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

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).

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).

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.

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).

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.

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.

CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from the Instituto de Salud Carlos III in Madrid, Spain. The authors acknowledge Amanda Prowse for providing support in the manuscript editing.

No potential conflicts of interest relevant to this article were reported.

All of the authors researched data, wrote the manuscript, contributed to discussion, and reviewed and edited the manuscript. D.M. is the guarantor of this work and, as such, had full access to the content and takes responsibility for the accuracy of the data.