Editorial N° 132

Unmet therapeutic needs:
what are the new frontiers
and treatment paradigms
in type 2 diabetes?

by S. Del Prato, Italy


Department of Clinical &
Experimental Medicine
Section of Metabolic Diseases
and Diabetes
University of Pisa

Diabetes has now reached epidemic proportions, with a population of 415 million people living with diabetes worldwide.1 According to the International Diabetes Federation, this figure will increase by 55% in the next 20 to 25 years, with close to 600 million individuals affected by the disease by 2040.1 What is, however, more worrisome is that along with the increase in the number of people developing hyperglycemia, there will be more people exposed to the risk of developing chronic complications, the main cause of loss of quality of life and increased health care costs. According to data from clinical studies,2 the prevalence of coronary heart disease and stroke range between 5%-35% and 3%-12%, respectively. With a prevalence of 19%-42% for overt nephropathy, 10%-55% for retinopathy, and 8%-68% for neuropathy, microvascular complications remain a considerable burden. Microvascular complications are known to be strictly related to chronic exposure to glucose and, as shown recently, to be an important amplifier of cardiovascular risk.3 The immediate implication is that ensuring good glycemic control from the time of diagnosis can significantly reduce the risk of microvascular complications and, therefore, contribute to reducing the risk of macrovascular events. In spite of the documented beneficial effects of good glycemic control, the number of people with elevated glycated hemoglobin (HbA1c) levels remains high.

In the United States, in the period 1999-2002 only 44% of the diabetic population had HbA1c values <7% and 33% had HbA1c values >7.9%. The picture has marginally improved over the next decade, with 52% of the individuals achieving a target HbA1c<7%, though the percentage of those with HbA1c values >7.9% has decreased to 22%.4 The PANORAMA survey (Quality of life and treatment satisfaction of people with type 2 diabetes: a European survey), carried out in 9 European countries, estimated that 37% of people with type 2 diabetes did not achieve their target goal.5 The survey also showed that the percentage of people not at target increased with escalation of the glucose-lowering treatment. In summary, these observations emphasize the need for achieving and maintaining glycemic control targets throughout the course of the disease in a larger percentage of the diabetic population. The limited success in achieving better glycemic control is the likely consequence of several unmet needs. This editorial will review and discuss those that require immediate action.

Better understanding of the pathophysiology of type 2 diabetes

Over the past decades it has become clear that multiple mechanisms contribute to the development and progression of hyperglycemia in type 2 diabetes. However, the available data continue to point to progressive loss of β cell function as the main factor determining the gradual worsening of glycemic control and the need for treatment escalation. The central role of β cell function has been corroborated in different ethnic groups. Thus, a longitudinal study in the Pima Indians of Arizona found that when glucose tolerance progressed from normal to impaired glucose tolerance, and then to overt diabetes, insulin resistance did not change much, while each step toward diabetes was associated with a significant loss of β cell function.6 Similarly, in the UKPDS study (United Kingdom Prospective Diabetes Study) there was little change in insulin sensitivity over the study follow-up, while β cell function progressively declined in a manner that was unaffected by any concomitant treatment.7 Therefore, understanding the nature of β cell defects remains key in designing ad hoc therapeutic interventions. What we still need to understand is to which extent the progressive impairment in insulin secretion is functional in nature and whether or not it is due to the loss of β cell mass and, finally—and even more importantly—we need to identify the intrinsic mechanisms supporting this phenomenon.

More effective glucose-lowering agents

The efficacy of glucose-lowering agents is usually evaluated in relatively short clinical trials. However, the efficacy of a treatment should actually refer to its ability to achieve sustained glycemic control over a much longer period of time. This information is key to appreciate the durability of efficacy, a concept that has both clinical and economic implications. Persistence of the glucose-lowering efficacy of a drug is likely to be strictly connected with its ability to preserve β cell function. For instance, the efficacy of sulfonylureas has been shown to be short-lived,8 and, according to in vitro data, some sulfonylureas could induce β cell apoptosis.9 The potential of glucagon-like peptide 1 (GLP-1) in preserving functional β cell mass initially led to great expectations,10 though studies in humans remain limited. Of interest, it was found that a 3-year treatment with exenatide was associated with an improvement in β cell function, which was not the case with insulin glargine, despite both drugs achieving similar glycemic control.11 Ad hoc studies, such as the RISE study (Restoring Insulin Secretion)12 or the VERIFY study (Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of T2DM),13 will provide better insight on the potential of incretin-based therapies.

Personalized medicine

As mentioned, the pathophysiology of type 2 diabetes is complex, and multiple pharmacological targets have been identified. However, both the selection of the drug(s) and the timing of their use are still largely empirical. A more rational approach can be expected to provide better efficacy and greater safety. Genetic studies have identified a number of genetic variants that convey an increased risk of developing diabetes, but despite the enormous investment and research, they are still far from providing treatment guidance. They are actually more likely to help identify individuals who may be exposed to a greater risk of side effects, as seems to be the case for carriers of variants of the organic cation transporter 1 (OCT1) gene treated with metformin.14 The prediction algorithm may be improved by the introduction of biomarkers that can track the underlying major pathophysiological mechanism(s) and monitor the impact of treatments. However, the identification of such biomarkers is still in its infancy. What will be needed in the future is the combination of biological (“omics”) and clinical data in concert with “big data” collected through electronic sensors as well as social media.15 Altogether they may help to build a knowledge network that will generate a new taxonomy of the disease, leading to a more precise diagnosis, better treatments, and improved health outcomes.

Clinical inertia

Even the most effective drug must be used at the right time (and by the right person) to provide the best efficacy. Unfortunately, the treatment of type 2 diabetes is still limited by excessive delays in introducing glucose-lowering agents when glycemic control starts drifting off target. In a retrospective analysis in more than 80 000 patients with type 2 diabetes, a significant delay in treatment escalation was found, resulting in >6 years of exposure to excessive hyperglycemia.16 This is particularly striking in light of the dramatic burden that just one year of delay can bring about: in patients with HbA1c levels ≥7%, delaying treatment intensification by one year is associated with a 53% increase in the risk of cardiovascular events compared with patients with HbA1c levels <7%.17 Several factors favor clinical inertia, including the physician’s concern about side effects, which can also be a source of discomfort and risk for the patients. For instance, the medical community appreciates the clinical and economic implications of hypoglycemia. The occurrence of a severe hypoglycemic episode is associated with more frequent and prolonged hospital admissions and outpatient visits and, in turn, leads to an increase in health care expenses.18 While hypoglycemia can have immediate consequences, the increase in body weight that some glucose-lowering treatment may be associated with is not perceived as benign by the medical community. Weight gain is more likely to be associated with diabetes progression and contributes to insulin resistance and worsening of the cardiovascular risk profile. On the other hand, a weight loss of at least 5% is associated with multiple metabolic and hemodynamic improvements. Therefore, along with continuous education and a more effective delivery of diabetes care, the use of glucose-lowering agents that may, per se, contribute to reducing the risk of hypoglycemia and weight gain in a timely treatment escalation is advisable to ensure durable glycemic control.

Medication adherence

Medication adherence remains an important issue in diabetes care.19 Poor adherence is associated with a worsening of glycemic control and an increased risk of hospitalization and mortality. As a consequence, poor treatment adherence leads to increased resource utilization and diabetes-related costs. Several factors contribute to poor adherence, including perceived treatment (in) efficacy, fear of hypoglycemia, treatment complexity and convenience, costs, personal beliefs, and physician trust. Overcoming some of these barriers can bring significant benefits since improved adherence can significantly reduce the odds of having poor glycemic control. Novel treatment strategies may help to tackle some of these factors. Reducing the frequency of administration may be of benefit, and approaches that provide sustained and constant drug delivery over months are currently under evaluation. One such novel approach is ITCA650 (Intarcia Therapeutics, Inc., Boston, MA, USA), which allows continuous delivery of exenatide for up to 6-12 months via a subcutaneous osmotic minipump. This device not only takes advantage of the characteristic efficacy of exenatide (glucose lowering, body weight reduction, low risk of hypoglycemia), but also results in full treatment adherence as long as the minipump is kept in place. Fixed-dose combinations, either for oral and injectable glucose-lowering agents, will represent another opportunity to improve adherence. In summary, improving treatment adherence will require new pharmacological approaches as well as new nonpharmacological strategies involving new technologies and more patient-oriented health care delivery systems.

Going beyond glucose lowering

Glucose control is key in reducing the risk of diabetes complications. However, while the relationship between glucose exposure and microvascular complications is well established, several other factors contribute to the increased risk of cardiovascular disease in type 2 diabetes. Therefore, treatments that may confer cardiovascular protection will be of growing importance in the future. A new era has begun following the request from the FDA and EMA to perform cardiovascular trials for all new glucose-lowering agents, and we now have evidence that these treatments are safe. Some of them (empagliflozin,20 liraglutide,21 and semaglutide22) are actually associated with significant reductions in cardiovascular events. Of interest, the beneficial effect of these agents appears to be largely independent of their glucose-lowering effect, though their exact mechanism(s) of action remain to be defined. By the same token, antidiabetic drugs may possess ancillary properties that may lend them an advantage against specific diabetes complications, as it has been recently suggested, for instance, for the nephroprotective effects of SGLT2-inhibitors.23

In summary, the treatment of type 2 diabetes has emerged from decades of “dark times” when the only therapeutic options were insulin, sulfonylureas, and metformin. We are now experiencing a “renaissance” of the treatment of type 2 diabetes, with 9 classes of glucose-lowering agents. This treatment palette offers renewed opportunities for ensuring more durable glycemic control, but is still not the optimal solution. Such a solution, ie, one that would ensure the best glycemic control for the largest number of patients with diabetes, will require addressing a number of unmet needs. It will be difficult to meet some of these needs, but given the increasing number of people who will continue to develop the disease, this is the only way—along with efficacious prevention—to reduce the risk of having hundreds of millions of individuals with a dramatically lower quality of life, and putting the global economy at risk. ■

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Keywords: adherence; clinical inertia; glucose-lowering agent; personalized medicine; type 2 diabetes