Use of Antidiabetic Drugs in the U.S., 2003 2012 and …care.diabetesjournals.org/content/diacare/37/5/1367.full.pdfUse of Antidiabetic Drugs in the U.S., ... The antidiabetic drug

Use of Antidiabetic Drugs in theU.S., 2003–2012Diabetes Care 2014;37:1367–1374 | DOI: 10.2337/dc13-2289

OBJECTIVE

To describe market trends for antidiabetic drugs, focusing on newly approveddrugs, concomitant use of antidiabetic drugs, and effects of safety concerns andaccess restrictions on thiazolidinedione use.

RESEARCH DESIGN AND METHODS

Nationally projected data on antidiabetic prescriptions for adults dispensed fromU.S. retail pharmacies were extracted from IMS Health Vector One National andTotal Patient Tracker for 2003–2012 and from Encuity Research TreatmentAnswers and Symphony Health Solutions PHAST Prescription Monthly for 2012.

RESULTS

Since 2003, the number of adult antidiabetic drug users increased by 42.9% to 18.8million in 2012. Metformin use increased by 97.0% to 60.4 million prescriptionsdispensed in retail pharmacies in 2012. Among antidiabetic drugs newly approvedfor marketing between 2003 and 2012, the dipeptidyl peptidase-4 (DPP-4) in-hibitor sitagliptin had the largest share with 10.5 million prescriptions in 2012.Rosiglitazone use plummeted to <13,000 prescriptions dispensed in retail ormail-order pharmacies in 2012. Concomitancy analyses showed that 44.9% ofmetformin use was for monotherapy. Between 33.4 and 48.1% of sulfonylurea,DPP-4 inhibitor, thiazolidinedione, and glucagon-like peptide 1 analog use was notaccompanied by metformin.

CONCLUSIONS

The antidiabetic drug market is characterized by steady increases in volume, andnewly approved drugs experienced substantial uptake, especially DPP-4 inhibi-tors. The use of rosiglitazone has been negligible since restrictions were put inplace in 2011. Further study is needed to understand why one-third to one-half ofother noninsulin antidiabetic drug use was not concomitant with metformin usedespite guidelines recommending that metformin be continued when otheragents are added to treatment.

In 2010, 18.8 million adults in the U.S. had been diagnosed with diabetes mellitus,7.0 million additional Americans were affected by undiagnosed diabetes, and anestimated 1.9 million adults received a new diagnosis of diabetes during that year(1). The number of Americans with diabetes who have or have not received a di-agnosis is expected to increase to 44.1 million in 2034 (2). In 2012, the total cost ofdiabetes was estimated at $245 billion, including $176 billion in direct medical costsand $69 billion in reduced productivity (3). Spending on antidiabetic drugs ac-counted for $18.3 billion (3).

1Division of Epidemiology-I, Office of Pharmaco-vigilance and Epidemiology, Office of Surveil-lance and Epidemiology, Center for DrugEvaluation and Research, U.S. Food and DrugAdministration, Silver Spring, MD2Division of Medication Error Prevention andAnalysis, Office of Medication Error Preventionand RiskManagement, Office of Surveillance andEpidemiology, Center for Drug Evaluation andResearch, U.S. Food and Drug Administration,Silver Spring, MD3Division of Epidemiology-II, Office of Pharmaco-vigilance and Epidemiology, Office of Surveil-lance and Epidemiology, Center for DrugEvaluation and Research, U.S. Food and DrugAdministration, Silver Spring, MD

Corresponding author: Christian Hampp, [email protected].

Received 30 September 2013 and accepted 15January 2014.

This article reflects the views of the authors anddoes not necessarily reflect the views or policiesof the U.S. Food and Drug Administration.

© 2014 by the American Diabetes Association.See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

Christian Hampp,1

Vicky Borders-Hemphill,2

David G. Moeny,3 and Diane K. Wysowski1

Diabetes Care Volume 37, May 2014 1367

EPIDEM

IOLO

GY/H

EALTH

SERVICES

RESEA

RCH

Although intensive lifestyle interven-tions (4) and bariatric surgery in obesediabetic patients (5–7) have been shownto improve or even reverse diabetesmellitus, most patients require pharma-ceutical management of their disease(8). Indeed, between 2007 and 2010,only 52.2% of diabetic patients hadHbA1c levels ,7.0%, and only 14.3%met the combined goal of controlledHbA1c level, blood pressure, and LDLcholesterol level and nonsmokingstatus (8).The antidiabetic drug market is char-

acterized by a number of new drugsthat have been introduced during thelast decade. These are the amylin analogpramlintide (approved in 2005); glucagon-like peptide 1 (GLP-1) analogs (exenatideimmediate release, 2005; liraglutide,2010; exenatide extended release,2012); dipeptidyl peptidase-4 (DPP-4) in-hibitors (sitagliptin, 2006; saxagliptin,2009; linagliptin, 2011; alogliptin, 2013);a bile acid sequestrant (colesevelam,2009); a dopamine agonist (bromocriptine,2009); and a sodium glucose transportprotein-2 inhibitor (canagliflozin, 2013).Several of these agents were also ap-proved as combination products con-taining metformin or simvastatin.The field of antidiabetic drugs experi-

enced not only the addition of newdrugs, but also emerging safety con-cerns of established drugs. In 2007, ameta-analysis (9) raised concerns re-garding the cardiovascular safety of ro-siglitazone, which was later pulled fromthe European market (10), and its usewas severely restricted in the U.S. (11).Safety concerns also arose about theother remaining thiazolidinedione,pioglitazone, regarding its role in heartfailure (12) and bladder cancer (13).This study describes the U.S. market

trends for prescription antidiabeticdrugs from 2003 through 2012. Wehighlight the market uptake of drugs ap-proved during this decade and how theuse of thiazolidinediones was affectedby recent safety concerns. Additionaldetails by active ingredients are pro-vided for all antidiabetic drugs for theyear 2012, including an analysis of con-comitant use.

RESEARCH DESIGN AND METHODS

We queried the IMS Health Vector OneNational and Total Patient Tracker data-bases for prescription antidiabetic drug

use in the U.S. adult population (ages$20 years), annually from 2003 through2012. The IMS Health databases arelarge commercial prescription and pa-tient databases of drugs dispensedfrom outpatient retail pharmacies. IMSHealth contracts with retail pharmacies,software providers, and pharmacyclaims aggregators to obtain dispensedprescription data from two-thirds of the;59,000 U.S. retail pharmacies, ac-counting for approximately one-half ofall retail prescriptions dispensed in theU.S. On an ongoing basis, IMS Healthprojects these data to the national levelby using a proprietary method incorpo-rating geography, pay type, and class oftrade (e.g., retail, independent, massmerchandisers).

Based on IMS Health data and U.S.Census Bureau population estimates,we calculated the annual population-adjusted rates of antidiabetic drug users,and the proportion of insulin users andusers of noninsulin antidiabetic drugs.These categories were not mutually ex-clusive, and users of noninsulin antidia-betic drugs included patients who usedinsulin in addition to their noninsulin an-tidiabetic drug. Next, we obtained theannual number of prescriptions dis-pensed by class for all antidiabetic drugclasses and prescriptions dispensed byactive ingredient for noninsulin antidia-betic drugs that were newly introducedto themarket during the observation pe-riod. Additional analyses in the IMSHealth databases focused on the annualuse of thiazolidinediones, and, for theyear 2012, the number of prescriptionsand users by active ingredient. Toinvestigate a shift from retail to mail-order pharmacies as a consequence ofrestricted distribution of rosiglitazone,we accessed the Symphony Health Sol-utions PHAST Prescription Monthly da-tabase, which, unlike the IMS Healthdatabases used in our primary analyses,also contains mail-order prescriptions.This analysis was not restricted toadult use.

We further extracted information onthe concomitant use of antidiabeticdrugs during the year 2012 using theEncuity Research Treatment Answersdatabase. This database includes datafrom a survey of .3,200 office-basedphysicians representing 30 specialtiesacross the U.S. who report on all patientactivity during 1 typical workday per

month. Encounter forms include basicpatient demographic information, diag-noses, and treatments. Physicians arerecruited by region and specialty basedon the American Medical Associationmailing list, which includes memberand nonmember physicians. No filter isapplied with regard to physician affilia-tion, and physicians in large health caresystems are also invited to participate.We interpreted an office visit wheremore than one antidiabetic drug wasmentioned as concomitant use of thesedrugs. In this context, drugs mentionedduring an office visit include ongoingtherapy, issuance of prescriptions, orthe dispensing of drug samples. Combi-nation products were treated as con-comitant use of two antidiabetic drugs.The Treatment Answers database wasalso used to investigate diagnoses asso-ciated with the use of metformin. Alldata are nationally projected.

Our analyses included all antidia-betic drugs available in 2012, with theexception of colesevelam. Colesevelamwas approved for treatment of type 2diabetes in 2009, but it also carries anestablished indication for hypercholes-terolemia, thus not permitting us toanalyze its use for the treatment of di-abetes in the IMS Health database.Bromocriptine was also approvedfor type 2 diabetes in 2009, and it isan established therapy for Parkinson’sdisease, hyperprolactinemia, and acro-megaly. However, one bromocriptineproduct (Cycloset; Santarus, San Diego,CA) is exclusively indicated for thetreatment of type 2 diabetes melli-tus, and we included Cycloset in ouranalyses.

Summary statistics and linear regres-sion analysis to describe longitudinaltrends in the total number of antidia-betic drug users were computed in Excel2010 (Microsoft, Redmond, WA). Popu-lation rates of drug use were calculatedusing U.S. Census Bureau estimates ofthe U.S. adult population (14).

RESULTS

Longitudinal Trends in AntidiabeticDrug UseAccording to IMS Health data, ;18.8million adults filled antidiabetic drugprescriptions from U.S. retail pharma-cies in 2012. This number represents a42.9% increase from 13.2 million in2003, and an average annual increase

1368 Use of Antidiabetic Drugs in the U.S. Diabetes Care Volume 37, May 2014

by 650,229 (95% CI 519,490–780,968).On a per capita level, 81.3 per 1,000adults filled antidiabetic drug prescrip-tions in 2012, a 28.9% relative increasefrom 63.1 per 1,000 adults in 2003. Al-though rates of antidiabetic drug usehave increased since 2003, the propor-tion of insulin users (27.1% in 2012) andthe proportion of noninsulin antidia-betic drug users (86.7% in 2012) amongall antidiabetic drug users remainedconstant over time.Figure 1A shows an increase in the

total number of prescriptions for non-insulin antidiabetic drugs by 36.2%,from 88.8 million prescriptions in 2003to 120.9 million in 2012. During this de-cade, the use of biguanides (metformin)increased by 97.0% to 60.4 million

prescriptions in 2012. The use of sulfo-nylureas remained constant in terms ofprescription volume, but their shareamong noninsulin antidiabetic drug pre-scriptions decreased from 36.3% in 2003to 26.7% in 2012. During this period, theuse of thiazolidinediones decreased by64.0%.

Among the noninsulin antidiabeticdrugs that were newly introduced tothe market between 2003 and 2012,the DPP-4 inhibitor sitagliptin gainedthe largest share with 10.5 million pre-scriptions (single ingredient or combina-tion products) in 2012 (Fig. 1B). AmongGLP-1 analogs, immediate-release exe-natide (Byetta; Bristol-Myers Squibb,New York, NY) first entered the markedin 2005, and its use peaked in 2008 at 2.5

million prescriptions. An increase in theuse of liraglutide, which first assumedleadership of the GLP-1 analog marketin 2011, was paralleled by a 49.5% de-cline in the use of exenatide-containingproducts. A once-weekly extended-release version of exenatide (Bydureon;Bristol-Myers Squibb) was approved bythe U.S. Food and Drug Administration(FDA) in January 2012 and represented20.3% of all exenatide prescriptions in2012 (data from both exenatide productsare combined in Fig. 1B).

The use of thiazolidinediones is char-acterized by recent steep declines (Fig.2). Rosiglitazone-containing productsdeclined from their peak in 2006, when12.7 million prescriptions were dis-pensed, to ,1,000 prescriptions dis-pensed by retail pharmacies in 2012.The use of pioglitazone-containingproducts started a slow decline follow-ing its peak in 2008 when 14.2 millionprescriptions were dispensed. This de-cline accelerated in recent years, and6.8million prescriptions were dispensedin 2012, down 52.1% from the peak in2008. Using the Symphony Health Solu-tions PHAST Prescription Monthly data-base, we found 12,597 prescriptions ofrosiglitazone-containing products dis-pensed in a retail or mail-order settingin 2012. Unlike analyses based on IMSHealth data, this estimate was not re-stricted to adult use.

Antidiabetic Drug Use in 2012In 2012, 154.5 million prescriptionswere dispensed for antidiabetic drugs,78.4% of which were for noninsulin an-tidiabetic drugs (Table 1). About one inevery two noninsulin antidiabetic drugprescriptions was for single-ingredientmetformin,whichwasusedby11.8millionof 16.3 million noninsulin antidiabeticdrug users (72.3%).More than one-quarterof noninsulin antidiabetic drug pre-scriptions was for sulfonylureas, andalmost all of them were divided betweenthree second-generation sulfonylureas(glipizide, glimepiride, and glyburide).DPP-4 inhibitors dominated the new classof incretin mimetic drugs, which also in-cludes the GLP-1 analogs. In comparison,the use of some other drugs that were re-cently introduced to the diabetic market,such as pramlintide and bromocriptine,was infrequent.

In 2012, 33.4 million insulin prescrip-tions were dispensed to 5.1 million

Figure 1—A: Trends in noninsulin antidiabetic drug prescriptions filled in U.S. retail pharmacies2003–2012. B: Prescriptions of recently approved noninsulin antidiabetic drugs filled in U.S.retail pharmacies, 2003–2012. AD, antidiabetic drugs. Source: IMS Health Vector One National.

care.diabetesjournals.org Hampp and Associates 1369

patients. The insulin market was domi-nated by long-acting human analog in-sulin, mostly insulin glargine, followedby fast-acting human analog insulin,mostly insulin aspart and insulin lispro.In 2012,metforminwas predominantly

used for the treatment of diabetes-related diagnoses (97.6%). Other useswere for gynecologic diagnoses (1.8%,predominantly for polycystic ovary dis-ease), disorders related to obesity (0.1%),or other diagnoses (0.5%).

Concomitant Antidiabetic Drug Use in2012Concomitant use of more than one an-tidiabetic drug class in 2012 is displayedin Table 2 for the most commonly usedantidiabetic drug classes. This tableshows that 44.9% of metformin usewas for monotherapy, 22.1% was con-comitant with the use of sulfonylureas,22.0% was concomitant with the use ofDPP-4 inhibitors, and 9.7% was concom-itant with the use of long-acting insulin.In contrast, between 51.9% (GLP-1 ana-logs) and 66.6% (thiazolidinediones) ofnoninsulin antidiabetic drug use wasconcomitant with the use of metformin.Almost one-third of long-acting insulinuse was concomitant with the use offast-acting insulin, and, conversely, al-most two-thirds of fast-acting insulinuse was concomitant with the use oflong-acting insulin.

CONCLUSIONS

This study adds current and nationallyprojected estimates to previous studiesdescribing the use of antidiabetic drugs(15–19).Wedocumented a steady increase

in the number of patients who usedantidiabetic drugs and in the numberof dispensed prescriptions in U.S. re-tail pharmacies. Our estimate of 18.8million antidiabetic drug users in 2012is identical to the Centers for DiseaseControl and Prevention estimate (1) ofpatients in whom diabetes has been di-agnosed (18.8 million in 2010). How-ever, our number should not be takenas the actual number of diabetic pa-tients because not every patient whoreceives a diagnosis of diabetes usesantidiabetic drugs, the number of pa-tients with diagnosed diabetes likelyincreased during the 2 years betweenthe Centers for Disease Control andPrevention estimate and our estimate,and not all antidiabetic drugs are usedsolely for diabetes. Nevertheless, thefact that these numbers are so similar,although obtained through very differ-ent methodology, provides reassur-ance regarding data validity.

Our study illustrated the roles thatdifferent antidiabetic drugs play in themanagement of diabetes; chief amongthem was metformin, which representsone of every two prescriptions for non-insulin antidiabetic drugs. This marksthe continuation of a remarkable trend:in 1996, the year after metformin wasapproved in the U.S., 19.0% of all oralantidiabetic drug prescriptions were formetformin, and this proportion in-creased to 32.7% in 2001 (19). Almost11.8 million patients (62.7% of all pa-tients who received antidiabetic drugs)used single-ingredient metformin in2012 (Table 1), and 44.9% of patientsto whom metformin was dispensed

used the drug as monotherapy (Table2), consistent with recommendationsby the American Diabetes Associationand the European Association for theStudy of Diabetes to use metformin asfirst-line therapy (20). Although metfor-min was used for other indications, thevast majority of prescriptions was forthe treatment of diabetes.

While the share of sulfonylurea usedecreased, antidiabetic drugs thatwere approved during the last decadequickly gained significant market share.The most commonly prescribed newclass was the DPP-4 inhibitors, whichare available as oral tablets. InjectableGLP-1 analogs have also been widelyused; however, between them, liraglu-tide has continued to gain market sharewhile the use of exenatide declined. Lir-aglutide requires one daily injection,compared with twice-daily injections re-quired for immediate-release exena-tide, which may partially explain thistrend. An extended-release version ofexenatide, which requires only oneweekly injection, was approved by theFDA in January 2012, and it reached a20% share of all exenatide prescriptionsduring that year.

During the last decade, several com-bination products were approved, andtheir early rise in prescriptions hasbeen documented before (15). Alexanderet al. (15) found that 15% of treatmentvisits in 2004 were associated with oralcombination products (first introducedin 2000), but this increase did not con-tinue (13% in 2007). We found that in2012, only 6.7% of noninsulin anti-diabetic drug prescriptions were forcombination products, predominantlycombinations of metformin with eithersitagliptin or glyburide. While combi-nation products using metformin rep-resented a substantial share of DPP-4inhibitor–containing products, they playeda smaller role among sulfonylureas orthiazolidinediones.

Our analysis of the concomitant useof antidiabetic drugs in 2012 showedthat only one-half to two-thirds of sul-fonylurea, DPP-4 inhibitor, thiazolidine-dione, and GLP-1 analog use wasconcomitant with metformin use. Thisoccurred despite guideline recommen-dations of continuing metformin usewhen adding another noninsulin antidia-betic drug to therapy, unlessmetformin iscontraindicated or not well-tolerated

Figure 2—Thiazolidinedione prescriptions filled in U.S. retail pharmacies, 2003–2012. Source:IMS Health Vector One National.

1370 Use of Antidiabetic Drugs in the U.S. Diabetes Care Volume 37, May 2014

Table

1—Antidiabetic

dru

gdispensingin

U.S.retailpharmacies,

2012

Drugclass

Totalp

rescriptions(N

)Prescriptions,sharein

NIADorinsulin

(%)

Patien

ts(N

)*Drug

Prescriptions,share

inclass(%

)Patien

ts(N

)*

Noninsulin

antidiabeticdrugs

121,05

5,25

010

016

,316

,580

Biguanides

60,368

,335

49.9

11,792

,980

Metform

in10

0.0

11,792

,980

Sulfonylureas

32,341

,020

26.7

6,12

1,488

Glipizide

44.7

2,75

7,53

2Glim

epiride

33.0

2,06

4,24

1Glyburide

22.3

1,45

7,50

4Chlorpropam

ide

,0.1

3,23

5Tolbutamide

,0.1

1,09

9Tolazamide

,0.1

938

Acetohexam

ide

,0.1

2DPP

-4inhibitors

9,70

3,82

18.0

1,87

0,819

Sitagliptin

76.4

1,43

1,12

4Saxagliptin

17.3

331,983

Linagliptin

6.4

160,825

AD/ADcombination

8,10

9,41

36.7

1,50

4,542

Sitagliptin/m

etform

in38

.560

0,099

Glyburide/metform

in35

.152

1,878

Pioglitazone/metform

in11

.818

0,681

Saxagliptin/m

etform

in9.8

165,633

Glipizide/metform

in3.5

57,467

Pioglitazone/glim

epiride

0.8

11,408

Linagliptin/m

etform

in0.5

14,398

Rep

aglinide/metform

in0.1

1,26

7Rosiglitazone/metform

in,0.1

252

Rosiglitazone/glim

epiride

,0.1

62Thiazolidined

iones

5,77

0,13

14.8

1,08

3,193

Pioglitazone

100.0

1,08

2,93

8Rosiglitazone

,0.1

350

GLP-1

analogs

3,13

6,56

42.6

673,367

Liraglutide

59.1

415,075

Exen

atide

40.9

286,613

Meglitinides

1,07

9,35

60.9

226,628

Rep

aglinide

54.0

122,959

Nateglinide

46.0

106,235

a-Glucosidaseinhibitors

356,85

20.3

80,506

Acarbose

92.0

74,794

Miglitol

8.0

6,04

4Amylin

analogs

110,37

30.1

28,809

Pram

lintide

100.0

28,809

Dopam

inereceptoragonist

66,999

0.1

17,808

Bromocriptine

100.0

17,808

AD/non-ADcombination

12,386

0.0

3,57

1Sitagliptin/sim

vastatin

100.0

3,57

1

Insulinsandinsulin

analogs

33,406

,589

100

5,08

8,495

Analoghuman

long-acting

17,311

,225

51.8

3,65

0,111

Insulin

glargine

81.3

2,97

4,37

3Insulin

detem

ir18

.776

7,443

Analoghuman

fast-acting

9,05

6,52

327

.12,17

2,770

Insulin

aspart

51.8

1,21

2,20

8Insulin

lispro

43.8

969,550

Insulin

glulisine

4.4

101,156

Con

tinu

edon

p.13

72

care.diabetesjournals.org Hampp and Associates 1371

(20). Previous studies (21–25) have iden-tified the presence of contraindicationsamong users of metformin; however,whether contraindications or lack oftolerability explain why metformin isnot used more often with second-lineantidiabetic drugs is subject to furtherresearch.

A steepdecline in theuseof rosiglitazone-containing products after the publica-tion of the meta-analysis by Nissen andWolski (9) reporting an association be-tween rosiglitazone and cardiovascu-lar events has been well-documented,both in the U.S. (26–32) and abroad(33–35). However, to our knowledge,our study is the first to also evaluatethiazolidinedione use patterns afterrosiglitazone restrictions were imple-mented by the FDA in May 2011 (11).Since then, rosiglitazone-containing prod-ucts have been limited to patients alreadybeing successfully treated with thesemedicines, and to patients whose bloodglucose level cannot be controlled withother antidiabetic drugs and who, afterconsulting with their health care pro-viders, do not wish to use pioglitazone-containing medicines. To implement thisrestriction, since November 2011, healthcare providers and patients had to be en-rolled in a special access program, androsiglitazone-containing products couldbe obtained only through specially certi-fied mail-order pharmacies. Our analysisfound12,597prescriptionsof rosiglitazone-containing products dispensed in a retailor mail-order setting in 2012. Comparedwith ,1,000 rosiglitazone prescriptionsdetected in our primary analysis basedon retail pharmacies, this number indi-cates that the majority of rosiglitazonewas obtained through mail order. Never-theless, the overall use of rosiglitazone-containing products in 2012 was almostnegligible. Pioglitazone-containingproducts represented almost all thia-zolidinedione use, with 6.8 million dis-pensed prescriptions in 2012. Yet, thisnumber reached only half of the peakuse in 2008, despite the approval of thefirst generic form of pioglitazone inAugust 2012, highlighting the impactof potential safety concerns. InNovember2013, the FDA announced the removal ofrestrictions for rosiglitazone on patients,prescribers, and pharmacies (36). Futureresearch should describe the impact ofrelaxing prescription requirements onrosiglitazone use.

Table

1—Continued

Drugclass

Totalp

rescriptions(N

)Prescriptions,sharein

NIADorinsulin

(%)

Patien

ts(N

)*Drug

Prescriptions,share

inclass(%

)Patien

ts(N

)*

Analoghuman

insulin

combinations

2,59

0,15

37.8

519,50

4Insulin

aspartprotamine/insulin

aspart

63.4

345,653

Insulin

NPL/insulin

lispro

19.4

91,009

Insulin

lispro

protamine/lispro

17.2

109,526

Human

insulin

combinations

1,88

4,24

55.6

371,34

1Insulin

human/insulin

NPH

human

100.0

371,579

Human

insulin

interm

ediate-acting

1,40

0,09

44.2

317,34

1Insulin

NPH

human

recombinant

62.9

207,487

Insulin

NPH

human

semi-synthesized

37.1

126,908

Human

insulin

fast-acting

1,16

4,30

03.5

343,36

0Insulin

regu

larhuman

recombinant

67.1

229,552

Insulin

regu

larhuman

semi-synthesized

32.9

127,267

Other

insulins

49,0.1

43Anim

alinsulins,human

insulin

long-acting,insulin

zinc,insulin

human

(isophane/regu

lar)

100.0

49

Total

154,46

1,839

18,810

,311

AD,antidiabeticdrugs;N

IAD,noninsulin

antidiabeticdrug;TZD,thiazolidined

ione;NPL,neu

tralprotaminelispro.Source:IM

SHealthVectorOneNationalandTotalPatientTracker.*Patientcountsacrossdrugs

inoneclassmay

notaddupto

totalp

atientcountsforthat

classbecause

patients

could

haveusedmore

than

onemem

ber

ofthedrugclassin

2012,

butwould

onlybecountedonce

ontheclasslevel.

1372 Use of Antidiabetic Drugs in the U.S. Diabetes Care Volume 37, May 2014

One strength of this study is the useof nationally projected data, withoutbeing limited to a certain health caresetting or population. However, wewere able to provide data only on anti-diabetic drug prescriptions dispensedfrom U.S. retail pharmacies. Usingwholesale sales data obtained fromthe IMS Health National Sales Perspec-tive, we estimated that in 2012, 68% ofnoninsulin antidiabetic drug containerswere shipped to retail pharmacies,while 21% were shipped to mail-orderpharmacies and 11% to nonretail set-tings, including, among others, clinics,hospitals, and long-term care facilities.For insulin, 59%, 23%, and 18% of drugcontainers were shipped to retail phar-macies, mail-order pharmacies, or thenonretail setting, respectively. We expectthat the total number of antidiabeticdrug users is still a valid estimate, asmost patients will fill a prescription forat least one antidiabetic drug in a retailpharmacy in a given year and, thus,would be included in our analysis. How-ever, users of our data should keep inmind that the total number of prescrip-tions dispensed applies only to the retailsetting. Similarly, our data did not cap-ture the use of over-the-counter insulin.Further, while the sample of retail phar-macies is large, representativeness is notnecessarily guaranteed, and changes inthe sampling scheme could affect trenddata.This study documented a 42.9% in-

crease in the number of patients whofilled antidiabetic drug prescriptions inU.S. retail pharmacies between 2003 and2012. Among 154.5 million antidiabetic

drug prescriptions in 2012, metforminwas the dominant noninsulin antidia-betic drug. Since 2003, several newclasses of antidiabetic drugs havegained significant market share, mostprominently DDP-4 inhibitors andGLP-1 analogs. This study further pro-vided patterns of thiazolidinedioneuse after restrictions were placed onrosiglitazone in 2011. In 2012, the useof rosiglitazone was almost negligible,and the use of pioglitazone decreasedto half of its peak level from 2008. Fi-nally, our concomitancy analysis foundthat about one-third to one-half ofsulfonylurea, DPP-4 inhibitor, thia-zolidinedione, and GLP-1 analog usewas not accompanied by metforminuse, despite recommendations in diabe-tes treatment guidelines.

Acknowledgments. The authors thank JustinMathew, Division of Epidemiology-II, Office ofPharmacovigilance and Epidemiology, Office ofSurveillance and Epidemiology, Center for DrugEvaluation and Research, U.S. Food and DrugAdministration, for his assistance in the extrac-tion of drug utilization data.Duality of Interest. No potential conflicts ofinterest relevant to this article were reported.Author Contributions. C.H. conceived anddesigned the study, acquired the data, per-formed analysis and interpretation of the data,drafted the manuscript, and performed thestatistical analysis. V.B.-H. and D.G.M. con-ceived and designed the study, acquired thedata, performed analysis and interpretationof the data, and performed critical revision ofthe manuscript. D.K.W. conceived and de-signed the study, and performed critical re-vision of the manuscript. C.H. is the guarantorof this work and, as such, had full access to allthe data in the study and takes responsibility for

the integrity of the data and the accuracy of thedata analysis.Prior Presentation. An earlier version of thisstudy with data through 2011 was presented as aposter at the International Conference on Phar-macoepidemiology and Therapeutic Risk Man-agement, Barcelona, Spain, 23–26 August 2012.

References1. Centers for Disease Control and Prevention.National Diabetes Fact Sheet: National Esti-mates and General Information on Diabetesand Prediabetes in the United States [Internet],2011. Atlanta, GA, U.S. Department of Healthand Human Services, Centers for Disease Con-trol and Prevention. Available from http://www.cdc.gov/diabetes/pubs/factsheet11.htm.Accessed 28 May 20132. Huang ES, Basu A, O’Grady M, Capretta JC.Projecting the future diabetes population sizeand related costs for the U.S. Diabetes Care2009;32:2225–22293. American Diabetes Association. Economiccosts of diabetes in the U.S. in 2012. DiabetesCare 2013;36:1033–10464. Gregg EW, Chen H, Wagenknecht LE, et al.;Look AHEAD Research Group. Association of anintensive lifestyle intervention with remissionof type 2 diabetes. JAMA 2012;308:2489–24965. Buchwald H, Estok R, Fahrbach K, et al.Weight and type 2 diabetes after bariatric sur-gery: systematic review and meta-analysis. Am JMed 2009;122:248–256, e56. Schauer PR, Kashyap SR, Wolski K, et al. Bari-atric surgery versus intensivemedical therapy inobese patients with diabetes. N Engl J Med2012;366:1567–15767. Mingrone G, Panunzi S, De Gaetano A, et al.Bariatric surgery versus conventional medicaltherapy for type 2 diabetes. N Engl J Med2012;366:1577–15858. Ali MK, Bullard KM, Saaddine JB, Cowie CC,Imperatore G, Gregg EW. Achievement of goalsin U.S. diabetes care, 1999-2010. N Engl J Med2013;368:1613–16249. Nissen SE,Wolski K. Effect of rosiglitazone onthe risk of myocardial infarction and death fromcardiovascular causes. N Engl J Med 2007;356:2457–2471

Table 2—Concomitant therapy among the most common antidiabetic drug classes, 2012

Use of thisclass

Concomitant with

No otherantidiabetic drug Biguanides Sulfonylureas

DPP-4inhibitors TZDs

GLP-1analogs

Insulin, analog humanlong-acting

Insulin, analog humanfast-acting

Biguanides 44.9 d 22.1 22.0 8.0 4.0 9.7 2.4

Sulfonylureas 28.0 61.0 d 15.4 9.4 3.7 10.3 1.9

DPP-4inhibitors 25.5 65.1 16.4 d 5.3 1.3 8.7 2.7

TZD 19.4 66.6 28.5 14.9 d 5.6 7.9 ,1.0*

GLP-1 analogs 37.3 51.9 17.3 5.5 8.7 d 18.7 3.2

Insulin, analoghuman

Long-acting 32.7 31.7 12.3 9.7 3.1 4.8 d 31.4Fast-acting 25.7 16.1 4.6 6.2 ,1.0* 1.7 64.1 d

Data are given as %. Row totals can exceed 100% because of patients usingmore than two antidiabetic drugs. TZD, thiazolidinedione. Source: EncuityResearch Answer Generator. *Shares ,1.0% are not displayed.

care.diabetesjournals.org Hampp and Associates 1373

10. European Medicines Agency. EuropeanMedicines Agency Recommends Suspension ofAvandia, Avandamet and Avaglim [Internet],2010. London, U.K., European MedicinesAgency. Available from http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/09/news_detail_001119.jsp&mid=WC0b01ac058004d5c1. Accessed 29May 201311. U.S. Food and Drug Administration. FDADrug Safety Communication: Updated Risk Eval-uation and Mitigation Strategy (REMS) to Re-strict Access to Rosiglitazone-ContainingMedicines Including Avandia, Avandamet, andAvandaryl [Internet], 2011. Silver Spring, MD,U.S. Food and Drug Administration. Availablefrom http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm. Accessed 29 May 201312. U.S. Food and Drug Administration. Informa-tion for Healthcare Professionals: PioglitazoneHCl (Marketed as Actos, Actoplus Met, andDuetact) [Internet], 2007. Silver Spring, MD,U.S. Food and Drug Administration. Availablefrom http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124178.htm. Accessed 29May 201313. U.S. Food and Drug Administration. Actos(Pioglitazone): Ongoing Safety ReviewdPotentialIncreased Risk of Bladder Cancer [Internet],2011. Silver Spring, MD, U.S. Food and DrugAdministration. Available from http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm226257.htm. Accessed 29 May 201314. U.S. Census Bureau. National PopulationProjections [Internet], 2012. Washington, DC,U.S. Census Bureau. Available from http://www.census.gov/population/projections/files/downloadables/NP2012_D1.csv. Accessed 30May 201315. Alexander GC, Sehgal NL, Moloney RM,Stafford RS. National trends in treatment oftype 2 diabetesmellitus, 1994-2007. Arch InternMed 2008;168:2088–209416. Johnson JA, Pohar SL, Secnik K, Yurgin N,Hirji Z. Utilization of diabetes medication andcost of testing supplies in Saskatchewan, 2001.BMC Health Serv Res 2006;6:159

17. Theodorou A, Johnson K, Ward M,Szychowski JA. 2010 drug utilization and costtrends for antidiabetic agents. Am J Pharm Ben-efits 2011;3:54–6118. Margolis DJ, Leonard CE, Razzaghi H, et al.Utilization of Antidiabetic Drugs Among Medi-care Beneficiaries With Diabetes, 2006-2009,Data Points Publication Series [Internet], 2012.Rockville, MD, Agency for Healthcare Researchand Quality. Available from http://www.ncbi.nlm.nih.gov/books/NBK92702/. Accessed 20January 201419. Wysowski DK, Armstrong G, Governale L.Rapid increase in the use of oral antidiabeticdrugs in the United States, 1990-2001. DiabetesCare 2003;26:1852–185520. Inzucchi SE, Bergenstal RM, Buse JB, et al.;American Diabetes Association (ADA); Euro-pean Association for the Study of Diabetes(EASD). Management of hyperglycemia in type2 diabetes: a patient-centered approach: posi-tion statement of the American Diabetes Asso-ciation (ADA) and the European Association forthe Study of Diabetes (EASD). Diabetes Care2012;35:1364–137921. Sulkin TV, Bosman D, Krentz AJ. Contraindi-cations to metformin therapy in patients withNIDDM. Diabetes Care 1997;20:925–92822. Calabrese AT, Coley KC, DaPos SV, SwansonD, Rao RH. Evaluation of prescribing practices:risk of lactic acidosis with metformin therapy.Arch Intern Med 2002;162:434–43723. Kennedy L, Herman WH; GOAL A1C StudyTeam. Renal status among patients using met-formin in a primary care setting. Diabetes Care2005;28:922–92424. Vasisht KP, Chen SC, Peng Y, Bakris GL. Lim-itations of metformin use in patients with kid-ney disease: are they warranted? Diabetes ObesMetab 2010;12:1079–108325. Horlen C, Malone R, Bryant B, et al. Fre-quency of inappropriate metformin prescrip-tions. JAMA 2002;287:2504–250526. Starner CI, Schafer JA, Heaton AH, GleasonPP. Rosiglitazone and pioglitazone utilizationfrom January 2007 through May 2008 associ-ated with five risk-warning events. J ManagCare Pharm 2008;14:523–531

27. Stewart KA, Natzke BM,Williams T, GrangerE, Casscells SW, Croghan TW. Temporal trendsin anti-diabetes drug use in TRICARE followingsafety warnings in 2007 about rosiglitazone.Pharmacoepidemiol Drug Saf 2009;18:1048–105228. Cohen A, Rabbani A, Shah N, Alexander GC.Changes in glitazone use among office-basedphysicians in the U.S., 2003-2009. DiabetesCare 2010;33:823–82529. Shah ND, Montori VM, Krumholz HM, Tu K,Alexander GC, Jackevicius CA. Responding to anFDA warningdgeographic variation in the useof rosiglitazone. N Engl J Med 2010;363:2081–208430. Shi L, Zhao Y, Szymanski K, Yau L, Fonseca V.Impact of thiazolidinedione safety warnings onmedication use patterns and glycemic controlamong veterans with diabetes mellitus. J Diabe-tes Complications 2011;25:143–15031. Marks DH. Drug utilization, safety and clin-ical use of Actos and Avandia. Int J Risk Saf Med2013;25:39–5132. Hurren KM, Taylor TN, Jaber LA. Antidia-betic prescribing trends and predictors of thia-zolidinedione discontinuation following the2007 rosiglitazone safety alert. Diabetes ResClin Pract 2011;93:49–5533. Rawson NS, Terres JA. Rosiglitazone useand associated adverse event rates in Canadabetween 2004 and 2010. BMC Res Notes2013;6:8234. Ruiter R, Visser LE, van Herk-SukelMP, et al.Prescribing of rosiglitazone and pioglitazone fol-lowing safety signals: analysis of trends in dis-pensing patterns in the Netherlands from 1998to 2008. Drug Saf 2012;35:471–48035. Morrow RL, Carney G, Wright JM, Bassett K,Sutherland J, Dormuth CR. Impact of rosiglita-zone meta-analysis on use of glucose-loweringmedications. Open Med 2010;4:e50–e5936. U.S. Food and Drug Administration. FDA Re-quires Removal of Certain Restrictions on theDiabetes Drug Avandia [Internet]. Silver Spring,MD, U.S. Food and Drug Administration. Avail-able from http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm376516.htm. Accessed 3 December 2013

1374 Use of Antidiabetic Drugs in the U.S. Diabetes Care Volume 37, May 2014