Type 2 Diabetes in the Real World: the Elusive Nature of Glycemic

Diabetes Care Volume 40, November 2017 1425

Type 2 Diabetes in the Real World: Steven V. Edelman1,2,3 and William H. Polonsky 4,5 The Elusive Nature of Glycemic

Control CARE IN PERSPECTIVES

Diabetes Care 2017;40:1425–1432 | https://doi.org/10.2337/dc16-1974

Despite U.S. Food and Drug Administration (FDA) approval of over 40 new treatment options for type 2 diabetes since 2005, the latest data from the National Health and Nutrition Examination Survey show that the proportion of patients achieving glycated hemoglobin (HbA1c) <7.0% (<53 mmol/mol) remains around 50%, with a negligible decline between the periods 2003–2006 and 2011–2014. The Healthcare Effective- ness Data and Information Set reports even more alarming rates, with only about

40% and 30% of patients achieving HbA1c <7.0% (<53 mmol/mol) in the commercially insured (HMO) and Medicaid populations, respectively, again with virtually no change over the past decade. A recent retrospective cohort study using a large U.S. claims database explored why clinical outcomes are not keeping pace with the availability of new treatment options. The study found that HbA1c reductions fell far short of those reported in randomized clinical trials (RCTs), with poor medication adherence emerging as the key driver behind the disconnect. In this Perspective, we examine the implications of these ﬁndings in conjunction with other data to highlight the discrep- ancy between RCT ﬁndings and the real world, all pointing toward the underrealized promise of FDA-approved therapies and the critical importance of medication adherence. While poor medication adherence is not a new issue, it has yet to be effectively addressed in clinical practicedoften, we suspect, because it goes unrecognized. To support the busy health care professional, innovative approaches are sorely needed.

ACHIEVEMENT OF HbA1c GOALS IN THE REAL WORLD 1Division of Endocrinology and Metabolism, Large randomized controlled trials (RCTs) have clearly demonstrated that achieving and School of Medicine, University of California, San Diego, San Diego, CA sustaining optimal glycemic control prevents or delays the development of microvas- 2 – Veterans Affairs Medical Center, San Diego, CA cular and macrovascular disease (1 3). Although the risk of developing diabetes- 3Taking Control of Your Diabetes, Del Mar, CA 4 related complications rises steadily when glycated hemoglobin (HbA1c) values are in Department of Psychiatry, University of Califor- excess of 6.5% (48 mmol/mol) (4,5), an HbA1c of ,7% (,53 mmol/mol) is generally nia, San Diego, San Diego, CA considered a target goal for diabetes management (6). In truth, it is now widely 5Behavioral Diabetes Institute, San Diego, CA recognized that individualizing the HbA1c goal for each patient is critically important, Corresponding author: Steven V. Edelman, especially when the presence of comorbidities necessitates less stringent targets (6). [email protected]. However, most government and private insurer reports continue to use 7% as a point Received 13 September 2016 and accepted 25 of reference; therefore, we focus herein on this marker of glycemic control. March 2017. Despite our growing understanding of diabetes and the availability of new medica- © 2017 by the American Diabetes Association. Readers may use this article as long as the work tions and technologies, a substantial number of individuals are not at their glycemic is properly cited, the use is educational and not goal. Of note, recent data indicate that 85.6% of adults with diagnosed diabetes are for proﬁt, and the work is not altered. More infor- treated with diabetes medication (7). Results from the National Health and Nutrition mation is available at http://www.diabetesjournals Examination Survey (NHANES) indicate that only about 50% of American adults with .org/content/license. diabetes are achieving HbA1c ,7.0% (,53 mmol/mol) (8), and it is estimated that only See accompanying articles, pp. 1469 64% are reaching individualized glycemic goals (9). These ﬁndings are noteworthy and 1588. 1426 Elusive Glycemic Control in the Real World Diabetes Care Volume 40, November 2017

because they provide nationally repre- 40% of commercially insured HMO patients distressing lack of improved glycemic sentative snapshots with which to assess and 30% of government-insured patients control in this country over the past de- care outcomes realized over time in real- achieved HbA1c ,7.0 (,53 mmol/mol), cade, as well as the notable gap between world settings. After an initial increase in again with no change over the past de- clinical trial and real-world results, and thepercentageofpatientsattaining cade (10) (Fig. 1B). provides an urgent challenge to consider HbA1c ,7.0% (,53 mmol/mol) between While these worrisome findings are new approaches to achieving meaningful the survey periods 1988–1994 (44%) and certainly skewed, at least to some extent, and sustained outcomes. 2003–2006 (57%), performance stag- by the unknown number of individuals WHY IS OUR LARGE AND EVER- nated, with a new wave of data showing whose individualized HbA targets 1c GROWING DIABETES TOOLBOX percentages for the 2007–2010 and are .7%, it remains evident that a con- NOT LEADING TO IMPROVED AND 2011–2014 periods at 52% and 51%, re- siderable percentage of U.S. adults with SUSTAINED GLYCEMIC CONTROL? spectively (9) (Fig. 1A). diabetes are in persistent poor glycemic TheHealthcareEffectivenessDataand control. The question of why these pop- The number of diagnosed cases of diabe- Information Set (HEDIS) results, which ulation trends stand in such sharp con- tes has increased fourfold from 1980 include data from over 1,000 health plans trast to the generally favorable results through 2014 (from 5.5 million to 22.0 covering over 171 million people in 2014, are emerging from RCTs has not been fully million), with type 2 diabetes making up even more troubling. In 2014, approximately explored. This Perspective calls out the the vast majority of cases (11). While a growing number of options are available to treat type 2 diabetesdover 40 new drugs, including combination products, for type 2 diabetes have been approved since 2005 (12)dthe most recent analysis of NHANES data currently being prepared for publication suggests that this explo- sion in available options has not contrib- uted to a meaningful improvement in glycemic control (8,9). This has profound implications, considering that poorly controlled diabetes is a recognized cause of severe microvascular and macrovascular complications (7). If the present trends in incidence and prevalence continue without change, it is estimated that one-third of Americans will have diabetes by 2050, portending even higher rates of morbidity and mortality as a result of poor glycemic control (13). Efficacy Unrealized: The Disconnect Between Clinical Trial and Real-World Results RCTs have been the “gold standard” of study design because they tightly control the setting and delivery of interventions, minimize the effect of external factors on outcomes, and lead to a random distribu- tion of unmeasured confounders. Yet the degree to which results obtained under RCT conditions can be extrapolated to real life remains an open question (14,15). Indeed, it is important to be aware of the ways in which clinical trial results might inflate expectations of treatment efficacy. First, therapy interventions are often more focused in the unusual setting of the clin- fi Figure 1—Percentage of patients with diabetes achieving HbA1c ,7% over the last decade has not ical trial, where patients may bene tfrom improved. A: Nationally representative real-world snapshot of the percentage of patients with more frequent face-to-face visits, conve- , type 1 or type 2 diabetes achieving HbA1c levels 7% from 2003 to 2006 (N = 999) (8), 2007 to nient access to therapy, closer monitor- 2010 (N = 1,444) (7), and 2011 to 2014 (N = 2,677) (9) using data derived from the NHANES database. B: Only approximately 40% of patients with either type 1 or type 2 diabetes in the HMO population ing, and wider availability of educational – or 30% of patients in the Medicaid population consistently achieved HbA1c levels ,7% over a time resources and support services (14,16 18). period spanning 2007 to 2014 accordingly to data obtained from the HEDIS database (10). Second, trial participants are often more care.diabetesjournals.org Edelman and Polonsky 1427

concerned with their health and treat- from 20.47% to 20.90% for the DPP-4 key biobehavioral factors, including base- ment and thus more motivated to actively inhibitor groups (Fig. 2). The finding that line patient characteristics, drug therapy, participate in their own care. Third, com- HbA1c reductions were similar between and medication adherence (21). Signifi- mitting to a protocol over a defined pe- the real-world treatment groups for cantly, the key driver was poor medica- riod of time, sometimes with the benefit GLP-1 RAs and DPP-4 inhibitors was sur- tion adherence, accounting for 75% of the of financial incentives, may make it easier prising considering that clinical trial com- gap (Fig. 3). Adherence was defined, fol- for patients to follow medication instruc- parisons of incretin-based therapies lowing the Centers for Medicare & Med- tions appropriately (19,20). consistently show greater HbA1c reduc- icaid Services recommendation, as the We now have the opportunity to use tions from baseline with GLP-1 RAs than filling of one’s diabetes prescription often administrative claims data in conjunction with DPP-4 inhibitors (33). enough to cover $80% of the time one with clinical trial data to guide clinical To better understand the differences be- was recommended to be taking the med- decision-making.Inthecaseoftype2di- tweenusualcareandclinicaltrialHbA1c ication (34). By this metric, proportion of abetes, evidence from a new claims data results, multivariate regression analysis days covered (PDC) $80%, only 29% of study (21) may help to explain the dis- assessed the relative contributions of patients were adherent to GLP-1 RA couraging NHANES and HEDIS findings mentioned above and, in so doing, vali- date what we intuitively know to be truedthat clinical trial outcomes and actual clinical care often tell different stories. Using a large electronic medical record– administrative claims database (Optum Humedica SmartFile, 2007–2014), this retrospective analysis was undertaken to assess HbA1c reductions in patients initiating a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or a dipeptidyl peptidase 4 (DPP-4) inhibitor, to quantify the gap between real-world (i.e., usual care) and RCT efficacy, and to calculate the relative contribution of various biobehavioral factors in explaining this gap (21). Specifically, investigators identified adult patients with type 2 diabetes who initiated a GLP-1 RA (n =221)orDPP-4 inhibitor (n = 652) and then compared their real-world HbA1c change over a 12-month period with that of participants in 11 pivotal RCTs, seven for the GLP-1 RA class and four for the DPP-4 inhibitor class (22–32). Of note is that although HbA1c change was measured over a 12-month period for the real-world samples, only three of the 11 comparator RCTs were of similar length (27,29,32). This may some- what reduce the gap between real-world HbA1c change and the changes seen in the comparator RCTs. Additionally, the data set does not provide data regarding dosages in the real-world samples, which may differ from the dosages used in the comparator RCTs. Nevertheless, the study (21) revealed that in patients with similar inclusion criteria characteristics, HbA re- 1c Figure 2—Reductions in tightly controlled clinical trials are not being translated into real-world ductions in the usual care group fell far HbA1c outcomes. A: Conceptually, there is an efficacy gap between clinical trial results and real- short of those reported in the RCTs: HbA1c world outcomes. Patients with diabetes in the real world are experiencing less meaningful and less reductions in the real-world group were sustained improvements resulting in an efficacy gap. B: A retrospective study identified 11 pivotal 20.52% for the GLP-1 RAs and 20.51% RCTs with patients who initiated GLP-1 RAs (seven studies, n = 2,600) or DPP-4 inhibitors (four studies, n = 1,889) that included measurements of HbA1c at both drug initiation and after 1 year of for the DPP-4 inhibitors, whereas in the treatment. Data from the 2007–2014 Optum Humedica database served as a resource for the real- RCTs the changes ranged from 20.84% world data, and a cohort of patients with characteristics similar to the pivotal clinical trials was to 21.60% for the GLP-1 RA groups and identified (21). DPP-4i, DPP-4 inhibitor. 1428 Elusive Glycemic Control in the Real World Diabetes Care Volume 40, November 2017

treatment and 37% to DPP-4 inhibitor treatment.

A CLOSER LOOK AT THE PROBLEM These data are consistent with previous real- world studies, which have demonstrated that poor medication adherence to both oral and injectable antidiabetes agents is very common (35–37). For example, a retrospective analysis of the MarketScan Commercial and Medicare Supplemental databases targeting adults initiating oral agents in the DPP-4 inhibitor (n = 61,399), sulfonylurea (n = 134,961), and thiazolidinedione (n = 42,012) classes found that adherence rates, as measured by PDC $80% at the 1-year mark after the initial prescription, were below 50% for all three classes, at 47.3%, 41.2%, and 36.7%, respectively (36). Rates dropped even lower at the 2-year follow-up (36) (Fig. 4A). Another claims database study of 1,321 patients with type 2 diabetes who were treated with once-daily liraglutide under- scores the particular challenge posed by the injectable GLP-1 RA class, as only 34% (n = 454) were classified as adherent as measured by PDC $80% (37). Further- more, as one might expect, patients in the adherent versus poorly adherent group were more likely to achieve HbA1c goals of ,7.0% (,53 mmol/mol) (50% vs. 39%, P , 0.001) and to have at least a 1.0% reduction in their HbA1c (38% vs. 32%, P =0.022). Data exploring persistence, defined as the continuation of treatment for the prescribed duration but allowing for a strictly defined permissible gap (e.g., days or months) after the last expected refill date, show even more alarming trends. A Figure 3—75% of the efficacy gap is due to poor adherence (21). A multivariate regression model 2013 utilization study conducted in the was generated to estimate the change in HbA1c 1 year after initiating GLP-1 RAs (A)orDPP-4 Truven Health Analytics MarketScan com- inhibitors (B). Adherence to the index drug was measured using a single variable based on PDC with mercial health insurance database re- a nonoverlapping supply of the index drug (GLP-1 RA or DPP-4) during the follow-up period. Patients were classified as adherent if PDC was $80%. Dosing of the index drug during the follow-up period vealed that only 18% of DPP-4 inhibitor was also captured based on the last fill of the index drug in the follow-up period. The estimated users (n = 208,683) and 11% of GLP-1 RA coefficients were used to calculate the predicted change in HbA1c levels in trial and real-world users (n = 124,925) were persistent with settings, estimate the gap, and describe factors contributing to the gap in outcomes. The therapy (nonpersistence in this study was fi predicted change in HbA1c in trial settings was calculated by multiplying each estimated coef cient defined as a gap of over 30 days after the by the value of that covariate in trials and summing the products. The predicted change in HbA1c fi fi levels in real-world settings was estimated in the same way and was found to be mathematically last expected re ll date) during the rst identical to the actual real-world change in HbA1c levels. The prediction model controlled for various year of treatment (38) (Fig. 4B). parameters, including baseline characteristics (such as age, diabetes complications, and prior drug therapy), addition of diabetes medications, and differences in adherence. The contribution of the The Adherence and Persistence factors to the gap between real-world (GLP-1 RAs, 221 patients; DPP-4 inhibitors, 652 patients) Challenge May Be Underestimated outcomes and clinical trial (predicted) results was calculated; it was found that for both GLP-1 RAs Our current ability to assess adherence and DPP-4 inhibitors, 75% of the gap was due to poor adherence. Adherence rate in the real world was 29% for GLP-1 RAs and 37% for DPP-4 inhibitors. Adherence was defined as PDC by drug $80%. and persistence is based primarily on re- It should be noted that only three of the comparator RCTs were 52 weeks in length (27,29,32); view of pharmacy records, which may un- among the remaining eight studies, two were 24 weeks (25,29), five were 26 weeks (22–25,28), and derestimate the extent of the problem. one was 30 weeks in length (31). For example, using the definition of adherence of the Centers for Medicare & care.diabetesjournals.org Edelman and Polonsky 1429

(39,40). Thus, a patient may have a gap of up to 90 days and still be considered persistent. Additionally, one must also consider the issue of primary nonadherence; adherence and persistence studies typically only include patients who have completed a first refill. A recent study of e-prescription data among 75,589 insured patients found that nearly one-third of new e-prescriptions for diabetes medications were never filled (41). Finally, none of these measures take into account if the patient is actually ingesting or inject- ing the medication after acquiring his or her refills.

The Ultimate Price of Poor Adherence and Persistence Acknowledging and addressing the problem of poor medication adherence is pivotal because of the well-documented dire consequences: a greater likelihood of long-term complications, more frequent hospitalizations, higher health care costs, and elevated mortality rates (42–45). In patients younger than 65, hospitalization risk in one study (n = 137,277) was found to be 30% at the lowest level of adherence to antidiabetes medications (1–19%) versus 13% at the highest adherence quintile (80–100%); hospitalization risk was defined as the probability of one or more all-cause hospitalizations during a 12-month period (43). In patients over 65, a separate study (n = 123,235) found that all-cause hospitalization risk was 37.4% in adherent cohorts (PDC $80%) versus 56.2% in poorly adherent cohorts (PDC ,20%) (45). This latter study also found better adherence to be associated with significantly lower all-cause outpa- tient costs, acute care costs, and total medical costs when compared with poorer adherence thresholds (all P , 0.001) over — Figure 4 Patients with type 2 diabetes demonstrate adherence rates less than 50% and persistence rates 3 years. Better adherence was also linked less than 25% over 1 year. A: A real-world study of 238,372 patients with type 2 diabetes taking oral diabetes medications found that adherence rates, defined as a PDC $80%, were consistently less than 50% across to fewer emergency room visits, shorter three oral drug classes at the 1-year time point and dropped to approximately 40% at the 2-year hospital length of stay, and lower risk of follow-up (35). Using administrative claims from a U.S. health plan affiliated with Optum, a retrospective acute complications (all P , 0.001) (45). study of 1,321 patients with type 2 diabetes treated with liraglutide once daily found that adherence rates Furthermore, for every 1,000 patients were 34% for injectable GLP-1 RAs (36). B: A retrospective cohort study, conducted using data extracted who increased adherence to their antidia- from Truven Health Analytics MarketScan commercial health insurance database, found that less than 25% of patients on DPP-4 inhibitors were persistent with therapy at 12 months; the rate for GLP-1 RAs even betes medications by just 1%, the total worse, with only approximately 15% of the more than 134,000 patients who initiated GLP-1 RAs considered medical cost savings was estimated to persistent with therapy (38). The median time to discontinuation was 90 days for the GLP-1 RA cohort and be $65,464 over 3 years (45). 120 days for the DPP-4 inhibitor cohort. A patient was defined as persistent with therapy if he or she had less The cumulative impact of poor adher- than a 30-day gap in therapy. DPP-4i, DPP-4 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. ence is also supported by an earlier retrospective cohort study of 11,532 patients Medicaid ServicesdPDC $80%dapa- retrospective studies of persistence, the with diabetes in the Kaiser Permanente of tient could miss up to 20% of days cov- permissible gap after the last expected Colorado registry. There was a 39% in- ered and still be considered adherent. In refill date often extends up to 90 days creased risk for all-cause mortality associated 1430 Elusive Glycemic Control in the Real World Diabetes Care Volume 40, November 2017

with poor adherence to oral hypoglycemic Wesuspectthattheefficacy of behav- implicated in higher morbidity, mortality, agents (42). Additionally, an overlooked ioral interventions to address medication and health care costs (43,44). Achieving result of the recently completed Liraglu- adherence will continue to be limited until meaningful and sustained glycemic con- tide Effect and Action in Diabetes: Evalu- there are more focused efforts to address trol requires innovative approaches for ation of Cardiovascular Outcome Results three common and often unappreciated the real world. In order to help our pa- (LEADER) trial provides further insight re- patient obstacles. First, taking diabetes tients achieve meaningful and sustained garding the influence of adherence. While medications is a burdensome and often HbA1c reductionsdand move the dial the primary analysis showed that liraglu- difficult activity for many of our patients. positively on the next NHANES and HEDIS tide lowered cardiovascular deaths by Rather than just encouraging patients to HbA1c analysesdwe appeal to the diabe- 22% compared with placebo in the global do a better job of tolerating this burden, tes community to drive even harder for findings, this reduction in risk was not more work is needed to make the process innovative approaches designed with the observed in the North American sample; easier and more convenient. For example, realworldinmind. according to the study sponsor, “for rea- once-weekly medications, combination sons that are still unclear, the N.A. [North pills, and new innovations in delivery American] patient groups tend to have methods may be beneficial. Acknowledgments. The authors thank Carol A. lower compliance and adherence com- Second, poor medication adherence Verderese, The Diabetes Education Group, pared to global rates during large cardio- often represents underlying attitudinal Lakeville, CT, and Christopher G. Parkin, CGParkin vascular studies” (46,47). problems that may not be a strictly be- Communications, Inc., Boulder City, NV, for their editorial support. fi havioral issue. Speci cally, negative be- Funding. Intarcia Therapeutics, Inc. provided Poor Adherence Is Difficult to Address liefs about prescribed medications are funding for editorial support in the writing of this In total, these new data oblige those of us pervasive among patients, and behavioral manuscript. who treat people with diabetes to be interventions cannot be effective unless Duality of Interest. S.V.E. is a consultant for In- tarcia, Sanofi, AstraZeneca, Eli Lilly, Dexcom, even more mindful of the potential for these beliefs are addressed directly (35). Bayer, Abbott, and Johnson & Johnson. W.H.P. poor adherence. There are many poten- Therefore, improved communication be- is a consultant for Intarcia, Sanofi, Eli Lilly, Novo tial contributors to poor medication ad- tween patients and clinicians regarding Nordisk, Dexcom, Roche, Abbott, and AstraZeneca. herence, including depressive affect, the benefits and risks of specific treat- No other potential conflicts of interest relevant to negative treatment perceptions, lack of ment options, as well as wider adoption this article were reported. patient-physician trust, complexity of of shared decision-making strategies, is References the medication regimen, tolerability, and warranted (35). 1. UK Prospective Diabetes Study (UKPDS) cost (48). Although these factors have not Third, the issue of access to medications Group. Intensive blood-glucose control with been well studied, it is believed that many remains a primary concern. A study by sulphonylureas or insulin compared with conven- of them can be addressed with appropri- Kurlander et al. (51) found that patients tional treatment and risk of complications in ate education, thorough instruction in selectively forgo medications because patients with type 2 diabetes (UKPDS 33). Lancet – medication administration, ongoing and of cost; however, noncost factors, such 1998;352:837 853 2. The Diabetes Control and Complications Trial respectful patient-physician interactions, as beliefs, satisfaction with medication- Research Group. The effect of intensive treatment and shared decision-making between related information, and depression, are of diabetes on the development and progression patients and health care professionals also influential. of long-term complications in insulin-dependent (49–51). However, these results are often diabetes mellitus. N Engl J Med 1993;329:977– SUMMARY 986 not easy to achieve, especially given the 3. 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Update to a position statement of the American Diabetes As- applied successfully to all patients with in real-world clinical practice has been sociation and the European Association for the type 2 diabetes (53). Additional evidence minimal. Study of Diabetes. Diabetes Care 2015;38:140– indicates that improvements resulting Poor medication adherence and persis- 149 from the few effective interventions, tence continue at alarming rates. They 7. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of such as pharmacy-based counseling or are demonstrably key contributors to diabetes and its burden in the United States, nurse-managed home telemonitoring, the disconnect between RCT and real- 2014 [Internet], 2014. Atlanta, GA, U.S. Department often wane once the programs end (54,55). world results in lowering HbA1c and are of Health and Human Services. Available from care.diabetesjournals.org Edelman and Polonsky 1431

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