabetes

Approach	What to Do	Evidence/Examples
Provider education	Enhance providers’ medical knowledge on diabetes and its treatment, including:	Redesign professional health education to adapt professional competencies to specific contexts (58) (e.g., teaching about ethics and social science as part of the undergraduate/ graduate medical curriculum to convince providers of the benefit of applying rules of best practice and of their importance as health care providers (41).
	• The natural history of the disease, from correcting modifiable risk factors to drug treatment and further need for titration
	• The evidence coming from guidelines
	• How to use clinical guidelines
	• The reasons behind therapeutic decisions and appropriate selection of medications
	• The appropriateness of guidelines for each particular patient
	• The phenomenon of lack of patient engagement and therapeutic inertia
	Promote continuing medical education throughout professional life.	Educational meetings and interactive workshops improve professional practice and health care outcomes for patients (59,60). Simulated case-management interventions have also been shown to improve the diabetes management skills, knowledge, and confidence of primary care residents (61).
	Use reminders (e.g., in the form of an electronic spreadsheet) and feedback systems (e.g., regarding patients’ treatment target attainment).	Reminders and feedback have been shown to improve physicians’ use of clinical practice guidelines and ability to overcome therapeutic inertia in diabetes and hypertension (62).
Facilitation	Simplify treatments and/or use medications with fewer side effects.	Complex treatments lower patient engagement (63), and fear of side effects can lead to less medication taken and to providers’ therapeutic inertia. The use of medications with fewer side effects or using combined forms of medications may reduce therapeutic inertia and improve treatment success (64,65). The use of improved insulin delivery devices helps to reduce patient nonadherence (66).
	Use protocols and algorithms to reduce decision uncertainty.	Giving simple algorithms of titration to providers has a positive effect on treatment intensification and improves glucose and blood pressure levels (67). The use of computer-assisted decision support in primary care is effective in improving the management of type 2 diabetes (68).
	Use electronic medical records.	The use of electronic medical records and implementation of electronic reminders help in monitoring patients and have a positive effect on quality of diabetes care (69–73).
	Implement disease management programs.	Disease management programs or structured treatment plans help patients better manage their disease and maintain and improve quality of life (e.g., including medication and other treatments, training courses, and regular checkups). Implementation of disease management programs in diabetes has shown improvements in glycemic levels, screening rates, and engagement (74–76).
	Establish coordinated health care plans aligned with policy initiatives to increase the accountability and patient-centeredness of disease management.	Disease management at the population level has significant potential for improving diabetes care and outcomes, but published evaluations of specific diabetes population care approaches are scarce (77,78).
	Overcome providers’ lack of time through health information technologies (telemedicine).	Compared with standard care, the addition of health information technologies, and in particular mobile phone–based approaches and systems that allow medication adjustments, is an effective tool for glycemic management among people with type 2 diabetes (79,80).
	Increase sharing of patient data among health care professionals.	Improved access to patient data among health care professionals, combined with data-sharing agreements, may facilitate timely intensification by primary care providers and therefore improved glycemic levels in type 2 diabetes (81).
Reinforcement of health professionals	Provide incentives from health authorities (i.e., pay-for-performance models) to motivate providers to improve their practices.	There is evidence of improvement in achieving A1C targets using financial incentives to primary care physicians in the United Kingdom, although the evidence is limited in other countries and the effect is variable (82,83). In the United States, financial incentives improved glucose monitoring during the incentive period but did not significantly improve glycemic levels among adolescents and young adults with type 1 diabetes (84).
	Provide incentives from peers.	Communication and collaboration between diabetologists and primary care providers is important to overcome therapeutic inertia (85). Concurrent visit reviews with peers have been shown to increase intensification rates (86).
	Provide incentives by other health care professionals (e.g., pharmacists and nurses)	A study in the Netherlands showed that therapeutic inertia was less frequent when physicians were assisted by a nurse (87). Collaboration between physicians and pharmacists has been shown to decrease clinical inertia scores for blood pressure treatment (88).
Reinforcement of patients	Develop shared treatment decision-making between providers and patients in a patient-centered approach.	Shared decision-making in type 2 diabetes has been reported to improve engagement with health care recommendations and glycemic levels (89,90).
	Encourage patients through structured self-management education (e.g., on side effects, managing injections, and insulin dose adjustments).	Providing patients with the ability and skills necessary for proper diabetes management determines treatment satisfaction and is effective at improving aspects of diabetes care (91,92). Remote type 2 diabetes care (nurse-led online management program) can facilitate glycemic control compared with usual care (93).
	Remove financial barriers and reduce patients’ out-of-pocket costs.	High out-of-pocket costs are a barrier to self-management and result in increased likelihood of elevated glycemic levels and intermediate outcomes and lower engagement with regard to diabetes medications (94).
	Address psychosocial issues.	Increasing patients’ perceptions about their own abilities and self-efficacy is an important factor related to improved diabetes self-management and treatment outcomes (94). Psychological barriers such as inadequate family or social support, misinformation or inaccurate beliefs about illness and treatment, emotional distress or depression symptoms, or deficits in problem-solving or coping skills are associated with lower adherence to diabetes medications (95). Intensive psychosocial interventions are associated with significant reductions in both diabetes distress and A1C in patients with elevated glucose levels and at least one risk factor for poor outcomes (96).

Briefly, providers require education to achieve sound knowledge on all aspects of the disease (e.g., modifiable risk factors, natural history, and proper management through clinical guidelines) and also need to continue medical education throughout their professional life. Moreover, they may benefit from the use of telemedicine, electronic medical records, and computerized reminders (e.g., providing patient-specific recommendations or information on target attainment). The use of protocols and titration algorithms to overcome decision uncertainty is also helpful to facilitate the choice of the simplest or most tolerable available treatment. In addition, providers may increase their motivation through feedback from other health care professionals (e.g., regular visit reviews with an endocrinologist to analyze decisions if in primary care, collaboration with pharmacists, and assistance from nurses). Finally, providers must consider clinical factors together with patient preferences to mutually agree with patients on the most adequate treatment (i.e., shared treatment decision-making).

From their side, patients need to be educated in self-care behaviors through educational programs, and their emotional status and psychosocial issues (e.g., diabetes-related distress) have to be taken into consideration to improve their quality of life.

From the health authority perspective, therapeutic inertia can be tackled through initiatives to motivate providers to improve their practice (e.g., financial incentives) and through the implementation of coordinated health care plans and disease management programs aligned with policy initiatives to increase the patient-centered management of diabetes.

Last but not least, there is a need to tackle out-of-pocket costs and financial barriers to decreasing drug costs and providing covered treatment for all patients. This aspect is particularly important in countries or regions in which there is partial medication coverage or reimbursement (e.g., copayment or coinsurance) or where administrative restrictions to specific glucose-lowering drugs apply (e.g., negative economic incentives for physicians when prescribing the newest and more expensive drugs).

The Need to Move Beyond a Glycemic-Centered View of Therapeutic Inertia in Diabetes

Therapeutic inertia is not only a barrier to the appropriate management of glycemia, but is also present in the treatment of other conditions involved in the risk for CVD. Indeed, therapeutic inertia in the management of hypertension and LDL cholesterol in patients with diabetes has been estimated to occur in 68 and 80% of clinical practice consultations, respectively (43). As a result, it has been estimated that therapeutic inertia related to the management of diabetes, hypertension, and lipid disorders may contribute to up to 80% of heart attacks and strokes (44). This situation is worrisome if we take into account the corresponding legacy effect through the reported persistent benefits of early and intensive blood pressure and lipid-lowering therapies in lowering all-cause mortality and death due to CVD (45–50).

As recently reviewed (51), there is evidence of the long-term benefit of lowering multiple risk factors. The Danish Steno-2 trial randomized patients with type 2 diabetes and albuminuria to intensified multifactorial intervention targeting known modifiable risk factors with individualized lifestyle interventions and tailored polypharmacy (i.e., strict glycemic, lipid, and blood pressure targets and the use of ACE inhibitors and aspirin). Compared with subjects with targets based on the Danish national standards of care, those on intensified multifactorial interventions had a reduction in the risk of microvascular complications of ∼50% after 4 years of intervention (52), a 53% reduction in CV end points after 8 years of intervention (53), a 46% reduction in total mortality at 13 years of follow-up (54), and a reduction in overall and CV mortality and a reduced risk of hospitalization for heart failure by 70% 21 years after trial initiation (55). Moreover, the benefits of multitargeted intervention have also been reported recently in Chinese primary care patients with type 2 diabetes (56). Of note, achieving a greater number of targets (i.e., glycemia, blood pressure, and LDL cholesterol) incrementally reduced the risk of CV outcomes, and the benefit seemed to be greatest among subjects at early disease stages (56,57). Given these results, it seems clear that, while overcoming therapeutic inertia with regard to managing glycemic levels is essential, there is also a true need to act on additional therapeutic goals to prevent long-term complications of diabetes.

Conclusion

The concept of therapeutic inertia should be reviewed and further studied through the distinction of the appropriateness of the therapeutic decision, namely appropriate inaction versus inappropriate inertia, the latter including both the failure to advance and to deintensify therapy. This approach would allow the accurate assessment of overtreatment in patients for whom harm is likely to outweigh benefit (e.g., vulnerable and frail populations).

Moreover, there is a need to raise awareness that therapeutic inertia regarding glycemic management and other risk factors (e.g., hypertension and dyslipidemia) has a deleterious effect in long-term CV outcomes and that these risk factors have to be tackled early in the course of the disease. In a patient-centered approach to diabetes management, it is key that providers, in particular those in general practice, pay attention to therapeutic inertia from a global perspective and provide integrated multifactorial treatment. This approach entails actions not only focused on physicians’ attitudes and actions, but also necessarily includes involving other health professionals (e.g., nurses, psychologists, and pharmacists); promoting patient education, self-management, and well-being; and calling on health systems to implement effective policies that have a direct impact on the unmet needs of patients with diabetes.