The high prevalence of diabetes and cardiovascular disease (CVD) has tasked the medical community to not only treat but to better identify people at risk for these diseases. Risk factors for diabetes had been identified more than 90 years ago, and the term metabolic syndrome emerged in the late 1970s.

 In the late 1980s, a potential link had been identified—insulin resistance, which itself has been strongly associated with obesity.

 On the other hand, some believe that insulin resistance contributes to the development of the risk  actors but is not the underlying cause.

 Identifying a cluster of predictive risk factors would enable healthcare providers to identify and  treat patients with metabolic syndrome, thus reducing the risk for a progression to diabetes, CVD, or both.

The Controversy: What Is Metabolic Syndrome, and Is It a Treatable Disorder?

Metabolic syndrome (sometimes referred to as “syndrome X” or “insulin-resistance syndrome”) is defined as a grouping of several related risk factors,

Merriam-Webster defines the term syndrome as “a group of signs and symptoms that occur together and characterize a particular  abnormality.”

 What is truly more important to the final objective of preventing diabetes and CVD—identification of the underlying mechanism(s) for the syndrome, or identification of the risk factors that occur together and usually lead to diabetes and CVD?

This question defines the debate within the healthcare community: Is metabolic syndrome a cluster of risk factors or a syndrome? Proponents for  characterizing metabolic syndrome as a syndrome believe that the evidence linking the risk factors with the development of diabetes and CVD supports the view that it is a treatable entity. Detractors believe that metabolic syndrome is really just a clustering of risk factors, without any known underlying mechanism  that associates the maladies. Confounding the discussion is whether metabolic syndrome is a pre-morbid condition—whether metabolic syndrome can only  be recognized before a patient is given a diagnosis of diabetes or CVD, thus excluding the population with these highly prevalent chronic conditions. On the other hand, an actual diagnosis of diabetes or CVD does not affect the underlying mechanism (eg, insulin resistance or some other factor still exists).

Regardless of whether  professional organizations are supporters or skeptical of metabolic syndrome, the medical community as a whole believes that additional research is needed to better understand its etiology.

In 2005, the American Diabetes Association and the European Association for the Study of Diabetes published a statement underscoring their concerns regarding metabolic syndrome.

 Their concerns included the value of including diabetes in the definition, whether the criteria have accurate thresholds and are completely explanatory, and the omission of other cardiovascular disease risk factors. They worried that if the cardiovascular risk for metabolic  syndrome is the same as the sum of the individual risk factors, treatment of the syndrome would be the same as the treatment for each of the respective risk  factors. Furthermore, these professional societies were not convinced that insulin resistance is the unifying mechanism and whether there is overall value in  diagnosing the syndrome.

Yet, 2 American professional organizations and several international societies generally agree on the risk factors that should be included in the definition of  metabolic syndrome. Until this time, there were several different criteria discussed for metabolic syndrome, most notably from the World Health Organization, the National Cholesterol Education Program Adult Treatment Panel III, the International Diabetes Foundation, and the American Heart Association/National Heart, Lung, and Blood Institute. These organizations agreed on the risk factors that should be included in a definition of metabolic syndrome; however, they differed on the definition of the components and the number of risk factors that needed to be present to constitute the diagnosis. Members from these  organizations came together in 2009 to meld together consistent criteria for metabolic syndrome.

 Most disagreement involved whether body mass index or  waist circumference should be used as the indicator for central obesity. They concluded that waist circumference was a useful screening tool and should  correlate with specific country or population demographics, and that further research was required.

This coalition of professional societies did agree that having 3 of the abnormal findings from the cluster of 5 maladies would constitute a diagnosis of  metabolic syndrome (

). They also agreed that people with any of the identified risk factors usually also present with a prothrombotic and proinflammatory state.

Obesity and physical inactivity have been found to be important contributors to metabolic syndrome.

Other contributing factors include genetic and racial composition, aging, and the presence of other endocrine disorders. Patients with metabolic syndrome are usually susiceptible to additional problems as well, some that may be associated with its individual component risk factors:

Assuming one accepts the definition of metabolic syndrome, it is unsurprising that its prevalence has increased over  time, perhaps reflecting the obesity  epidemic and predictions of greater incidence of diabetes.

 An analysis of the 2003 to 2006 National Health and Nutrition Examination Survey revealed  that, based on a waist circumference threshold of ≥102 cm for men and ≥88 cm for  women, the age-adjusted prevalence of metabolic syndrome in American adults was 34.3% (36.1% for men; 32.4% for women). This percentage increased to 38.5% for all adults when racial- or ethnic-specific criteria were used (41.9% for men; 35.0% for women). The prevalence increases with age, peaking in the 60- to 69-years group, which parallels a correlation with weight gain  with increasing age. Caucasian and Mexican-American men had a higher prevalence of metabolic syndrome than African American men, whereas the  prevalence for women was lower among Caucasian women than for African American or Mexican American women.

Among the risk factors, abdominal obesity is observed in the majority (53.6% total [45.8% men; 61.2% women]) of the population with metabolic syndrome. The other risk factor components in the total population are, in descending order of prevalence, hyperglycemia, high triglyceride levels, elevated blood  pressure, and low concentrations of high-density lipoprotein cholesterol.

Although each of the components of metabolic syndrome increases the risk for CVD, the combination of the risk factors appears to increase it substantially. The presence of metabolic syndrome is associated with a 2-fold increased risk for CVD (and a 5-fold greater risk for the development of type 2 diabetes).

  Traditional risk algorithms for CVD, such as the Framingham Risk Score, may be more accurate in risk prediction.

The Cost Implications of Metabolic Disease for Payers

Unsurprisingly, patients diagnosed with metabolic disease can be expected to utilize more health resources than those individuals without it. A study of  patients in 3 health plans confirmed this statement—members meeting at least 3 criteria for metabolic syndrome had 60% higher annual costs compared with patients without metabolic syndrome ($5732 vs $3581, respectively), and these costs increased incrementally by 24% when they met 4 or more risk  factors.

 When patients progressed to a diagnosis of diabetes, the healthcare costs were higher in patients with diabetes and metabolic syndrome than in  those patients with diabetes without metabolic syndrome ($7896 vs $6038, respectively). Patients with diabetes do not necessarily meet all of the criteria  required to be considered to have metabolic syndrome.

Similar results were seen in a health plan that assessed the direct medical costs associated with patients who were overweight, obese, or met risk criteria for  metabolic syndrome using a cost model.

 Comparing patients who were overweight or obese with those who were not, direct costs were $4563 versus $4015, respectively. The highest annual costs (>$5000) were in the patients with risk factors meeting the requirements of metabolic syndrome. This cost was  $2061 higher than in those without the risk factors for metabolic syndrome.

 Both of the above studies support the hypothesis that there are increased costs associated with patients meeting the risk factor criteria for metabolic syndrome.

However, another study of health plan members concluded that the higher costs were associated with the individual risk factors rather than with a clustering of the risk factors. In this analysis, 5 years of health data were evaluated for adults with metabolic syndrome risk factors  and their impact on direct medical costs. They compared total annualized direct costs for all possible combinations of the metabolic syndrome risk components.Every risk factor except for impaired fasting glucose led to increased annual medical costs; however, the higher costs were independent of the other risk factors. The presence of each of the risk  factors was associated with higher future medical costs, which were mostly attributable to the development of diabetes or the need for hospitalization due to  cardiovascular disease.

Current Approaches to Managing Metabolic Syndrome

Currently, there is no 1 specific treatment for treating patients meeting thecriteria for metabolic syndrome. Rather, lifestyle modification and weight  reduction, along with drug therapy for the respective risk factors (eg, hypertension, dyslipidemia, hyperglycemia, and weight reduction) are employed.  Pharmaceutical companies have found it challenging to develop medications, as they would need to address multiple aspects of metabolic syndrome in  order to be approved for the indication.

 As a result, clinicians utilize available tools to address these risk factors (and usually, on an individual basis).

From  the clinical and public health standpoint, however, the need for better tools to prevent and manage metabolic syndrome is urgent (

 Until an  underlying mechanism is positively identified (or insulin resistance is finally recognized as the “smoking gun”), medications will be utilized that address the  respective components of metabolic syndrome.

Patient Management and Metabolic Syndrome

The most important benefit of using the term metabolic syndrome appears to be that it focuses attention on an important clustering of health problems. Each of the criteria, as well as the clustering of the criteria, increase the risk for future disease. Lifestyle modifications can address each of the criteria for metabolic syndrome; however, each component requires separate, focused treatment.

Use of the term metabolic syndrome has been educational for both healthcare professionals and patients.

 It has provided an easily understandable public health message, raised awareness of risk factor clustering as well as the need to identify additional risk factors among healthcare providers, and been an  impetus for healthcare professionals to look beyond only diagnosed diabetes and cardiovascular disease to risk factors that progress to these diseases.

Finally, additional research should be conducted to fully understand and appreciate the clustering of risk factors identified as metabolic syndrome. Further investigation will be required to better understand if there is underlying  cause, such as a genetic defect. Finding an underlying mechanism would help settle  the controversy as to whether the syndrome is a treatable entity or metabolic syndrome is just a clustering of risk factors. Until that time, educational  endeavors need to continue to identify and reduce the modifiable risk factors for diabetes and CVD. Population-based strategies need to be further  developed and implemented because of the importance of these diseases.

Professional organizations and government agencies are not currently in agreement about whether metabolic syndrome is clinically relevant in predicting the development of diabetes or CVD. Fundamentally, there is disagreement whether metabolic syndrome even fits the criteria of a treatable entity. We do  know that the individual risk factors play an integral role in the development and advancement of these 2 important diseases. Until additional information is  available regarding the potential underlying mechanism of this syndrome, healthcare professionals need to address the rising incidence of obesity and a  sedentary lifestyle that are major contributors to the development of diabetes and heart disease. 

EBDM: The term “metabolic syndrome” is fairly controversial. What’s your view on whether this classification is practical as a disease or entity? 

 I believe it’s a legitimate entity. The guidelines issued jointly from the American Heart Association (AHA) and the National Heart, Lung, and Blood  Institute (NHLBI) in 20051 were a scientific, evidence-based approach to this multiple risk factor complex. It arises from a combination of insulin resistance,  abdominal obesity (abnormal fat disposition), dyslipidemia (high triglycerides and low high-density lipoprotein cholesterol levels), and high blood pressure. The science definitely supports the connection of metabolic disease to coronary heart disease and type 2 diabetes mellitus. According to these guidelines, if  you have at least 3 of the 5 risk factors, you’re at greater risk for these clinical consequences,

I know it’s controversial, but where  there is some predictive value behind it, in terms of diabetes and cardiovascular events, I agree with it.

Articles

Evidence-Based Diabetes Management

The Controversial Question of Metabolic Syndrome

Diabetes, a progressive disease of the endocrine system with a significant economic burden, is estimated to affect more than 371 million people worldwide   and over 24 million Americans in 2012. In 2011, 4.6 million deaths could be attributed to diabetes, and diabetes healthcare expenditures, including costs to the healthcare system and the patient, were at least 465 billion US dollars, of which 11% of total healthcare expenditures were from adults aged 20 to 79 years, and 75% of that cost was spent on those aged 50 to 79 years.

Current American Diabetes Association (ADA) Standards of Care recommend metformin for pharmacologic management of type 2 diabetes mellitus (T2DM),  if no contraindications are present, at the time of diagnosis. If therapeutic goals are not met with monotherapy at maximal doses, a second oral agent, such  as a glucagon-like peptide-1 (GLP-1) agonist or insulin, are recommended for addition. For patients who are newly diagnosed, markedly symptomatic upon diagnosis, and/or have markedly elevated blood glucose or glycated hemoglobin (A1C) levels, initial pharmacologic therapy with insulin should be considered, with or without the addition of other agents.

The current classes of medications that are available to treat T2DM include biguanides, sulfonylureas, meglitinides, thiazolidinediones (TZDs), alpha glucosidase inhibitors, dipeptidyl peptidase-IV (DPP-4) inhibitors, GLP-1 agonists, bile acid sequestrants, dopamine-2 agonists, and insulin. Although these agents are effective initially, glucose-lowering effects are not typically sustained long term as beta cell dysfunction progresses. Therefore, newer agents that are able to lower glucose long term without causing hypoglycemia, delay decline in beta cell dysfunction, assist with weight loss, and have beneficial effects on  cardiovascular disease need to be developed. It is important to acknowledge that, in addition to the aforementioned therapeutic effects, adverse effects must be  minimized. 

 Several new classes of medications are currently in development, as well as a new long-acting insulin.

Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2)

SGLT-2, a low-affinity but high-capacity transporter found in the brush border of the proximal tubule, is a mediator of glucose reabsorption in the kidneys.  The kidneys contribute to glucose homeostasis via renal gluconeogenesis, glucose utilization, and reabsorption from glomerular filtration.

 Data suggest  that renal gluconeogenesis, renal glucose uptake, and renal glucose reabsorption are all increased in patients with T2DM due to the upregulation of  SGLT-2.

 In essence, SGLT-2 inhibitors exert their effects by causing the kidneys to excrete glucose into the urine. The effects are also independent of  insulin secretion. These proposed mechanisms make SGLT-2 a viable target to help combat hyperglycemia in patients with T2DM. A review of the literature,  conducted through a PubMed search of SGLT-2 inhibitors through April 2012, found that these agents decreased A1C anywhere from 0.5 to 1.5%, promoted  weight loss, and demonstrated low incidences of hypoglycemia. Incidence of adverse effects with these agents has been low with no severe episodes of hypoglycemia documented. The most common adverse effects reported with these agents were urinary tract infections (UTIs) and/or genital tract infections.

Dapagliflozin, a first-in-class SGLT-2 inhibitor, has been studied the most extensively. In a small study that evaluated 5 doses of dapagliflozin (2.5, 5, 10, 20,  or 50 mg), extended-release metformin (titrated to 1500 mg), and placebo in drug-naïve patients with T2DM, dapagliflozin demonstrated statistically significant reductions in A1C of 0.55% to 0.9% over 12 weeks when compared with a decrease of 0.18% with placebo. A reduction of 0.73% was noted with patients taking metformin. Additionally, weight loss of 1.3 kg to 2 kg was observed in study participants.7 Patients with T2DM who were inadequately  controlled on metformin were evaluated in a phase 3, double-blind, placebo-controlled randomized controlled trial (RCT). Patients received metformin plus  once-daily dapagliflozin 2.5, 5, or 10 mg, or matching placebo. Statistically significant decreases in mean A1C from baseline at 24 weeks were observed  when dapagliflozin was compared with placebo (2.5 mg: −0.67%, 5 mg: −0.7%, 10 mg: −0.84%, placebo: —0.3%). Weight loss was also seen in the  dapagliflozin groups. Dapagliflozin was well tolerated; however, more genital infections were seen in patients receiving dapagliflozin.

 A more recently  published study shared results of the effects of dapagliflozin in patients not controlled with the TZD pioglitazone. Patients were randomized to receive open-label pioglitazone plus either 5 mg or 10 mg of dapagliflozin for 48 weeks after a 10-week dose optimization phase with pioglitazone. Statistically significant reductions in A1C were seen after 24 weeks with both 5- and 10-mg strengths (5 mg: —0.82%, 10 mg: –0.97%, pioglitazone monotherapy: 0.48%), and these reductions were maintained through week 48. The decrease in A1C at 48 weeks was greater with each group: 0.95%, 1.21%, and 0.54%, respectively. Dapagliflozin also decreased the effect of pioglitazone-associated weight gain and edema. Overall, dapagliflozin was well tolerated; however,  the incidence of genital infections was increased compared with placebo.

 A total of 800 patients with T2DM who were inadequately controlled on 30 units  or more of insulin were evaluated in a double-blind, placebo-controlled RCT that investigated the effects of 24 weeks of dapagliflozin or placebo on A1C.  Patients may have been also taking up to 2 oral antidiabetic agents. Patients were randomized to receive 2.5, 5, or 10 mg of dapagliflozin or placebo in addition to their usual insulin dose and oral agents. At 24 weeks, patients receiving dapagliflozin experienced statistically significant decreases in A1C (2.5 mg: —0.79%, 5 mg: –0.89%, 10 mg: –0.96%) compared with placebo (–0.39%). A secondary outcome was to evaluate the change in A1C at week 48.  Statistically significant decreases in A1C were maintained (2.5 mg: –0.79%, 5 mg: –0.96%, 10 mg: –1.01%). Over 48 weeks, increases in mean insulin doses increased with time in patients of the placebo group (10.54 units) but not with dapagliflozin therapy. Decreases in body weight were observed in patients  taking dapagliflozin, but increased with the placebo. Rates of hypoglycemic episodes, genital infection, and UTIs were higher in patients taking dapagliflozin.

 Despite the positive effects on A1C, dapagliflozin has not been approved by the US Food and Drug Administration (FDA) due to concerns of a potential link to breast and bladder cancers.

 SGLT-2 is not thought to be expressed in either bladder or breast tissue, and therefore the mechanism of  SGLT-2 inhibitors should not have a link to breast and bladder cancer risk; however, long-term surveillance is needed to exclude the association.

 Proposed explanations for the increased incidence include the use of more urinalyses due to the increased incidence of UTIs, which may have led to earlier findings of  hematuria or other abnormalities that are suggestive of bladder cancer. As far as the breast cancer incidences, breast masses may have been more easily   identified after weight loss occurred in patients taking dapafliglozin.

 The co-developers of dapagliflozin remain devoted to the development of the SGLT-2  inhibitor and will provide additional information as requested by the FDA.

Canagliflozin is another SGLT-2 inhibitor currently in phase III development. A dose-ranging, double-blind RCT of canagliflozin added to metformin therapy demonstrated A1C reduction over a 12-week period. Canagliflozin therapy (50, 100, 200, or 300 mg once daily or 300 mg twice daily) was compared with the DPP-4 inhibitor, sitagliptin, which was used as an active reference treatment   group, or placebo. A1C reduction with canagliflozin was noted with all doses investigated; however, the largest reductions were seen with 300 mg daily  (—0.92%) and 300 mg twice daily (–0.95%) versus with placebo (–0.22%). A weight loss of 2 kg to 2.9 kg was noted with canagliflozin compared with 0.8 kg with placebo and 0.4 kg with sitagliptin. Canagliflozin was well tolerated; however, females experienced an increased frequency of genital infections, including vulvovaginal mycotic infections and candidiasis, which responded to standard antifungal treatment and did not lead to patients discontinuing the study. It is thought that this increase in mycotic genital infections is due to the increased urinary excretion of glucose that occurs with SGLT-2 inhibitors, thus leading to increased colonization with 

A third SGLT-2 inhibitor in phase III development is empagliflozin. Empagliflozin demonstrated A1C lowering and improvements in glucose tolerance in  animal studies, and had the highest selectivity of the SGLT-2 receptors compared with dapagliflozin, canagliflozin, and other SGLT-2 inhibitors.

Data from pooled phase IIb studies demonstrating that empagliflozin lowers A1C, weight, and systolic blood pressure were presented at the 48th European  Association for the Study of Diabetes annual meeting.

 A phase III clinical program is currently ongoing, which includes 10 phase III studies with a goal of  enrolling over 14,500 patients. In addition to studies that are evaluating effects on glucose and weight, a large cardiovascular outcome trial will be  included.

LY2605541 is a long-acting basal insulin analogue that is currently being evaluated in phase III studies in T2DM patients.

Insulin lispro is modified with a  20 kDa polyethylene glycol moiety that results in a molecule with large hydronamic size. The proposed effects of this larger molecule are a delay in insulin absorption and reduced clearance, thus leading to a longer duration of action.

 Additionally, transport may be greater into the liver relative to muscle and fat tissues, which may result in more hepatic action.

The results of an RCT phase II study that compared LY2605541 with insulin glargine, an  FDA-approved basal insulin, demonstrated that after 12 weeks of treatment, fasting blood glucose levels were similar. Investigators also noticed reduced  weight loss and less nocturnal hypoglycemia with LY2605541. Three phase III trials are ongoing and are currently investigating T2DM patients using  LY2605541. IMAGINE 2 compares the use of LY2605541 with insulin glargine over 52 weeks. This study, which is longer than previously published studies, will evaluate the changes in A1C from baseline to 52 weeks. Additionally, other secondary outcomes, which include nocturnal  hypoglycemia events, weight, and liver transaminases, will be evaluated.

 Another phase III study, IMAGINE 4, will compare the effects of LY2605541 with insulin glargine on A1C after  26 weeks in patients also receiving patient-specific preprandial and supplemental doses of the rapid-acting insulin analogue, insulin lispro.

 The third  actively recruiting study is IMAGINE 5, which may last up to 52 weeks. The primary objective of this study is to examine the changes in A1C over 26 weeks.  LY2605541 compared with insulin glargine alone or in combination with up to 3 pre-study oral antihyperglycemia medications will be evaluated.

11-β-hydroxysteroid dehydrogenase type 1 (11-β-HSD1)

The glucocorticoid, cortisol, serves several biological purposes which include the stimulation of gluconeogenesis in the liver and hindering insulin-mediated glucose uptake into adipose and muscle tissues.

 Studies have demonstrated that 11-β-HSD1 is a catalyst capable of reactivating inert cortisone into cortisol within non-adrenal tissue, including adipose and liver tissues. Preclinical evidence indicates that 11-β-HSD1 has a function in both obesity and  metabolic disease in rodents, which suggests that inhibiting this catalyst in liver and adipose tissues may lead to enhanced hepatic and peripheral insulin  sensitivity, thus improving overall glucose levels and possibly decreasing overall macrovascular risk.

 A 12-week, randomized, double-blind, placebo-controlled study evaluated the 11-β-HSD1 inhibitor, INCB13739, in patients with T2DM receiving a mean dose of 1.5 g per day of metformin. Investigators  demonstrated a dose-dependent reduction in A1C, the primary objective, in patients receiving INCB13739 plus metformin versus metformin alone. A1C  reduction was greatest among patients receiving 200 mg daily (the maximum dose in the study) and in those with a body mass index over 30 kg/m2. INCB13739 was well tolerated with no drug-related serious adverse effects or hypoglycemic episodes occurring during the treatment phase.

Glucokinase plays a role in glucose metabolism and adenosine triphosphate (ATP) production via glucose phosphorylation. The production of ATP has an effect on insulin secretion by closing potassium-ATP channels, thus triggering calcium ion channels to open, thereby activating calciumdependent enzymes  hat control the release of insulin. The development of glucokinase activators has provided another pharmacologic mechanism to increase insulin secretion  and decrease glucose secretion by enhancing the effects of glucokinase in beta cells. It is also thought that these agents have a secondary mechanism which  decreases hepatic glucose metabolism, further decreasing glucose concentration. Unfortunately, these agents do have adverse effects. Incidences of  increased triglyceride levels and hypoglycemia have been associated with the glucokinase activators.

LY2599506, a glucokinase activator 1, was  nvestigated in a phase II study; however, the study was terminated after enrolling 38 patients, due to non-clinical safety effects. The non-clinical safety effects were not identified.

Incretins are intestinal factors that are released in response to nutrients, contributing to blood glucose lowering. Incretin mimetics, such as exenatide and  liraglutide, along with DPP-4 inhibitors, are currently available to treat patients with T2DM by addressing decreased concentrations of GLP-1. Aless-well-known incretin is glucosedependent insulinotropic peptide, or GIP. Currently in development, glucagon receptor antagonists (GRAs) belong to a new  class of oral drugs that block the actions of GIP. In animal models, this blockade results in increasing energyless-well-known incretin is glucosedependent insulinotropic peptide, or GIP. Currently in development, glucagon receptor antagonists (GRAs) belong to a  new class of oral drugs that block the actions of GIP. In animal models, this blockade results in increasing energy expenditure, as well as reduced fat deposition and lipotoxicity.

 Investigators have  identified MK-0893, a potent, selective, small-molecule GRA (which is a reversible and competitive agonist) with high binding affinity.

 MK-0893 demonstrated 24-hour weighted mean glucose lowering effects similar to those seen with the combination of sitagliptin and metformin.

 In this phase II study that evaluated MK-0893 with 2000 mg metformin daily, MK-0893 with sitagliptin 100 mg daily, or 100 mg sitagliptin plus 2000 mg metformin daily, MK-0893 plus sitagliptin was statistically less effective than the sitagliptin/metformin combination.

 LY2409021, a potent and selective GRA, has been evaluated in phase I and II studies.

The results of a phase I, first-in-man study resulted in clinically significant glucose lowering without incidences of  hypoglycemia or changes in laboratory tests, vital signs, or electrocardiograms.

 Although both GRAs have been well tolerated, concerns about increased  liver transaminases have arisen. A study evaluating the effects of LY2409021 on the liver is currently recruiting.

Several other agents are being investigated for the management of T2DM. Glycogen phosphorylase is a catalyst for glycogenolysis, which increases glucose  output from the liver. In a preclinical study, a glycogen phosphorylase inhibitor, CP-316819, prevented hyperglycemia after a glucagon challenge.

 Protein  tyrosine phosphatase 1B inhibitors enhance the effects of insulinby decreasing dephosphorylation of the β-subunit of insulin receptors, thus extending  phosphorylation after insulin binding. In hyperglycemic animal models, protein tyrosine phosphatase 1B inhibitors reduce blood glucose levels, and may  also improve weight loss and endothelial function.

 In patients with T2DM, one consideration in postprandial hyperglycemia is the reduction of glucose- stimulated insulin secretion (GSIS). Activation of G protein—coupled receptor (GPR) 119, which is primarily expressed in pancreatic β-cells and intestinal  L-cells, leads to insulin and GLP-1 release. A preclinical study demonstrated that AS1535907, a GPR119 agonist, stimulated the first phase of GSIS, resulting in an insulin release which was greater than that seen with the comparator sulfunoylurea.

 Another study demonstrated that, in vitro, AS1535907  howed selective agonist activity for human GPR119 and could activate human insulin promoter. The study also demonstrated A1C-lowering effects in  diabetic animal models.

GPR119 agonists currently in development include MBX-2982 and GSK-1292263.

Diabetes has profound effects on the economic burden of both patients and healthcare system. While new pipeline agents are currently in development, the cost-benefit analysis must be scrutinized in the presence of often less-expensive standards of care. Several novel agents have shown promise in the treatment  of T2DM; however, it is too soon to determine their clinical and financial impacts. It is unclear if these agents will be used in combination with  current therapies or primarily as first-line agents, but the ability of some of these drugs to mitigate weight gain suggests that they may have a role in both.  Further, if ongoing studies validate the additive benefits seen with reducing macrovascular complications and blood pressure, there is a greater opportunity  to influence current prescribing patterns. However, in the absence of long-term studies, caution should be exercised when considering a change from current  therapies. Adverse effects of the new medication classes may limit their utility. That being said, when the costs of the drugs are known, these newer agents should be watched closely by benefit managers to evaluate the impact on total costs of care, as the benefit may outweigh the increased medication costs. Overall, the emphasis in the treatment of T2DM should still remain heavily on lifestyle modifications in conjunction with the use of evidencebased practice guidelines. 

 From the University of Louisiana at Monroe College of Pharmacy—Baton Rouge Campus, Baton Rouge, LA.

The author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

 Brice Labruzzo Mohundro, PharmD, BCACP, University of Louisiana at Monroe College of Pharmacy—Baton Rouge Campus, 3849N Boulevard, Baton Rouge, LA 70806. E-mail: labruzzo@ulm.edu.

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Benefits May Outweigh Increase to Costs of Care

New Developments in the Treatment of Type 2 Diabetes Mellitus

Diabetes mellitus is a condition first recognized 3500 years ago in ancient Egypt and named 2000 years ago by a Greek, Aretaeus. It is characterized by hyperglycemia resulting from the body’s inability to appropriately metabolize glucose into energy.

 In 2008, the Centers for Disease Control and Prevention estimated that 23.6 million Americans, or 7.8% of the population, had diabetes and another 57 million had prediabetes.

 By 2010, that number had increased to 25.6 million Americans (8.3% of the population) with diabetes.

 Those numbers represent increases of at least 50% in 42 states and 100% in 18 states.

 And, the prevalence of diabetes will continue to get worse. Within the next 25 years, the number of individuals with diabetes is expected to increase to more than 44 million individuals and, as Huang et al

 note, “without significant changes in public or private strategies, this population and cost growth are expected to add a significant strain to an overburdened healthcare system.”

“Private strategies” employed by payers who either assume full risk or manage risk on behalf of government/others certainly have and will continue to play a role in addressing the needs of the diabetic population when it comes to our “overburdened healthcare system.” In fact, with the anticipated millions of newly insured achieving coverage through health insurance exchanges by January 1, 2014, payers will need to develop and promote changes in how they manage the diabetes benefit—the tactics of the past 2 decades will, by necessity and by practicality, yield to newer methods of cost control through promoting member health improvement. As the great Bob Dylan sang long ago, “For the times, they are a-changin’.”

The Evolution of Payer Strategies for Diabetes

When it comes to addressing any benefit, let alone the benefits specific for members with diabetes, payers utilize multiple methods for “management.” Each management method addresses a different stakeholder who is impacted by how the payer manages the diabetes benefit leading to a specific end product of said strategy. These payer strategies used to manage the needs of members with diabetes are not only applicable to other chronic conditions besides diabetes but are also currently in various states of flux as they evolve from where they are to where they need to be. The Table assists in showing the necessary evolution.

When it comes to how payers manage the needs of members with diabetes, the current state leaves much to be desired. Typically, most payers, to analogize the Donabedian model of quality assessment, have set into place a structure whereby a simple process exists for the member with diabetes to obtain his or her medication—the physician writes a prescription for the requisite drug and the pharmacy charges that patient a portion of the medication cost as either a copayment or coinsurance. Despite the plethora of studies that have shown that there is benefit to the member’s health when a so-called value-based benefit design (VBBD) is introduced, the great majority of payers have yet to fully embrace such a model in its complete incarnation&mdash;a recent survey showed that only 20% to 30% of large employers utilize some form of VBBD.

However, with payers adopting new philosophies with respect to improving the health of members with diabetes, VBBD may still have not maximized its full potential.

The basic premise for a VBBD program is to reduce member cost sharing for services, such as medications or preventive eye examinations, in which the affected outcome of said services (eg, promoting medication adherence or diagnosing diabetic retinopathy early) provide clinically relevant health benefits. Such benefits have accrued from limiting the costly implications for members seeking this care.

 As payers promote VBBD programs for diabetes (or for other chronic conditions), their management of the condition in question evolves into one where, rather than focusing on mere process, the payers now focus on the outcomes of the process in question. Outcomes of care are where “the rubber meets the road,” as it is this end product that determines member health and, as a consequence of member health, potential payer remuneration in the form of bonuses.

 Given the number of members with diabetes and the dollars involved, it shouldn’t be a big surprise that payer strategies for managing the diabetes benefit should include some form of VBBD.

An alternative method of managing a member’s diabetes benefit, while less transparent to the member, is quite efficient. Payers manage the diabetes benefit through the physician caring for that member. Such management falls under the rubric of utilization management. For the physician caring for a patient with diabetes, this means managing of the member’s utilization addresses 2 key factors—first, it ensures that the member receives the appropriate medication or other service needed to address the diabetes and, second, it discourages the wasting of dollars on unnecessary or inefficient care. Physicians are quite aware of this technique of “prior authorization” and, while they may not like it, they work within the prescribed parameters. Typically, a payer’s prior authorization approvals follow and support clinical practice guidelines of key constituencies (eg, the American Diabetes Association or the American Academy of Clinical Endocrinologists). Physicians, even while tending to dislike these practices, still managed to increase their share of, for example, drug formulary use such that their use of specific medications became non-managed.

 Changes to this area require payers to “manage the physician” less than they had been. This shift coincides well with payers’ continuing evolution in diabetes benefit management. This shift also entails a change from a utilization management strategy toward one of quality management. For the purposes of benefit management, payers choose to focus more on improving the quality of care that physicians provide, and are doing so through incentives promoting good care. Examples that specifically address the diabetes realm include the creation of a patient-centered medical home for patients with diabetes as part of a pay for performance program in which objective improvements in a patient correlate with improved health.

 Given that early returns from medical home initiatives show promise, this type of diabetes benefit management may be expected to increase or, better yet, to enlarge in scope through aligning a broader network of participants.

As payers align diabetes care management strategies for both patients, through VBBD, and physicians, through financial incentives, the next logical step is broadening the impact of diabetes management. Currently, payers manage their diabetic members’ services at hospitals or other large entities contractually. Many payers look merely at the services provided, such as hospitalizations, bundle them together under a contractual diagnosis-related group payment, and adjudicate the claim. Payments of this type led to payer-provider negotiations where victory was “all about cost” and dollars. However, as payers develop newer strategies, as noted above, the next logical step aligns larger entities together. Following the recommendations of Fisher et al,

 payers began to explore and have now contracted with accountable care organizations (ACOs). ACOs are accountable to payers for the overall cost and quality of care provided to, for our purposes, a population of individuals with diabetes. ACOs should not be viewed as a method for payers to manage the diabetes benefit per se, as their specific function involves redesigning healthcare delivery to result in more units of health, defined as total benefit, per unit of cost. In that way, ACOs are “all about value.” For example, as more people with diabetes are better cared for and experience fewer readmissions, then the ACO physician members would share in the savings accrued from this endeavor. ACOs become a natural and logical extension of paying for outcomes on a grand scale.

As discussed earlier in this article, diabetes is and will continue to be a national problem. However, this national problem trickles down to a community level. In that respect, as they address the full ramifications of diabetes with their individual members, their contracted physicians, and with ACOs, payers are also changing how they are working with the communities in which they operate. More recently, payers defined their community contributions through their public relations departments—a payer’s effectiveness resulted from their CAHPS (Consumer Assessment of Healthcare Providers and Systems) results or if they had fewer complaints filed against them with the Department of Insurance. Payers looked at their claims data historically and descriptively. But this, too, is changing. Following the proposals of Sinek,

 payers are also moving away from explaining what they do to promoting why they do it. Payers know that addressing the diabetes epidemic requires engaging more than their individual members and the physicians or organizations providing care for them— making a difference in diabetes requires community engagement and community engagement requires data mining and predictive analytics. Payers already know who their members with diabetes are; now they need to identify which of these members will experience a myocardial infarction or a stroke or who is less likely to comply with a given medication regimen. The ability to leverage “big data” from the claims they have allows payers to promote healthier communities in concert with how they are managing the diabetes benefit in other ways. These changes are already evident, with one national payer defining itself through its “expertise in health benefits solutions and health information technology,”

 whereas another one defines itself as committed to “improving the health and well-being of our members, our associates, the communities we serve, and our planet.”

Just as there are many ways to treat a condition such as diabetes, there are also many ways for payers to manage the diabetes benefit. Although none of these methods is specifically right or wrong, they are grounded in a payer’s philosophy and created in response to the needs of the time. Yet, just as in any other business, new ideas and, for diabetes, new scientific discoveries will surely mandate new strategies to achieve goals. As payers find themselves adapting to new political realities and new partnerships, one cannot be sure if their new strategies will succeed or not. But, in actuality, this becomes moot as the 1 point we can be sure of is that benefit management will continue to evolve.

Dr Tzeel reports employment with Humana Inc, as well as stock ownership. He also reports receiving consulting fees from Amylin Pharmaceuticals.

 Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and administrative, technical, or logistic support.

 Albert Tzeel, MD, MHSA, FACPE, National Medical Director, HumanaOne & KMG, Clinical Leadership & Policy Development, Humana, N19 W24133 Riverwood Dr, Ste 300, Waukesha, WI 53188. E-mail: atzeelmd@humana.com.1. Sattley M. The History of Diabetes. www. diabeteshealth.com/read/2008/12/17/715/the-historyof-diabetes/. Published December 17, 2008. Accessed November 24, 2012.

2. US Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet Press Release. www.cdc.gov/media/releases/2011/ p0126_diabetes.html. Accessed November 24, 2012.

3. US Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed November 24, 2012.

4. Steenhuysen J. Big rise in Americans with suppl):S277-S283.

5. Huang ES, Basu A, O’grady M, Capretta JC. Projecting the future diabetes population size and related costs for the U.S. Diabetes Care. 2009;32(12): 2225-2229.

6. Fendrick AM, Chernew ME, Levi GW. Valuebased insurance design: embracing value over cost alone. Am J Manag Care. 2009;15(10 2011;34(4):1047-1053.

7. Chernew ME, Juster IA, Shah M, et al. Evidence that value-based insurance can be effective. Health Aff (Millwood). 2010;29(3):530-536.

8. Jacobson G, Neuman T, Damico A, Huang J. Medicare Advantage Plan star ratings and bonus payments in 2012. www.kff.org/medicare/upload/ 8257.pdf. Accessed November 25, 2012.

9. Fang H, Rizzo JA. Managed care and physicians’ perceptions of drug formulary use. Am J Manag Care. 2009;15(6):395-400.

10. Curtin K, Beckman H, Pankow G, et al. Return on investment in pay for performance: a diabetes case study. J Healthc Manag. 2006;51(6):365- 374.

11. Bojadzievski T, Gabbay RA. Patient-centered medical home and diabetes. Diabetes Care. diabetes, especially in South. www.reuters.com/ article/ 2012/11/15/us-usa-diabetes-idUSBRE8AE 1HF20121115?feedType=RSS&feedName=healthNews&utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+reuters%2FhealthNews+%28Reuters+Health+News%29. Published November 15, 2012. Accessed November 24, 2012.

12. Fisher ES, Staiger DO, Bynum JPW, Gottlieg DJ. Creating accountable care organizations: the extended hospital medical staff. Health Affairs. 2007;26(1):w44-w57.

13. Sinek S. The Golden Circle. www.startwithwhy.com/About.aspx. Accessed November 28, 2012.

14. Aetna 2011 Annual Report. Uncommon Connections to Good Health. www.aetna.com/2011annual report/uncommon-connections.html. Accessed November 25, 2012.

15. Humana 2010-2011 Corporate Social Responsibility Report: Well-Being Starts With Us. http:// apps.humana.com/marketing/documents.asp? file=1853046. Accessed November 25, 2012.

Managing Benefits for Diabetes: Changing Payer Strategies for Changing Times

Moderator: How does the new way diabetes is managed compare with the older way?

Dr James Holly of SETMA stated that the biggest change is that providers now have a concept of accountability and that there is a renewed sense of responsibility to improve healthcare and lower costs. Dr Holly discussed quality metrics as a major determinant of medical care and compared quality metrics with a GPS system. A GPS system only works if you know where you are. “Can you imagine a GPS system that told you where Dallas was but wouldn’t tell you where you are and gave you no signposts along the way?” asked Dr Holly. A medical treatment plan is the same: you cannot have a system in which you only know what the end goal is. Constant and continuous quality metrics are needed so that adjustments can be made as the treatment proceeds. Those metrics need to be universal so that the pharmacist, the doctor, the patient, and the provider can all look at the metrics to understand how the treatment is proceeding. Dr Holly noted that if the patient knows where they are in the overall treatment plan, they will be more compliant and more involved in the treatment. Dr Holly also stated that the patient-centered health model can change how clinicians perform. If the patient has a public forum to report on a clinician’s or provider’s performance, that performance will improve. These changes may be challenging for some populations to adjust to, but adjustment will occur over time.

Dr Keith Shealy of Mackey Family Practice agreed with what was said by Dr Holly, adding that an open system is good for competition. “Doctors are competitive, very competitive,” said Dr Shealy. Doctors who are low on a public rating system will strive to do better, meaning better care for patients.

Dr Laura Long of BlueCross BlueShield, South Carolina, noted that traditionally, BlueCross BlueShield had a care management model in which coaches reached out to patients. During that period “We worked primarily with our members and we tried to coach them as best we could and we would periodically reach out to the physician but we weren’t necessarily collaborating,” said Dr Long, adding, “Historically, we were working in our traditional silos.” That has changed. Today, the patientcentered medical home model is more open. Dr Long added, “What we are doing in the patient-centered medical home is we are sharing information.” Claims information is shared with clinicians and case managers. Case managers can access the electronic medical records and add electronic “sticky notes” that clinicians can see and use to adjust treatment if necessary.

Another important change is that in addition to paying physicians for traditional services, BlueCross BlueShield is also paying physicians for outcomes in 2 new ways. First, clinicians can get reimbursed for additional services, including pharmacy visits, education visits, and home visits. Second, if clinicians are

doing a better job at controlling certain clinical parameters (eg, blood pressure) they will get paid more. Such measures lead to fewer emergency department and hospital visits and therefore are cost-effective for the provider.

Dr Sam Ho from UnitedHealthcare agreed with the other panelists on how significantly the healthcare system has changed in the last few years toward a more patient-centered system.

Dr Ho stated that the changes encompassed 5 levels:

1. Healthcare needs to be more patient centric instead of disease focused.

2. There needs to be a transformation of the records delivery system that allows all members of the team to be informed. For example, if a patient is in the emergency department and the primary care physician does not know that, the system is failing.

3. The payment system should be value based instead of volume based.

4. Transparency should be universal and encompass the consumers, the doctors, and the hospitals, and include data on how they are performing in relationship to standard guidelines.

5. The program should reward those who adhere to the treatment plan. If a patient is improving and adhering to the treatment, then premiums, copays, and out-of-pocket expenses should be reduced.

“He was angry, hostile, bitter, and mean.”

Dr Holly provided an example of patientcentered healthcare from his own practice. “I saw a man in the hospital; he was a patient of one of my partners, a new patient. He was angry, hostile, bitter, and mean. The nurses said, ‘You don’t want to go in there,’” explained Dr Holly. He took the time to talk with this man and he discovered that the patient had several problems: he couldn’t afford his medications, he was going blind due to his uncontrolled diabetes, he was incapacitated and could not work, he could not afford the gas to see the doctor or attend diabetes educational programs, he could not afford the copays for the educational programs, and he could not afford to go see an ophthalmologist to save his eyes. Dr Holly told the audience that he and his team used funds available for these patients and worked to get the patient gas cards, reduced copays, and an appointment with an ophthalmologist. As Dr Holly noted, “In a patient-centered medical home, we have not done our job unless we can give patients access to care that we have prescribed.” Dr Holly concluded the story by stating that he saw the patient 6 weeks later and “[the patient] had something I could not prescribe….He had hope, for the first time in years.”

Moderator: The emotional and social needs that often accompany a medical need have not always been addressed or covered by more conventional health insurers. How is your organization addressing those non-medical needs?

Dr Long noted that their organization recognizes that the social needs of a patient are often greater than the true medical needs and that social needs have a significant impact on medical care. Issues such as the person having financial or transportation problems, or other comorbidities, for example, depression, can have a major effect on treatment adherence. Dr Long also said many providers have programs in place to help patients. However, those programs are not effective if implemented in isolation from the physician. “The thing that has me excited about patient-centered medical homes is that they are now being integrated with the physician,” stated Dr Long. Also, the physicians are being incentivized in this new model for better outcomes instead of for the volume of patients they see. That means that a physician will be rewarded for taking the time to address some of the behavioral, financial, or emotional issues that can impede treatment. In return, the patient is rewarded with better care.

Dr Shealy stated that they screen all of their patients for mental and emotional issues. They are well aware that patients with depression cost more money, so an integrated behavioral health curriculum is part of their practice.

Moderator: What about physicians who don’t have their own private foundation? Who pays for that physician to develop a patient-centered model?

Dr Ho answered this question by admitting that it is a challenge. Developing a network of pharmacists, certified diabetes educators, social workers, nurse practitioners, and other providers can be done; however, much work is required. As more insurers and granting agencies accept the patientcentered approach to healthcare, such networks will likely become easier to establish.

Moderator: Is the patient-centered home model the basis of the care within accountable care organizations (ACOs) or will something else evolve?

Dr Long said, “I see the patient-centered model as the foundation for accountable care organizations.” According to Dr Long, the primary care physician is the basic provider of management services for patients with chronic conditions. From that foundation, specialists and other health professionals may be added; however, patients need to be able to return to their primary care physicians as the ACOs continue to expand and evolve.

Moderator: Will the patient-centered model work better for preventing diabetes or treating it?

Dr Long answered that the model is best designed to prevent diabetes. Historically, the medical community treats patients after they get sick: it is a reactive model. The patient-centered model is proactive: it provides rewards when patients do not get sick. Dr Long said doctors are aware of individuals in their patient populations who are at risk for a medical condition (diabetes, hypertension, etc) and they can develop algorithms and teaching programs for those patients before they get sick. Under the patient-centered model, doctors will be properly compensated for this care. “We know that prediabetes is a huge problem, especially in South Carolina, where the diabetes rate is very high. The way you can address that problem is [that] you can screen your patients at high risk for prediabetes, you can put in

place weight management programs, you can be aggressive with metformin, etc. And you can get reimbursed for that,” said Dr Long.

One thing that the patient-centered model is well suited for is preventive care. At the core of the model are the patient and the primary care physician. If the model allows the physician to take their time before medical problems develop and the doctor is properly compensated, the patient is healthier and the provider has lower healthcare expenditures. Everyone wins.

Reprinted from A Special Report on Diabetes Innovation 2012. 

A panel discussion on healthcare reimbursement and payment fees at Diabetes
Innovation 2012 that included leaders from diverse backgrounds in the healthcare industry was moderated by Susan Dentzer, editor-in-chief of Health Affairs and publisher of Project HOPE. Panelists included James (Larry) Holly, MD, chief executive officer of Southeast Texas Medical Associates (SETMA), LLP; Keith Shealy, MD, president of Mackey Family Practice; Laura Long, MD, MPH, vice president of clinical innovation for BlueCross BlueShield of South Carolina; and Sam Ho, MD, chief medical officer and executive vice president at UnitedHealthcare.

Examining Models of Care and Reimbursement, Including Patient Management Fees, ACOs, and PCMHs: A Panel Discussion

Disease management programs, particularly for diabetes care, have been part of managed care benefit offerings for roughly 20 years. They are offered by nearly every health plan, whether commercial, Medicare, or Medicaid. Most experts would acknowledgethat disease management programs can improve the health of patients with chronic disease. However, little reliable, reproducible information is available to answer the question of whether these programs are cost saving.

With the evidence in hand that tight glycemic control can prevent long-term complications of diabetes mellitus

 and the ability to measure and monitora person’s blood glucose levels at a moment’s notice, a new medical concept and burgeoning industry spawned in just a few years. In 1991, the Boston Consulting Group characterized this as disease state management,

 and described it as a new way for the pharmaceutical industry to prove (and enhance) the value of its medications. Soon after, pharmaceutical companies like Pfizer and Zeneca Labs began their own disease management programs,

 shopping them to the health plans and insurers.

The health plans realized that the disease management process represented a workable way to improve clinical outcomes and health status over an entire population of patients and codified a way to broadly conduct and promote secondary prevention. Furthermore, disease management programs were acknowledged to be a type of quality improvement (QI) process, which helped managed care plans fulfill QI requirements for accreditation from the  National Committee for Quality Assurance. However, they had a choice of whether to contract with these pharmaceutical company—sponsored providers, work  with independent start-up disease management organizations (eg, Diabetes Treatment Centers of America [which later became Healthways] or Cardiac  Solutions [which later became Healthways]), or start their own internal programs.

Over time, pharmaceutical company programs became burdened with concerns regarding conflict of interest and were soon outpaced by independent vendors and health plan—sponsored programs. The concept, in any case, took off. By 2006, disease management programs were part of every managed care organization’s portfolio of benefits fits: a survey by the Boston Consulting Group revealed that 96% of health plans had disease management programs.

 In  2010, one source reported that 21% of patients with at least 1 chronic disease were in a disease management program.

Today, the domestic disease management market is $2.1 billion, but should grow significantly in 2014 (once health reform increases the size of the market for covered eligibles).

Although disease management can be applied to many chronic diseases, diabetes has been a prime target. Diabetes mellitus is highly prevalent, it results in tremendous costs (a significant portion of which are preventable), and it can be easily measured. The programs’ interventions also were well suited for QI: patients can be tracked, their pharmacy claims can be assessed for adherence, and their outcomes can  be quantified, in terms of glycated hemoglobin (A1C) levels, clinical events, and use of medical resources (including emergency department [ED] and  hospitalization).

According to the Care Continuum Alliance (formerly the Disease Management Association of America), the principal components of disease management programs include

• A method of identifying populations requiring secondary prevention

• Standards of care according to evidence-based practice guidelines

March/April

The Controversial Question of Metabolic Syndrome

New Developments in the Treatment of Type 2 Diabetes Mellitus

Managing Benefits for Diabetes: Changing Payer Strategies for Changing Times

Examining Models of Care and Reimbursement, Including Patient Management Fees, ACOs, and PCMHs: A Panel Discussion

Is There a Business Case for Diabetes Disease Management?

Real-World Examples of Patient-Centered Healthcare

Targeting Insulin Resistance: The Ongoing Paradigm Shift in Diabetes Prevention

Can Financial Incentives Improve Self-Management Behaviors?

Reexamining the Roles of Diabetes Educators

Diabetes and the Patient-Centered Medical Home

Measuring the Value of Better Diabetes Management