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The diabetes landscape has seen unprecedented changes over the recent past. On the one hand, there have been consistent and impressive advancements in clinical care, which include new therapeutic agents, novel dietary approaches, technical advances in glycemic monitoring and closed-loop technology, and a heightened awareness of individuals at risk. The tools required to treat and halt the progression of diabetes complications and the clinical evidence in support of effective management strategies have been established. On the other hand, the need for these developments has never been greater given the global burden of the diabetes epidemic. A particularly disturbing observation is that the “faces” of those who develop type 2 diabetes are becoming younger by the year as evidenced by the reports demonstrating the increased frequency of both type 1 and type 2 diabetes in youth (1–3). Until recent data were made available, it was really not known how adolescents would respond to therapies normally reserved for the adult population. We also had no evidence regarding the rate and severity of the complications in this age-group or the prevalence and progression of other risk factors. In this regard, the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) study has succeeded in filling a major gap in knowledge (4–10). Thus, given the importance of the problem of type 2 diabetes in youth and the need to effectively disseminate the information, our editorial team has elected to feature the TODAY study in this issue of Diabetes Care. Specifically, articles from the TODAY study researchers featured in this issue provide new data on the efficacy and safety of clinical treatment and longitudinal observations of specific risk factors and complications for the new “faces” of the type 2 diabetes epidemic—namely, adolescents!

this issue of Diabetes Care. Specifically, articles from the TODAY study researchers featured in this issue provide new data on the efficacy and safety of clinical treatment and longitudinal observations of specific risk factors and complications for the new “faces” of the type 2 diabetes epidemic—namely, adolescents! As I reflect on the problem of type 2 diabetes in adolescents, it is now hard to believe it was not that long ago that published reports viewed this condition as rare. For example, in a review reported in 1997, Glaser states, “Most subtypes of NIDDM that occur in childhood are uncommon, but some, such as early onset of ‘classic’ NIDDM, seem to be increasing in prevalence” (11). It is also remarkable that only 11 years ago, Drake et al. (12) reported on only four cases of type 2 diabetes in obese, white children in the U.K., at that time a rare observation. In the opening sentence of their article, they state, “Type 2 diabetes is still rare in childhood, but recent reports indicate an increasing prevalence in minority populations around the world. This is particularly the case in the USA, but has also been reported in Japan, Libya, Bangladesh, Australia, and Canada” (12). In their conclusion, Drake et al. state, “As far as we are aware, these are the first cases of type 2 diabetes described in white children in the UK; however, this phenomenon is likely to become increasingly common.” Again, I remind you that this report was only 11 years ago, and if a manuscript that described only four cases of type 2 diabetes in youth was submitted today, we would have a hard time justifying publication just based on novelty. However, the early reports did have one thing in common as they all seemed to portend much worse things to come, and that prediction appears to have come to fruition. The increasing frequency of type 2 diabetes in youth, in my opinion, is the most disturbing and worrisome aspect of the current diabetes epidemic.

velty. However, the early reports did have one thing in common as they all seemed to portend much worse things to come, and that prediction appears to have come to fruition. The increasing frequency of type 2 diabetes in youth, in my opinion, is the most disturbing and worrisome aspect of the current diabetes epidemic. Before we can even consider management strategies, a key first step would be to ascertain the characteristics of type 2 diabetes in youth, to obtain reliable data on how many children have type 2 diabetes, and to assess changes over time. As outlined in an accompanying commentary from the National Institutes of Health (NIH) (13), which also appears in this issue, these goals were essentially addressed in the SEARCH for Diabetes in Youth Study, a multicenter, epidemiological study initiated in 2000 and funded by the Centers for Disease Control and Prevention (CDC) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). As described, SEARCH evaluated the prevalence, incidence, and classification of diabetes mellitus in youth and was designed to characterize the burden of both type 1 and type 2 diabetes, along with the associated complications, the levels of care, and the impact on the daily lives of children and youth in the U.S. From this study we now have the critical information about the prevalence and incidence of type 1 and type 2 diabetes and stratification based on age, sex, and race (1,2). Importantly, we now have information on the risk factors and acute and chronic complications of both types of diabetes for adolescents (14–19).

U.S. From this study we now have the critical information about the prevalence and incidence of type 1 and type 2 diabetes and stratification based on age, sex, and race (1,2). Importantly, we now have information on the risk factors and acute and chronic complications of both types of diabetes for adolescents (14–19). Whereas SEARCH identified and further characterized the problem, TODAY evaluated the treatment strategies. As understood, the only approved therapies for children with type 2 diabetes are either metformin or insulin. In the TODAY study, children and teens aged 10–17 years and within 2 years of a diagnosis of type 2 diabetes were randomly assigned to one of three treatment groups: metformin alone, metformin plus rosiglitazone, or metformin plus intensive lifestyle changes designed to reduce weight and increase physical activity (4). The efficacy of the treatments, reported in 2012 (4), suggested that type 2 diabetes presenting in youth may have a much more aggressive course. Specifically, monotherapy with metformin was associated with durable glycemic control in approximately half of the children and adolescents with type 2 diabetes. Importantly, we learn so much more about the disease in this issue of Diabetes Care. As discussed in this issue, we now have new data about insulin sensitivity and B-cell function as favorable effects on insulin action and pancreatic function achieved early in the course of treatment with combination metformin/rosiglitazone may be the major contributing factors explaining the increase in glycemic durability over treatment with metformin alone and metformin plus lifestyle (5). We also learn that initial β-cell reserve and HbA1c observed at randomization appear to be independent predictors of glycemic durability. We now appreciate that the three treatment approaches were generally safe and well tolerated with the most common adverse events being gastrointestinal in nature. Interesting, this adverse event was lower in the group randomized to metformin/rosiglitazone (6). It was reported that despite differential effects on measures of adiposity among the treatment groups, group differences generally were small and unrelated to treatment effects in sustaining glycemic control (7).

n nature. Interesting, this adverse event was lower in the group randomized to metformin/rosiglitazone (6). It was reported that despite differential effects on measures of adiposity among the treatment groups, group differences generally were small and unrelated to treatment effects in sustaining glycemic control (7). Despite the observations on the metformin/rosiglitazone combination, one relevant question will be whether we can expect thiazolidinediones to be part of the routine treatment for children with type 2 diabetes given the concerns with adverse events with use of agents in this class. In this regard, I will refer you to an accompanying commentary on this very important topic appearing in this issue of Diabetes Care (20). Specifically, Tamborlane and Klingensmith comment on this very relevant question—and the topic of drug therapy in children in general—and provide a unique perspective for future clinical research in this area.

you to an accompanying commentary on this very important topic appearing in this issue of Diabetes Care (20). Specifically, Tamborlane and Klingensmith comment on this very relevant question—and the topic of drug therapy in children in general—and provide a unique perspective for future clinical research in this area. In addition to the data on glycemic durability and the most effective treatment options, the information from the TODAY study that reports on complications is of great interest. As designed, the TODAY study examined lipid profiles and inflammatory markers and compared changes across the treatment groups. The observations suggest that dyslipidemia and chronic inflammation were common in youth with type 2 diabetes and appeared to worsen over time (8). Despite some treatment group differences in lipid and inflammatory marker change over time, the TODAY study group reports that the specific diabetes treatment as outlined in the study was felt to be generally inadequate to control these specific risk factors (8). The prevalence of retinopathy and its association with HbA1c and diabetes duration in the TODAY cohort was reported to be similar to that previously reported in youth with type 1 diabetes and in adults with type 2 diabetes of known duration (9). Interestingly, adolescents in the highest BMI tertile appeared to have had the lowest prevalence of retinopathy, and the precise mechanism of action underlying the reduced risk of retinopathy in these individuals is unknown. In addition, TODAY provided novel information regarding incidence and progression of hypertension and microalbuminuria. During the TODAY study, hypertension and microalbuminuria were analyzed for effect of treatment, glycemic control, sex, and race/ethnicity, and the prevalence of both increased over time regardless of diabetes treatment (10). Male sex and higher BMI provided the greatest risk for hypertension, whereas the risk for microalbuminuria was more closely related to glycemic control (10).

analyzed for effect of treatment, glycemic control, sex, and race/ethnicity, and the prevalence of both increased over time regardless of diabetes treatment (10). Male sex and higher BMI provided the greatest risk for hypertension, whereas the risk for microalbuminuria was more closely related to glycemic control (10). It has been approximately 30 years since the initiation of the Diabetes Control and Complications Trial (DCCT), the landmark study evaluating glycemic control and complications in individuals with type 1 diabetes. As well appreciated, type 1 diabetes is considered the primary diabetes presentation in children. Who would have ever thought when the DCCT started that we would be at this stage that we would have to worry about the problem of type 2 diabetes in children? Again, the major concern is that type 2 diabetes has traditionally been a condition we associate with onset in adulthood and one that, when diagnosed in adulthood, is still associated with significant morbidity and mortality over time. And yet, in what seems like a “blink of an eye,” the presentation of the disease has taken on a completely different aspect. What can we expect 10, 20, or even 30 years from now? Indeed, only recently Imperatore et al. (3) estimated the future burden of diabetes in youth by type in the major race/ethnic groups in the U.S. using the most recent population-based estimates of diabetes incidence and prevalence and taking into account demographic changes over time. The authors projected that at the current incidence rates over the next 40 years, the number of youth with type 1 and type 2 diabetes may increase by 23 and 49%, respectively (3). However, from this article, a more dire prediction from the authors stated that “if the incidence of T1DM or T2DM increases, there may be more than a threefold increase in the number of youth with T1DM and about a fourfold increase in the number of youth with T2DM, especially among minority youth” (3).

espectively (3). However, from this article, a more dire prediction from the authors stated that “if the incidence of T1DM or T2DM increases, there may be more than a threefold increase in the number of youth with T1DM and about a fourfold increase in the number of youth with T2DM, especially among minority youth” (3). We are not prepared as a medical community or as a global society at this time to effectively address the growing problem of type 2 diabetes in youth. We should heed the advice as outlined in an elegant editorial by Dr. Robert Ratner, Chief Scientific and Medical Officer at the American Diabetes Association, who stated, “Research and public policy changes are required to slow and ultimately reverse the deleterious impact diabetes has on our population, our health care system, and our economy. Effective strategies must be identified before we are able to move forward on the prevention of type 1 diabetes, but type 2 diabetes must be addressed now” (21). Until such a coordinated attack on this problem is realized, we can expect to continue to see the increased morbidity and mortality associated with the disease.

fective strategies must be identified before we are able to move forward on the prevention of type 1 diabetes, but type 2 diabetes must be addressed now” (21). Until such a coordinated attack on this problem is realized, we can expect to continue to see the increased morbidity and mortality associated with the disease. If nothing else, with this issue of Diabetes Care featuring the TODAY study, it was my clear intent to sound the alarm of type 2 diabetes presenting in youth. As an editorial team, we desired to disseminate novel information on its treatment and to specifically focus on what I feel is one of the most significant medical problems facing our society. The statistics are sobering, and the problem is real! To state that we have a huge challenge ahead and no real solutions is an understatement. I applaud the NIH, the CDC, and the investigators of the TODAY and the SEARCH studies for their work, dedication, and support in providing us with a much better understanding of the problem of type 2 diabetes in youth and novel information on its treatment. These studies provide important first steps, but also provide for a major leap in knowledge that will guide the design of evolving strategies at multiple levels, e.g., health care policy, screening, medical and behavioral intervention, etc., which can begin to address the problem of type 2 diabetes in youth. The steps taken will ultimately help reduce disease burden for the changing and much younger “faces” of the type 2 diabetes epidemic. See accompanying articles from the TODAY Study Group beginning on p. 1735

If nothing else, with this issue of Diabetes Care featuring the TODAY study, it was my clear intent to sound the alarm of type 2 diabetes presenting in youth. As an editorial team, we desired to disseminate novel information on its treatment and to specifically focus on what I feel is one of the most significant medical problems facing our society. The statistics are sobering, and the problem is real! To state that we have a huge challenge ahead and no real solutions is an understatement. I applaud the NIH, the CDC, and the investigators of the TODAY and the SEARCH studies for their work, dedication, and support in providing us with a much better understanding of the problem of type 2 diabetes in youth and novel information on its treatment. These studies provide important first steps, but also provide for a major leap in knowledge that will guide the design of evolving strategies at multiple levels, e.g., health care policy, screening, medical and behavioral intervention, etc., which can begin to address the problem of type 2 diabetes in youth. The steps taken will ultimately help reduce disease burden for the changing and much younger “faces” of the type 2 diabetes epidemic. See accompanying articles from the TODAY Study Group beginning on p. 1735 Acknowledgments No potential conflicts of interest relevant to this article were reported.

In April 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a joint position statement titled “Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach” (1). It was an important update to earlier guidelines (2–8), providing a thorough examination of the ever-more-complex therapeutic options for glycemic management, the benefits and risks of tight glycemic control, the efficacy and safety evidence for new drug classes, and the data supporting withdrawals of or restrictions on other agents. Furthermore, it placed great emphasis on patient-centered and personalized care. These recommendations captured the attention of the Diabetes Care editorial team. On the one hand, the recommendations call for a more personalized approach, which, in theory, should be liberating for all health care providers (HCPs) involved in diabetes care. On the other hand, their “less prescriptive” nature has been viewed as providing insufficient guidance to some HCPs who may feel overwhelmed when trying to match the nuances of differences among the increasing number of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics.

the other hand, their “less prescriptive” nature has been viewed as providing insufficient guidance to some HCPs who may feel overwhelmed when trying to match the nuances of differences among the increasing number of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics. To explore these issues, we convened a Diabetes Care Editors’ Expert Forum in June 2012. Thirteen thought leaders from around the world convened and discussed approaches to personalized medicine, the rationale behind personalization in diabetes care, the tools necessary to implement such a strategy, and the current perceptions of personalized medicine. This narrative provides our view and clinical translation of the underlying issues that need to be considered for personalizing care and offers suggestions to stimulate future research in this area. Table 1 summarizes the main points discussed below. Table 1 Summary of the main points from the Diabetes Care Editors’ Expert Forum PRACTICAL APPROACHES TO PERSONALIZED MEDICINE From intervention trials to personalized targets There can be little more than semantic differences among the terms “personalized medicine,” “patient-centered care,” and “clinical judgment.” Factors such as patients’ preferences, life expectancy, disease duration, comorbid conditions, socioeconomic status, and cognitive abilities have long played a role in the selection of optimal therapeutic options and, more recently, in the selection of therapeutic targets.

tient-centered care,” and “clinical judgment.” Factors such as patients’ preferences, life expectancy, disease duration, comorbid conditions, socioeconomic status, and cognitive abilities have long played a role in the selection of optimal therapeutic options and, more recently, in the selection of therapeutic targets. In 1998, the UK Prospective Diabetes Study (UKPDS) showed that treating patients with recently diagnosed type 2 diabetes reduced the risk of microvascular, but not macrovascular, complications (9). Of the three subsequent randomized controlled trials (RCTs) on glucose lowering and cardiovascular outcomes, two—ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) and VADT (Veterans Affairs Diabetes Trial)—showed no statistically significant reduction in cardiovascular outcomes, while the glycemic intervention of the third—ACCORD (Action to Control Cardiovascular Risk in Diabetes)—was ended early because of increased mortality in participants randomized to intensive glycemic control (10–12). However, meta-analyses of the four intervention trials (UKPDS, ACCORD, ADVANCE, and VADT) have shown modest but statistically significant benefit of intensive glucose control on the risk for myocardial infarction, but not mortality (13).

reased mortality in participants randomized to intensive glycemic control (10–12). However, meta-analyses of the four intervention trials (UKPDS, ACCORD, ADVANCE, and VADT) have shown modest but statistically significant benefit of intensive glucose control on the risk for myocardial infarction, but not mortality (13). Post hoc analyses seeking explanations for these results set the stage for today’s new emphasis on personalized care. Suggestions that adverse effects of individual therapeutic agents or severe hypoglycemia were directly implicated in causing cardiovascular events were not supported by these analyses but cannot be ruled out because efforts to capture hypoglycemic events were probably inadequate, especially in individuals with hypoglycemia unawareness (13). However, individuals assigned to intensive therapy who failed to improve control to A1C levels <7.0% (<53 mmol/mol) in ACCORD fared poorly and had more severe hypoglycemia, and severe hypoglycemia was noted to be a risk marker for a wide range of medical conditions in ADVANCE (14,15). It was also suggested that individuals with long-standing type 2 diabetes, existing cardiovascular disease (CVD), and other comorbidities were unable to achieve cardiovascular benefit from better glucose lowering within the timeframe of these studies (16).

rker for a wide range of medical conditions in ADVANCE (14,15). It was also suggested that individuals with long-standing type 2 diabetes, existing cardiovascular disease (CVD), and other comorbidities were unable to achieve cardiovascular benefit from better glucose lowering within the timeframe of these studies (16). Accordingly, these trials and their subsequent analyses raised important questions about rigid, algorithm-based, “glucocentric” approaches to therapy. One message, then, is that “one size does not fit all” for glucose targets, choice of therapy, or number of therapies used in combination. However, some questions pertinent to personalization remain unanswered. What were the characteristics of the small group of individuals in ACCORD who failed to respond to further glucose-lowering therapy but who contributed much of the excess case fatality (12)? Similarly, what can these studies teach us about patients who benefitted most from the interventions? Gaining insight into the pathophysiological, genetic, lifestyle, adherence, comorbidity, or other factors responsible for these disparate responses could improve our ability to effectively personalize therapy.

ty (12)? Similarly, what can these studies teach us about patients who benefitted most from the interventions? Gaining insight into the pathophysiological, genetic, lifestyle, adherence, comorbidity, or other factors responsible for these disparate responses could improve our ability to effectively personalize therapy. The 2012 ADA/EASD position statement still recommends an A1C goal of <7.0% (<53 mmol/mol) for most individuals with type 2 diabetes if it can be achieved safely in low-risk individuals with early diabetes or a relatively long life expectancy; it suggests an acceptance of higher A1C targets for individuals with a history of severe hypoglycemia, limited life expectancy, long-standing diabetes, or advanced micro- and macrovascular complications (1). Prior guidelines from multiple organizations (3–8) included recommendations about setting personalized glycemic targets based on phenotype and empirically matching “the right drugs to the right patients,” but without hard evidence to substantiate such an approach. Personalized treatment was articulated more vigorously in the new position statement (1).

anizations (3–8) included recommendations about setting personalized glycemic targets based on phenotype and empirically matching “the right drugs to the right patients,” but without hard evidence to substantiate such an approach. Personalized treatment was articulated more vigorously in the new position statement (1). The challenges of personalized care Patient-centered personalized therapy, although appealing, may be difficult to implement without a good understanding of the ever-changing glucose-lowering armamentarium. β-Cell dysfunction is progressive in type 2 diabetes (9), and thus monotherapy, or even combinations of oral agents, is not likely to control hyperglycemia indefinitely (17), although the ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial demonstrated sustained normoglycemia with basal insulin glargine plus metformin and near-normoglycemia even with standard therapy using metformin plus a sulfonylurea over a 6–7 year period in early type 2 diabetes (18). At this time, the processes of assessing β-cell function and providing reliable clinical decisions based on this factor are less than optimal. Furthermore, so-called evidence-based guidelines may be limited in their ability to be more prescriptive given the lack of clinical trial evidence from properly conducted long-term RCTs comparing the effects of various agents on clinically important outcomes. Clinical inertia is also a problem, and most clinicians do not alter their patients’ glucose-lowering regimens until A1C is significantly elevated (19). Developing and implementing personalized care plans may be especially daunting for those HCPs whose practice extends beyond diabetes alone and who must address these issues in the context of limited time and resources.

ians do not alter their patients’ glucose-lowering regimens until A1C is significantly elevated (19). Developing and implementing personalized care plans may be especially daunting for those HCPs whose practice extends beyond diabetes alone and who must address these issues in the context of limited time and resources. The need for translational tools The task now at hand is clear: We should develop and make available tools that will enable effective translation of existing guidelines on targets and therapeutic options into practical clinical applications. It is one thing to assess the efficacy of an intervention within the context of a structured clinical trial setting, but entirely different to evaluate that intervention in ordinary clinical practices with resource variations, variable patient adherence, and sociodemographic and cultural differences. Thus, the translation of results from RCTs to real-world situations is not an exact science. Until more hard evidence becomes available, clinicians need well-structured and user-friendly evidence summaries that outline safe and effective processes for therapeutic intensification, while still allowing for the personalization of care.

slation of results from RCTs to real-world situations is not an exact science. Until more hard evidence becomes available, clinicians need well-structured and user-friendly evidence summaries that outline safe and effective processes for therapeutic intensification, while still allowing for the personalization of care. Although such an undertaking is beyond the scope of this discussion, we are providing a starting point that may guide the development of such tools to aid HCPs in personalizing both targets and therapeutic regimens. For target-setting, suggestions have been made in the past (20,21). Another possible starting place might be the decision-making scale developed by Ismail-Beigi et al. (22) and adapted for inclusion in the ADA/EASD position statement (1). That scale includes seven parameters to consider when determining glycemic targets. Expanding it or providing some means of rating each parameter for individual patients could help clinicians to better weigh factors such as life expectancy, duration of diabetes, risk from hypoglycemia, comorbidities, and availability of support systems. Such a tool could assist clinicians in choosing targets and help to involve patients in the decision-making process in an easily understood manner.

nts could help clinicians to better weigh factors such as life expectancy, duration of diabetes, risk from hypoglycemia, comorbidities, and availability of support systems. Such a tool could assist clinicians in choosing targets and help to involve patients in the decision-making process in an easily understood manner. Tools are also needed to help HCPs in selecting appropriate agents and intensifying therapy. The ADA/EASD position statement leaves treatment-goal decisions to clinicians and patients (1). However, some believe that because of the vast and expanding array of available drugs, there should be a systematic way to prioritize the selection of drugs in relation to their efficacy, safety, and cost. It is most important to emphasize that the percentage of patients who show sufficient clinical response to any of these drugs varies widely. Nonadherence to treatment regimens may be as high as 50% in patients with chronic diseases such as diabetes (23), often because of the patients’ lack of symptoms, negative emotions, and poor knowledge of their disease (24). Side effects are another cause of stopping or limiting treatment. Thus, patients must be adequately monitored, especially after changes to their treatment regimen, to evaluate whether they have reached targets and to ensure that there are no major side effects or adherence issues. This information is crucial to make informed decisions regarding whether to continue, change, or add to the therapy regimen.

be adequately monitored, especially after changes to their treatment regimen, to evaluate whether they have reached targets and to ensure that there are no major side effects or adherence issues. This information is crucial to make informed decisions regarding whether to continue, change, or add to the therapy regimen. STATE OF THE ART FOR PERSONALIZING MEDICINE Personalized medicine can be defined in many ways. A shared decision-making approach that takes patient preferences and values into account in developing a management plan is widely endorsed. Another definition involves identifying a particular set of phenotypic and genotypic markers that would define ideal and nonideal therapies for individuals based, to whatever extent possible, on evidence rather than on clinical impressions. Perhaps the most relevant question is whether current science is at a stage where specific patient characteristics—genetic, pathophysiological, or phenotypic—might effectively guide us in more general diabetes practice.

for individuals based, to whatever extent possible, on evidence rather than on clinical impressions. Perhaps the most relevant question is whether current science is at a stage where specific patient characteristics—genetic, pathophysiological, or phenotypic—might effectively guide us in more general diabetes practice. Contributions from genetics: a distant hope The field of genetics is not yet ready to contribute in these broader areas. Despite recent identification of monogenic forms of diabetes for which specific treatments seem to give benefit (25), for more typical type 2 diabetes, genetic information does not contribute greatly in guiding treatment choices. Recently, pharmacogenetic analysis has begun providing insights, finding possible links, for example, to poor responses to metformin (26,27) and glucagon-like peptide-1 (GLP-1) receptor agonists (28–30). Such research holds promise for eventually helping to identify individuals who are likely to be classified as “responders” or “nonresponders” to specific agents.

providing insights, finding possible links, for example, to poor responses to metformin (26,27) and glucagon-like peptide-1 (GLP-1) receptor agonists (28–30). Such research holds promise for eventually helping to identify individuals who are likely to be classified as “responders” or “nonresponders” to specific agents. Human genome sequencing also offers some hope, but again, in the distant future (31). Because the development of diabetes, patients’ responses to available therapies, and the risks for complications are all multifactorial and probably involve numerous genes, the chances are small that specific mutations will turn out to be powerful markers of diabetes risk or of variable treatment responses. Even assuming a significant increase in pharmacogenetics research and decreases in the costs associated with genome sequencing, for the foreseeable future these efforts will not significantly improve our ability to predict, prevent, or diagnose diabetes or illuminate definitive pathways for selecting drug therapies for specific individuals.

icant increase in pharmacogenetics research and decreases in the costs associated with genome sequencing, for the foreseeable future these efforts will not significantly improve our ability to predict, prevent, or diagnose diabetes or illuminate definitive pathways for selecting drug therapies for specific individuals. What can we learn from pathophysiology? Insulin resistance in the liver and muscle and islet β-cell failure represent the core pathophysiological defects in type 2 diabetes (32,33). Insulin resistance can often be demonstrated long before the onset of β-cell failure, but as long as the β-cells secrete sufficient amounts of insulin to offset the insulin resistance, glucose tolerance remains normal (32–36). With time, however, there is progressive β-cell failure, which leads to the development of impaired glucose tolerance and/or impaired fasting glucose and eventually type 2 diabetes (32–36). As the plasma insulin response declines, insulin resistance in the liver becomes manifest as an overproduction of glucose by the liver and the development of fasting hyperglycemia, while insulin resistance in muscle results in diminished glucose uptake and postprandial hyperglycemia (32,33).

ly type 2 diabetes (32–36). As the plasma insulin response declines, insulin resistance in the liver becomes manifest as an overproduction of glucose by the liver and the development of fasting hyperglycemia, while insulin resistance in muscle results in diminished glucose uptake and postprandial hyperglycemia (32,33). Although the relative contributions of β-cell failure (possibly more severe in Asian populations) and insulin resistance (more severe in Westernized societies with a high prevalence of obesity) may vary among different ethnic groups (37), virtually all adults with type 2 diabetes have some combination of the two. Thus, antihyperglycemic agents that improve β-cell function and enhance hepatic and muscle insulin sensitivity may have a more durable effect in reducing A1C (38–45). The importance of other pathophysiological disturbances in the development of type 2 diabetes is well recognized (32,33). These disturbances includeAdipocyte insulin resistance, which leads to increased lipolysis, increased plasma free fatty acids, and eventual β-cell failure and muscle and hepatic insulin resistance (46) Excess glucagon secretion by α-cells and enhanced hepatic sensitivity to glucagon, leading to increased basal hepatic glucose production and impaired suppression of hepatic glucose production after meals (47,48) Dysfunction related to incretin hormones (GLP-1 and glucose-dependent insulinotropic peptide) (49), which are responsible for ∼50% of the insulin secreted in response to meals

Excess glucagon secretion by α-cells and enhanced hepatic sensitivity to glucagon, leading to increased basal hepatic glucose production and impaired suppression of hepatic glucose production after meals (47,48) Dysfunction related to incretin hormones (GLP-1 and glucose-dependent insulinotropic peptide) (49), which are responsible for ∼50% of the insulin secreted in response to meals Possible renal adaptive mechanisms to hyperglycemia, which result in enhanced glucose reuptake leading to decreased urinary glucose clearance and the maintenance of established hyperglycemia (50) Central nervous system insensitivity to the anorectic effect of insulin and multiple neurotransmitter synaptic abnormalities resulting in excessive energy intake and obesity (33) No single antihyperglycemic agent can correct all of these pathophysiological abnormalities. Thus, many patients may require multiple agents with different mechanisms of action to achieve their individualized A1C goal (33). Patients with type 2 diabetes who have a high initial A1C, in particular, may require two or more antihyperglycemic agents to achieve their A1C goal (1,4,7,8,33,51,52). The precise choice of pharmacological agents to use remains a topic for debate, in part because of safety concerns involving several drug classes (53–55). But the basic point remains: To achieve durability of glycemic control, optimal regimens will likely need to address both insulin resistance and β-cell failure.

No single antihyperglycemic agent can correct all of these pathophysiological abnormalities. Thus, many patients may require multiple agents with different mechanisms of action to achieve their individualized A1C goal (33). Patients with type 2 diabetes who have a high initial A1C, in particular, may require two or more antihyperglycemic agents to achieve their A1C goal (1,4,7,8,33,51,52). The precise choice of pharmacological agents to use remains a topic for debate, in part because of safety concerns involving several drug classes (53–55). But the basic point remains: To achieve durability of glycemic control, optimal regimens will likely need to address both insulin resistance and β-cell failure. Does phenotype allow for personalized treatment? The main characteristics that might influence approaches to treatment can be divided into two categories: patient features and disease features. Among the patient features are race/ethnicity, sex, age of onset or diagnosis, duration of diabetes, body weight, frailty/comorbidities, complications, propensity for side effects/drug tolerance, personality and aspirations, and psychosocial-economic context. Among the disease features are the balance between insulin deficiency and insulin insensitivity, fasting versus postprandial hyperglycemia, short versus long disease duration, and special circumstances such as maturity-onset diabetes of the young (MODY) or latent autoimmune diabetes in adulthood (LADA).

onomic context. Among the disease features are the balance between insulin deficiency and insulin insensitivity, fasting versus postprandial hyperglycemia, short versus long disease duration, and special circumstances such as maturity-onset diabetes of the young (MODY) or latent autoimmune diabetes in adulthood (LADA). However, we are faced with a paucity of data on how patients with certain characteristics respond to specific therapies (56). We know that most glucose-lowering drugs for type 2 diabetes work in most patients. But we also know that there are nonresponders to any drug. Numerous post hoc studies have revealed some predictors of better responses, but the data are inconclusive (57–60). Furthermore, those response differences tend to be small, and the strongest predictor remains baseline A1C, with the patients with higher A1C levels responding with greater reductions although not necessarily attaining target levels (58,61).

ed some predictors of better responses, but the data are inconclusive (57–60). Furthermore, those response differences tend to be small, and the strongest predictor remains baseline A1C, with the patients with higher A1C levels responding with greater reductions although not necessarily attaining target levels (58,61). Indeed, the most fruitful phenotypic considerations for personalizing care today may be patients’ propensity for side effects and tolerance of various medicines. There may be practical value to using a trial-and-error, or “n of 1,” approach (62) based on the anticipation of a drug’s efficacy (for example, “Pioglitazone will be highly effective in this very insulin-resistant patient”), a patient’s need for certain added benefits (“A GLP-1 receptor agonist will help control hyperglycemia and may encourage weight loss in this obese patient”), and concerns about adverse events (“I will not prescribe a sulfonylurea for this elderly patient who lives alone and had a severe hypoglycemic episode a few years ago”). This is becoming standard clinical procedure for diabetes, just as it is for hypertension and numerous other chronic diseases.

n this obese patient”), and concerns about adverse events (“I will not prescribe a sulfonylurea for this elderly patient who lives alone and had a severe hypoglycemic episode a few years ago”). This is becoming standard clinical procedure for diabetes, just as it is for hypertension and numerous other chronic diseases. The challenge is how to proceed in more complex situations. How, for example, would one select an appropriate pharmacological regimen for a 68-year-old man with diabetes of 14 years’ duration who has coronary disease, obstructive sleep apnea, prostate cancer, and a history of possible pancreatitis; who is obese and has edema but no heart failure; who smokes and has a family history of bladder cancer; who has high fasting blood glucose and A1C levels; and who has some renal dysfunction and poorly controlled lipids? With so many competing comorbidities, what are this individual's targets and treatment options? Ultimately, clinicians must develop highly personalized care regimens, and, in the absence of other conclusive evidence, “n of 1” trials may prove to be the best approach, providing strong evidence of therapy effectiveness and safety at the individual level and incorporating shared decision making with patients.

The challenge is how to proceed in more complex situations. How, for example, would one select an appropriate pharmacological regimen for a 68-year-old man with diabetes of 14 years’ duration who has coronary disease, obstructive sleep apnea, prostate cancer, and a history of possible pancreatitis; who is obese and has edema but no heart failure; who smokes and has a family history of bladder cancer; who has high fasting blood glucose and A1C levels; and who has some renal dysfunction and poorly controlled lipids? With so many competing comorbidities, what are this individual's targets and treatment options? Ultimately, clinicians must develop highly personalized care regimens, and, in the absence of other conclusive evidence, “n of 1” trials may prove to be the best approach, providing strong evidence of therapy effectiveness and safety at the individual level and incorporating shared decision making with patients. ARE ADEQUATE THERAPEUTIC TOOLS AVAILABLE NOW FOR PERSONALIZED DIABETES CARE? Multiple glucose-lowering medication classes: freedom or confusion? We now have numerous classes of antihyperglycemic therapies (Table 2) and more are expected to be licensed. Does this extensive arsenal provide us with more flexibility in designing personalized diabetes regimens, or does it make the task more difficult by multiplying the options? For specialists, the answer is no doubt the former. But for many primary care providers who must simultaneously stay abreast of developments in numerous fields of medicine, the expanding array of choices may, at times, seem intimidating.

etes regimens, or does it make the task more difficult by multiplying the options? For specialists, the answer is no doubt the former. But for many primary care providers who must simultaneously stay abreast of developments in numerous fields of medicine, the expanding array of choices may, at times, seem intimidating. Table 2 Classes of antihyperglycemic agents Recent meta-analyses have shown that there is not much difference among available therapies in glycemic control (e.g., A1C reduction and likelihood of achieving targets when adding an agent to metformin). However, when one considers other benefits, such as the risk of hypoglycemia and effects on body weight (63,64), there appears to be separation among the agents. In addition to these agents’ relative glycemic efficacy and effects on body weight and hypoglycemia, HCPs immersed in diabetes care must balance the potential benefits of each agent against concerns that have been raised regarding possible associations between various agents and the risk of developing other diseases (65–67). Difficulties in making benefit-risk judgments are further amplified by the fact that marketing may seek to create demand for drugs that is out of proportion to their efficacy. In addition, there remains a general lack of adequate comparative and exploratory controlled trials between the medications available, not to mention a lack of research into phenotype- and pathophysiology-based regimens.

act that marketing may seek to create demand for drugs that is out of proportion to their efficacy. In addition, there remains a general lack of adequate comparative and exploratory controlled trials between the medications available, not to mention a lack of research into phenotype- and pathophysiology-based regimens. Developing a straightforward algorithm that narrows the field of viable options will clearly require more evidence than is currently available. Without such evidence, we can offer only opinion, albeit opinion based on an understanding of pathophysiology, epidemiology, pharmacodynamics, toxicology, and costs. Unfortunately, the studies needed to make evidence-based treatment decisions—those that involve comparisons among multiple agents and are adequately powered for important, long-term clinical outcomes—have, for the most part, not been performed. The upcoming GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial will address some of these points (68). In addition, studies on how best to combine the various agents, as well as the optimal timing (early combination therapy vs. the traditional step-wise approach), are urgently needed.

coming GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial will address some of these points (68). In addition, studies on how best to combine the various agents, as well as the optimal timing (early combination therapy vs. the traditional step-wise approach), are urgently needed. Furthermore, even the most carefully considered set of guidelines is based on averages—average A1C-lowering effect, average efficacy, average risk of adverse effects—without adequate consideration of the confidence intervals around those averages. Averages fail to identify subpopulations that respond better and have better tolerance to specific agents, and without these data, evidence-based personalized advice cannot be provided. For now, all HCPs, whether in specialty or primary care settings, should test the efficacy and weigh the safety risks of any given drug in each patient, ideally trying options over a period of months to see how well they work at the individual level. How will new and emerging therapies enhance our ability to personalize care? To complicate future decision making, there are many new therapies in the research and development pipeline, including newer and longer-acting injectable incretin-based drugs, newer basal insulins, oral sodium-glucose cotransporter-2 (SGLT-2) inhibitors, agents targeting the various peroxisome proliferator–activated receptors, and free fatty acid receptor agonists.

many new therapies in the research and development pipeline, including newer and longer-acting injectable incretin-based drugs, newer basal insulins, oral sodium-glucose cotransporter-2 (SGLT-2) inhibitors, agents targeting the various peroxisome proliferator–activated receptors, and free fatty acid receptor agonists. It is hoped that pharmaceutical companies developing new glucose-lowering agents will focus on providing some added value beyond what is already available by addressing unmet clinical needs such as the effects leading to a reduction in CVD risk factors and meaningful cardiovascular and other outcomes. Arguably, we lack what we seek most in a diabetes treatment: definitive demonstration that an agent can safely lower A1C in a sustained and durable manner by definitively modifying disease progression, does so with minimal side effects (e.g., hypoglycemia), favorably improves CVD risk factors (e.g., weight, lipids, and blood pressure), and reduces cardiovascular and other morbidity and mortality.

ration that an agent can safely lower A1C in a sustained and durable manner by definitively modifying disease progression, does so with minimal side effects (e.g., hypoglycemia), favorably improves CVD risk factors (e.g., weight, lipids, and blood pressure), and reduces cardiovascular and other morbidity and mortality. As new drugs continue to be developed and submitted to regulatory agencies for approval, we should also consider the limitations of RCTs for informing a personalized approach to diabetes care (69,70). RCTs, at least as currently carried out, focus on selected populations and have restricted inclusion and exclusion criteria. They are generally of short duration, making it impossible to assess durability. They do not test individual responder rates and are not designed to identify responders who have a low safety risk. These trials are conducted in artificial environments, which pose problems for realistically measuring adherence. Finally, RCTs are not powered to assess subpopulations prospectively. Thus, efforts to personalize therapy are hindered by our reliance on trials that may be neither generalizable to the larger population nor individualized to specific patients. Moving forward, there may be other informative data from these trials, not from the average results, but rather from outliers—the results from subjects who respond very well or not at all.

As new drugs continue to be developed and submitted to regulatory agencies for approval, we should also consider the limitations of RCTs for informing a personalized approach to diabetes care (69,70). RCTs, at least as currently carried out, focus on selected populations and have restricted inclusion and exclusion criteria. They are generally of short duration, making it impossible to assess durability. They do not test individual responder rates and are not designed to identify responders who have a low safety risk. These trials are conducted in artificial environments, which pose problems for realistically measuring adherence. Finally, RCTs are not powered to assess subpopulations prospectively. Thus, efforts to personalize therapy are hindered by our reliance on trials that may be neither generalizable to the larger population nor individualized to specific patients. Moving forward, there may be other informative data from these trials, not from the average results, but rather from outliers—the results from subjects who respond very well or not at all. REGIONAL PERSPECTIVES ON PERSONALIZED MEDICINE The questions, concerns, and practical considerations discussed here pose difficult challenges for diabetes HCPs throughout the world. Because diabetes is a burgeoning pandemic, it behooves us to understand the issues from an international perspective.

Moving forward, there may be other informative data from these trials, not from the average results, but rather from outliers—the results from subjects who respond very well or not at all. REGIONAL PERSPECTIVES ON PERSONALIZED MEDICINE The questions, concerns, and practical considerations discussed here pose difficult challenges for diabetes HCPs throughout the world. Because diabetes is a burgeoning pandemic, it behooves us to understand the issues from an international perspective. The viewpoint that personalized diabetes care may be too complex to be implemented in many care settings is common in Europe, as it is in the United States and elsewhere. In Italy, for example, the Renal Insufficiency And Cardiovascular Events (RIACE) multicenter study, which included 15,773 patients with type 2 diabetes attending hospital-based diabetes clinics, showed that 40% of patients were taking metformin, 15% were managed through diet only, 24% were on insulin, 18% were taking sulfonylureas, and 3% were taking thiazolidinediones (71). Strikingly, this pattern did not change with age or with renal function, duration of disease, or other stratifying criteria.

tes clinics, showed that 40% of patients were taking metformin, 15% were managed through diet only, 24% were on insulin, 18% were taking sulfonylureas, and 3% were taking thiazolidinediones (71). Strikingly, this pattern did not change with age or with renal function, duration of disease, or other stratifying criteria. The story is much the same in other parts of the world, although patient characteristics differ. In China, key issues include rapid nutritional and lifestyle transitions, large patient populations, young age of onset, and heterogeneous phenotypes characterized by β-cell dysfunction, insulin resistance, and visceral obesity (72,73). High rates of kidney disease and diabetes-related cancer complicate diabetes care (72,74,75). All of these problems are compounded by a relative scarcity of research, low levels of awareness, an insufficient number of trained HCPs, and less-organized health care and financing systems.

nce, and visceral obesity (72,73). High rates of kidney disease and diabetes-related cancer complicate diabetes care (72,74,75). All of these problems are compounded by a relative scarcity of research, low levels of awareness, an insufficient number of trained HCPs, and less-organized health care and financing systems. Given the large population and finite resources, one may argue for using risk algorithms and biomarkers, including genetic variants, to identify high-risk subjects for early or intensified intervention, although the cost-effectiveness of such an approach will need to be formally tested. As elsewhere, patients with insulin-resistant features such as fatty liver, high triglycerides, and low HDL cholesterol may benefit from initial treatment with metformin, pioglitazone, and GLP-1 receptor agonists, whereas patients who are lean and face a long disease duration may benefit from dipeptidyl peptidase-4 (DPP-4) inhibitors or sulfonylureas with the early use of insulin. Other drugs such as α-glucosidase inhibitors and SGLT-2 inhibitors may help to lower A1C with a low risk of hypoglycemia and weight gain.

or agonists, whereas patients who are lean and face a long disease duration may benefit from dipeptidyl peptidase-4 (DPP-4) inhibitors or sulfonylureas with the early use of insulin. Other drugs such as α-glucosidase inhibitors and SGLT-2 inhibitors may help to lower A1C with a low risk of hypoglycemia and weight gain. Although these phenotype-based therapies have a theoretical basis, clinical practice studies are needed to confirm their cost-effectiveness. There is also a need to empower medical and nonmedical personnel (diabetes educators) in clinics to collect patient data on demographics, risk factors, complications, social habits, emotional needs, self-care behaviors, compliance, expectations, and values to enable HCPs to personalize treatment goals, self-management strategies, and therapy regimens (76). These personnel should monitor patients’ adherence to treatment, as well as their achievement of treatment goals.

complications, social habits, emotional needs, self-care behaviors, compliance, expectations, and values to enable HCPs to personalize treatment goals, self-management strategies, and therapy regimens (76). These personnel should monitor patients’ adherence to treatment, as well as their achievement of treatment goals. In the United States, attempts to implement a concept as expansive as personalized care quickly run up against two opposing traditions that permeate not only the field of medicine, but indeed the entire U.S. culture. The first, rooted in American industrialism, is standardization, exemplified by the processes of production line efficiency and continuous quality improvement. One recognizes this tradition in the vision of industrialist Henry J. Kaiser, who founded the prototype nonprofit health system Kaiser Permanente (77). The second tradition, embodied by the image of artist Norman Rockwell’s humble country doctor, is personalization. This is apparent in the teachings of Dr. Francis W. Peabody, whose seminal dissertation on patient care concluded, “The secret of care of the patient is caring for the patient,” (78) and in the work of Dr. Elliott P. Joslin, who wrote that “ . . . unless the physician takes care, he will fall into schematic ways and forget that it is the patient who comes for treatment and not the diabetes. Each is a case unto itself” (79).

cluded, “The secret of care of the patient is caring for the patient,” (78) and in the work of Dr. Elliott P. Joslin, who wrote that “ . . . unless the physician takes care, he will fall into schematic ways and forget that it is the patient who comes for treatment and not the diabetes. Each is a case unto itself” (79). Recent guidelines for diabetes care in the United States have fallen somewhere along a continuum between these traditions. The ADA Standards of Care (80) have sought to straddle the line, whereas the algorithm-based 2009 ADA/EASD consensus statement (2) leaned more toward standardization, and the 2012 ADA/EASD position statement (1) evolved more toward personalized care. ENHANCING PERSONALIZED CARE THROUGH COMANAGEMENT Research has yielded strong evidence in favor of fairly standardized treatment goals and an algorithmic initial therapy pathway involving lifestyle modification, metformin, and the eventual addition of other oral agents (sulfonylureas and basal insulin, in most cases). This approach allows many newly diagnosed patients to attain a reasonable blood glucose range and to maintain it for some period of time.

d an algorithmic initial therapy pathway involving lifestyle modification, metformin, and the eventual addition of other oral agents (sulfonylureas and basal insulin, in most cases). This approach allows many newly diagnosed patients to attain a reasonable blood glucose range and to maintain it for some period of time. However, there will always be patients for whom the standard A1C target is not appropriate (Fig. 1). Likewise, patients’ clinical circumstances often become more complicated over time, at which point the core treatment algorithm must give way to a more personalized approach. In such situations, the ideal course of action would be a patient-centered comanagement approach involving primary and specialty care providers as well as diabetes educators, dietitians, psychologists, and other HCPs as warranted by individual patient needs. Figure 2 depicts such an approach, which could be invoked by specific triggers such as failure to respond to treatment (14,81), failure to attain A1C targets, drug intolerances or contraindications, severe hypoglycemia, hyperglycemia during hospitalization, pregnancy, suspicion of unusual variants such as LADA, MODY, or secondary diabetes, heavy proteinuria with short disease duration in the absence of other microvascular complications, or other complicating circumstances. Figure 1 Personalizing A1C targets for individuals with type 2 diabetes.

However, there will always be patients for whom the standard A1C target is not appropriate (Fig. 1). Likewise, patients’ clinical circumstances often become more complicated over time, at which point the core treatment algorithm must give way to a more personalized approach. In such situations, the ideal course of action would be a patient-centered comanagement approach involving primary and specialty care providers as well as diabetes educators, dietitians, psychologists, and other HCPs as warranted by individual patient needs. Figure 2 depicts such an approach, which could be invoked by specific triggers such as failure to respond to treatment (14,81), failure to attain A1C targets, drug intolerances or contraindications, severe hypoglycemia, hyperglycemia during hospitalization, pregnancy, suspicion of unusual variants such as LADA, MODY, or secondary diabetes, heavy proteinuria with short disease duration in the absence of other microvascular complications, or other complicating circumstances. Figure 1 Personalizing A1C targets for individuals with type 2 diabetes. Figure 2 A comanagement approach to personalized therapy for type 2 diabetes. The majority of patient care occurs in primary care settings with concurrent comanagement in specialty settings as warranted for individual patients. In such a model, the patient remains at the center of care, comanaging HCPs all provide algorithmic or personalized care as warranted, and communication occurs among all parties.

rity of patient care occurs in primary care settings with concurrent comanagement in specialty settings as warranted for individual patients. In such a model, the patient remains at the center of care, comanaging HCPs all provide algorithmic or personalized care as warranted, and communication occurs among all parties. Regardless of the final form such a process takes, it seems clear that personalizing diabetes care will require improved cooperation and comanagement of patients among HCPs in various disciplines. In such a paradigm, algorithmic care would be both a useful starting place for most patients with type 2 diabetes and a framework on which to build more personalized therapy as needed. CONCLUSIONS Publication of the latest ADA/EASD position statement on type 2 diabetes management has generated strong interest in the concept of a personalized medical approach for individuals with diabetes (1). However, there are a multitude of pharmacological antihyperglycemic therapies now available, often with incomplete evidence concerning their long-term efficacy, effectiveness, tolerability, and safety. Accordingly, questions remain regarding the best ways to implement the recommendations of the position statement in the care of patients.

a multitude of pharmacological antihyperglycemic therapies now available, often with incomplete evidence concerning their long-term efficacy, effectiveness, tolerability, and safety. Accordingly, questions remain regarding the best ways to implement the recommendations of the position statement in the care of patients. Emerging research in genetics, pathophysiology, metabolomics, and human behavior, as well as longer-term, randomized comparative trials could eventually yield new information to inform the personalization of care. In the meantime, we must develop tools to translate existing guidelines into practical clinical applications, and, more importantly, to develop processes that encourage the organized comanagement of patients by primary care providers, specialists, educators, dietitians, and other diabetes HCPs as patients’ unique needs and risks require. Another consideration is how well the tools we develop can be implemented around the globe given the differences in pathophysiology among ethnic groups, country-specific resources and medical care infrastructure, training level of providers, and knowledge of patients. We hope these reflections have provided a broad overview of the evidence deficits and procedural challenges that will need to be overcome to ensure success in our efforts to implement effective, personalized therapy regimens for patients with type 2 diabetes. A slide set summarizing this article is available online.

Emerging research in genetics, pathophysiology, metabolomics, and human behavior, as well as longer-term, randomized comparative trials could eventually yield new information to inform the personalization of care. In the meantime, we must develop tools to translate existing guidelines into practical clinical applications, and, more importantly, to develop processes that encourage the organized comanagement of patients by primary care providers, specialists, educators, dietitians, and other diabetes HCPs as patients’ unique needs and risks require. Another consideration is how well the tools we develop can be implemented around the globe given the differences in pathophysiology among ethnic groups, country-specific resources and medical care infrastructure, training level of providers, and knowledge of patients. We hope these reflections have provided a broad overview of the evidence deficits and procedural challenges that will need to be overcome to ensure success in our efforts to implement effective, personalized therapy regimens for patients with type 2 diabetes. A slide set summarizing this article is available online. Acknowledgments I.R. has served on the advisory boards of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck (MSD), and Novo Nordisk; as a consultant for Andromeda, AstraZeneca/BMS, Eli Lilly, HealOr, Insuline, Johnson & Johnson, Teva, and TransPharma; and as a member of the speaker’s bureau for AstraZeneca, Eli Lilly, Johnson & Johnson, Novo Nordisk, and Roche.

ry boards of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck (MSD), and Novo Nordisk; as a consultant for Andromeda, AstraZeneca/BMS, Eli Lilly, HealOr, Insuline, Johnson & Johnson, Teva, and TransPharma; and as a member of the speaker’s bureau for AstraZeneca, Eli Lilly, Johnson & Johnson, Novo Nordisk, and Roche. M.C.R. has received honoraria for consulting and/or research grant support through his institution from Amylin, Elcelyx, Eli Lilly, Sanofi, and Valeritas; these potential conflicts of interest have been reviewed and managed by Oregon Health and Science University. J.R. has received grants or research support from Amylin, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Lexicon, MannKind, Merck, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda and has served on advisory boards for and received honoraria or consulting fees from Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Lexicon, MannKind, Novo Nordisk, Sanofi, and Takeda.

on & Johnson, Lexicon, MannKind, Merck, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda and has served on advisory boards for and received honoraria or consulting fees from Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Lexicon, MannKind, Novo Nordisk, Sanofi, and Takeda. J.B.B. is an investigator and/or consultant without direct financial benefit under contracts between his employer and the following companies: Abbott, Amylin, Andromeda, AstraZeneca, Bayhill Therapeutics, BD Research Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Catabasis, Cebix, Diartis, Elcelyx, Eli Lilly, Exsulin, Genentech, GI Dynamics, GlaxoSmithKline, Halozyme, Hoffman-La Roche, Johnson & Johnson, LipoScience, Medtronic, Merck, Metabolic Solutions Development Company, Metabolon, Novan, Novella, Novartis, Novo Nordisk, Orexigen, Osiris, Pfizer, Rhythm, Sanofi, Spherix, Takeda, Tolerex, TransPharma, Veritas, and Verva. S.E.I. has served as a consultant for Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, and Takeda. P.D.H. has received (or institutions with which he is associated have received) funding for his educational, advisory, and research activities from AstraZeneca/BMS Collaboration, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen/Johnson & Johnson, Merck (MSD), Merck Serono, Novo Nordisk, Roche Diagnostics, Roche Pharmaceuticals, Sanofi, and Takeda.

ith which he is associated have received) funding for his educational, advisory, and research activities from AstraZeneca/BMS Collaboration, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen/Johnson & Johnson, Merck (MSD), Merck Serono, Novo Nordisk, Roche Diagnostics, Roche Pharmaceuticals, Sanofi, and Takeda. S.D.P. has served as a consultant for AstraZeneca/BMS Collaboration, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Intarcia Therapeutics, Janssen/Johnson & Johnson, Merck (MSD), Merck Serono, Novartis, Novo Nordisk, Roche Pharmaceuticals, Sanofi, and Takeda and has received research support from Bristol-Myers Squibb, Merck (MSD), Novartis, Novo Nordisk, and Takeda. E.F. has received honoraria for consulting and/or research grant support from AstraZeneca/BMS Collaboration, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Halozyme Therapeutics, Janssen/Johnson & Johnson, Merck (MSD), and Sanofi.

S.D.P. has served as a consultant for AstraZeneca/BMS Collaboration, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Intarcia Therapeutics, Janssen/Johnson & Johnson, Merck (MSD), Merck Serono, Novartis, Novo Nordisk, Roche Pharmaceuticals, Sanofi, and Takeda and has received research support from Bristol-Myers Squibb, Merck (MSD), Novartis, Novo Nordisk, and Takeda. E.F. has received honoraria for consulting and/or research grant support from AstraZeneca/BMS Collaboration, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Halozyme Therapeutics, Janssen/Johnson & Johnson, Merck (MSD), and Sanofi. J.C.N.C. is a board member of the Asia Diabetes Foundation. She is a consultant for AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Merck (MSD), Pfizer, Qualigenics, and Sanofi. She has received honoraria, travel expenses, and/or payments for development of educational presentations from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Merck Serono, Merck (MSD), Nestle Nutrition Institute, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda. Her institution, the Chinese University of Hong Kong, has received research grants from pharmaceutical companies for conducting clinical trials of drugs for individuals with diabetes and associated conditions.

Kline, Merck Serono, Merck (MSD), Nestle Nutrition Institute, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda. Her institution, the Chinese University of Hong Kong, has received research grants from pharmaceutical companies for conducting clinical trials of drugs for individuals with diabetes and associated conditions. L.A.L. has received research funding from, has provided continuing medical education on behalf of, and/or has acted as a consultant to AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Roche, Sanofi, Servier, and Takeda. D.L. is a consultant for AstraZeneca, Bristol-Myers Squibb, Janssen, Merck, and Sanofi. R.D. serves on advisory boards or is a consultant for Amylin, Boehringer Ingelheim, Bristol-Myers Squibb, Lexicon, Novo Nordisk, and Takeda; receives grants from Amylin, Boehringer Ingelheim (pending), Bristol-Myers Squibb, and Takeda; and is a member of the speaker’s bureau for Novo Nordisk. W.T.C. has served as a consultant for AstraZeneca, Bristol-Myers Squibb, Halozyme Therapeutics, Intarcia Therapeutics, Johnson & Johnson, Lexicon, and Sanofi and has served as a principal investigator on research studies awarded to his institution from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Lexicon, and MannKind. Writing and editing support services for this article were provided by Debbie Kendall of Kendall Editorial in Richmond, Virginia.

W.T.C. has served as a consultant for AstraZeneca, Bristol-Myers Squibb, Halozyme Therapeutics, Intarcia Therapeutics, Johnson & Johnson, Lexicon, and Sanofi and has served as a principal investigator on research studies awarded to his institution from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Lexicon, and MannKind. Writing and editing support services for this article were provided by Debbie Kendall of Kendall Editorial in Richmond, Virginia. This article contains no data or data analysis and therefore there is no guarantor of these. All authors contributed to the thinking behind and the writing of the manuscript.