Professional Documents
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PERSPECTIVES IN CARE
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 emerg-
ing 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 adher-
ence. 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.
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
the percentage of patients attaining 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 1c targets
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
The Healthcare Effectiveness Data and 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 con-
trolled diabetes is a recognized cause of
severe microvascular and macrovascular
complications (7). If the present trends in
incidence and prevalence continue with-
out 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-
Figure 1—Percentage of patients with diabetes achieving HbA1c ,7% over the last decade has not ical trial, where patients may benefit from
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 3
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. In the case of type 2 di- tween usual care and clinical trial HbA1c 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 ac-
tual 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 recep-
tor agonist (GLP-1 RA) or a dipeptidyl pep-
tidase 4 (DPP-4) inhibitor, to quantify the
gap between real-world (i.e., usual care)
and RCT efficacy, and to calculate the rel-
ative contribution of various biobehav-
ioral factors in explaining this gap (21).
Specifically, investigators identified
adult patients with type 2 diabetes who
initiated a GLP-1 RA (n = 221) or DPP-4
inhibitor (n = 652) and then compared
their real-world HbA 1c 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 dos-
ages 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, HbA1c re- 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.
4 Elusive Glycemic Control in the Real World Diabetes Care
with poor adherence to oral hypoglycemic We suspect that the efficacy 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, real world in mind.
according to the study sponsor, “for rea- once-weekly medications, combination
sons that are still unclear, the [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
Communications, Inc., Boulder City, NV, for their
vascular studies” (46,47). problems that may not be a strictly be- editorial support.
havioral issue. Specifically, 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
1998;352:837–853
medication administration, ongoing and of cost; however, noncost factors, such 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. Epidemiology of Diabetes Interventions and
limited time available for a meaningful Only about half of patients with type 2 Complications (EDIC) Research Group. Epidemiol-
discussion during typically short clinic vis- diabetes are meeting glycemic goals ogy of Diabetes Interventions and Complications
its. Medication adherence is not a single (8–10), and there has been negligible (EDIC). Design and implementation of a long-term
behavior but rather a dynamic constella- change in the percentage of individuals follow-up of the Diabetes Control and Complica-
tions Trial cohort. Diabetes Care 1999;22:99–111
tion of behaviors influenced by social, en- achieving their target goals over the last 4. Selvin E, Steffes MW, Zhu H, et al. Glycated
vironmental, and individual circumstances decade. Despite the approval of 40 new hemoglobin, diabetes, and cardiovascular risk in
that defy “one-size-fits-all” solutions (52). treatment options for type 2 diabetes nondiabetic adults. N Engl J Med 2010;362:800–
A recent review of interventions address- since 2005 (12), these therapies and ap- 811
5. Selvin E, Ning Y, Steffes MW, et al. Glycated
ing problematic medication adherence in proaches have not had a meaningful im-
hemoglobin and the risk of kidney disease and
type 2 diabetes found that few strategies pact on the degree of glycemic control retinopathy in adults with and without diabetes.
have been shown consistently to have a in a large subset of the population with Diabetes 2011;60:298–305
marked positive impact, particularly with diabetes (9). Although these treatment 6. Inzucchi SE, Bergenstal RM, Buse JB, et al. Man-
respect to HbA1c lowering, and no single options have shown notable efficacy in agement of hyperglycemia in type 2 diabetes,
2015: a patient-centered approach. Update to a
intervention was identified that could be RTCs, their impact on glycemic control 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 7
http://www.cdc.gov/diabetes/pubs/statsreport14/ 22. Pratley RE, Nauck M, Bailey T, et al.; 1860- meta-analysis and systematic review. Clin Ther
national-diabetes-report-web.pdf. Accessed 10 LIRA-DPP-4 Study Group. Liraglutide versus sita- 2012;34:1247–1258.e22
January 2016 gliptin for patients with type 2 diabetes who did 34. Centers for Medicare & Medicaid Services.
8. Ali MK, Bullard KM, Saaddine JB, Cowie CC, not have adequate glycaemic control with met- Medicare 2016 Part C & D star rating technical
Imperatore G, Gregg EW. Achievement of goals formin: a 26-week, randomised, parallel-group, notes (draft) [Internet], 2015. Available from
in U.S. diabetes care, 1999–2010. N Engl J Med open-label trial. Lancet 2010;375:1447–1456 https://www.cms.gov/Medicare/Prescription-
2013;368:1613–1624 23. Marre M, Shaw J, Brändle M, et al.; LEAD-1 Drug-Coverage/PrescriptionDrugCovGenIn/
9. Carls GS, Huynh J, Tuttle E, Edelman SV. SU study group. Liraglutide, a once-daily human Downloads/2016-Technical-Notes-Preview-1-
Achievement of glycated hemoglobin goals in GLP-1 analogue, added to a sulphonylurea over v2015_08_05.pdf. Accessed 22 November 2016
the U.S. remains unchanged through 2014. Poster 26 weeks produces greater improvements in gly- 35. Aikens JE, Piette JD. Diabetic patients’ medi-
(1515-P) presented at the 76th Scientific Sessions caemic and weight control compared with adding cation underuse, illness outcomes, and beliefs
of the American Diabetes Association, 10–14 June rosiglitazone or placebo in subjects with type 2 about antihyperglycemic and antihypertensive
2016, New Orleans, Louisiana diabetes (LEAD-1 SU). Diabet Med 2009;26:268– treatments. Diabetes Care 2009;32:19–24
10. National Committee for Quality Assurance. 278 36. Farr AM, Sheehan JJ, Curkendall SM, Smith
The State of Health Care Quality 2015 [E-pub], 24. Nauck M, Frid A, Hermansen K, et al; LEAD-2 DM, Johnston SS, Kalsekar I. Retrospective analysis
2015. Washington, DC, National Committee for Study Group. Efficacy and safety comparison of of long-term adherence to and persistence with
Quality Assurance. Available for download from liraglutide, glimepiride, and placebo, all in combi- DPP-4 inhibitors in US adults with type 2 diabetes
http://store.ncqa.org/index.php/catalog/product/ nation with metformin, in type 2 diabetes: the mellitus. Adv Ther 2014;31:1287–1305
view/id/2341/s/2015-state-of-health-care- LEAD (liraglutide effect and action in diabetes)-2 37. Buysman EK, Liu F, Hammer M, Langer J. Im-
quality-report/. Accessed 5 July 2016 study. Diabetes Care 2009;32:84–90 pact of medication adherence and persistence
11. Centers for Disease Control and Prevention. 25. Diamant M, Van Gaal L, Stranks S, et al. Once on clinical and economic outcomes in patients
Number (in millions) of civilian, non-institutionalized weekly exenatide compared with insulin glargine with type 2 diabetes treated with liraglutide: a
persons with diagnosed diabetes, United States, titrated to target in patients with type 2 diabetes retrospective cohort study. Adv Ther 2015;32:
1980–2014 [Internet], 1 December 2015. Available (DURATION-3): an open-label randomised trial. 341–355
from http://www.cdc.gov/diabetes/statistics/ Lancet 2010;375:2234–2243 38. Koro CE, Chhabra P, Stender M, Spain CV,
prev/national/figpersons.htm. Accessed 12 July 26. Blevins T, Pullman J, Malloy J, et al. Allen JK, Krzywy HJ. Treatment utilization patterns
2016 DURATION-5: exenatide once weekly resulted in of GLP-1 agonists and DPP-4 inhibitors among
12. U.S. Food and Drug Administration. greater improvements in glycemic control com- type 2 diabetics in a U.S. commercially insured
Drugs@FDA: FDA approved drug products [Inter- pared with exenatide twice daily in patients population: 2005–2011. Poster (1589-P) pre-
net]. Available from https://www.accessdata.fda with type 2 diabetes. J Clin Endocrinol Metab sented at the 73rd Scientific Sessions of the Amer-
.gov/scripts/cder/drugsatfda/. Accessed 12 July 2011;96:1301–1310 ican Diabetes Association, 21–25 June 2013,
2016 27. Garber A, Henry R, Ratner R, et al.; LEAD-3 Chicago, IL
13. Centers for Disease Control and Prevention (Mono) Study Group. Liraglutide versus glimepir- 39. Cramer JA, Roy A, Burrell A, et al. Medication
(CDC). Chronic disease prevention and health pro- ide monotherapy for type 2 diabetes (LEAD-3 compliance and persistence: terminology and
motion: at a glance fact sheets: diabetes [Inter- Mono): a randomised, 52-week, phase III, double- definitions. Value Health 2008;11:44–47
net], 2016. Available from https://www.cdc.gov/ blind, parallel-treatment trial. Lancet 2009;373: 40. Cai J, Wang Y, Baser O, et al. Comparative
chronicdisease/resources/publications/aag/ 473–481 persistence with antihyperglycemic agents used
diabetes.htm. Accessed 22 November 2016 28. Zinman B, Gerich J, Buse JB, et al.; LEAD-4 to treat type 2 diabetes mellitus in the real world.
14. van Onzenoort HA, Menger FE, Neef C, et al. Study Investigators. Efficacy and safety of the hu- Poster (1155-P) presented at the 76th Scientific
Participation in a clinical trial enhances adherence man glucagon-like peptide-1 analog liraglutide in Sessions of the American Diabetes Association,
and persistence to treatment: a retrospective co- combination with metformin and thiazolidine- 10–14 June 2016, New Orleans, LA
hort study. Hypertension 2011;58:573–578 dione in patients with type 2 diabetes (LEAD-4 41. Fischer MA, Stedman MR, Lii J, et al. Primary
15. Rothwell PM. External validity of randomised Met+TZD). Diabetes Care 2009;32:1224–1230 medication non-adherence: analysis of 195,930
controlled trials: “to whom do the results of this 29. Nauck MA, Meininger G, Sheng D, Terranella electronic prescriptions. J Gen Intern Med 2010;
trial apply?”. Lancet 2005;365:82–93 L, Stein PP; Sitagliptin Study 024 Group. Efficacy 25:284–290
16. U.S. National Library of Medicine. Benefits and safety of the dipeptidyl peptidase-4 inhibitor, 42. Ho PM, Rumsfeld JS, Masoudi FA, et al.
and risks of clinical trials [Internet], 2006. Avail- sitagliptin, compared with the sulfonylurea, glipi- Effect of medication nonadherence on hospitali-
able from https://www.nlm.nih.gov/services/ zide, in patients with type 2 diabetes inadequately zation and mortality among patients with di-
ctbenefits.html. Accessed 23 July 2016 controlled on metformin alone: a randomized, abetes mellitus. Arch Intern Med 2006;166:
17. Harvard Women’s Health Watch. What clini- double-blind, non-inferiority trial. Diabetes Obes 1836–1841
cal studies can do for you [Internet], July 2012. Metab 2007;9:194–205 43. Sokol MC, McGuigan KA, Verbrugge RR,
Available from http://www.health.harvard.edu/ 30. DeFronzo RA, Hissa MN, Garber AJ, et al.; Epstein RS. Impact of medication adherence on
staying-healthy/what-clinical-studies-can-do-for- Saxagliptin 014 Study Group. The efficacy and hospitalization risk and healthcare cost. Med Care
you. Accessed 23 July 2016 safety of saxagliptin when added to metformin 2005;43:521–530
18. Burgess LJ, Sulzer NU, Hoosain F, Leverton N, therapy in patients with inadequately controlled 44. Egede LE, Gebregziabher M, Echols C, Lynch
Bliganut S, Emanuel S. Patients’ motivations for type 2 diabetes with metformin alone. Diabetes CP. Longitudinal effects of medication nonadher-
participating in cardiovascular clinical trials: a local Care 2009;32:1649–1655 ence on glycemic control. Ann Pharmacother
perspective. Cardiovasc J Afr 2009;20:220–223 31. Arechavaleta R, Seck T, Chen Y, et al. Efficacy 2014;48:562–570
19. van Dulmen S, Sluijs E, van Dijk L, de Ridder D, and safety of treatment with sitagliptin or glime- 45. Boye KS, Curtis SE, Lage MJ, Garcia-Perez LE.
Heerdink R, Bensing J. Patient adherence to med- piride in patients with type 2 diabetes inade- Associations between adherence and outcomes
ical treatment: a review of reviews. BMC Health quately controlled on metformin monotherapy: among older, type 2 diabetes patients: evidence
Serv Res 2007;7:55–67 a randomized, double-blind, non-inferiority trial. from a Medicare Supplemental database. Patient
20. Jin J, Sklar GE, Min Sen Oh V, Chuen Li S. Diabetes Obes Metab 2011;13:160–168 Prefer Adherence 2016;10:1573–1581
Factors affecting therapeutic compliance: a re- 32. Göke B, Gallwitz B, Eriksson J, Hellqvist A, 46. Marso SP, Daniels GH, Brown-Frandsen K,
view from the patient’s perspective. Ther Clin Gause-Nilsson I; D1680C00001 Investigators. Sax- et al.; LEADER Steering Committee; LEADER Trial
Risk Manag 2008;4:269–286 agliptin is non-inferior to glipizide in patients with Investigators. Liraglutide and cardiovascular out-
21. Carls GS, Tuttle E, Tan RD, et al. Understand- type 2 diabetes mellitus inadequately controlled comes in type 2 diabetes. N Engl J Med 2016;375:
ing the gap between efficacy in randomized con- on metformin alone: a 52-week randomised con- 311–322
trolled trials and effectiveness in real-world use of trolled trial. Int J Clin Pract 2010;64:1619–1631 47. Reeves A. Novo Nordisk drug cuts diabetic
GLP-1 RA and DPP-4 therapies in patients with 33. Aroda VR, Henry RR, Han J, et al. Efficacy of deaths, but not enough for Wall Street [article
type 2 diabetes. Diabetes Care 2017;40:XXX–XXX GLP-1 receptor agonists and DPP-4 inhibitors: online]. Investor’s Business Daily, 14 June 2016.
8 Elusive Glycemic Control in the Real World Diabetes Care
Available from http://www.investors.com/news/ 50. Zolnierek KB, Dimatteo MR. Physician com- adherence to anti-diabetic medications in pa-
technology/novo-nordisk-drug-cuts-diabetic- munication and patient adherence to treatment: tients with type 2 diabetesdimpact on adher-
deaths-but-not-enough-for-street/. Accessed a meta-analysis. Med Care 2009;47:826–834 ence. PLoS One 2015;10:e0118296
18 July 2016 51. Kurlander JE, Kerr EA, Krein S, Heisler M, 54. Brennan TA, Dollear TJ, Hu M, et al. An in-
48. Garcı́a-Pérez LE, Alvarez M, Dilla T, Gil-Guillén Piette JD. Cost-related nonadherence to medica- tegrated pharmacy-based program improved
V, Orozco-Beltrán D. Adherence to therapies in tions among patients with diabetes and chronic medication prescription and adherence rates in
patients with type 2 diabetes. Diabetes Ther pain: factors beyond finances. Diabetes Care diabetes patients. Health Aff (Millwood) 2012;
2013;4:175–194 2009;32:2143–2148 31:120–129
49. Beck RS, Daughtridge R, Sloane PD. Physician- 52. Steiner JF. Rethinking adherence. Ann Intern 55. Wakefield BJ, Holman JE, Ray A, et al. Effec-
patient communication in the primary care office: Med 2012;157:580–585 tiveness of home telehealth in comorbid diabe-
a systematic review. J Am Board Fam Pract 2002; 53. Sapkota S, Brien JA, Greenfield J, Aslani P. A tes and hypertension: a randomized, controlled
15:25–38 systematic review of interventions addressing trial. Telemed J E Health 2011;17:254–261