Research
`
`JAMA I Original Investigation
`Association of Initiation of Basal Insulin Analogs vs Neutral
`Protamine Hagedorn Insulin With Hypoglycemia-Related
`Emergency Department Visits or Hospital Admissions
`and With Glycemic Control in Patients With Type 2 Diabetes
`
`l<asia J. Lipska. MD, MHS: Melissa M. Parker. MS: Howard H. Moffet. MPH: Elbert S. Huang. MD. MPH: Andrew J. Karter. PhD
`
`IMPORTANCE In clinical trials of patients with type 2 diabetes, long-acting insulin analogs
`modestly reduced the risk of nocturnal hypoglycemia compared with human neutral
`protamine Hagedorn (NPH) insulin. but cost 2 to 10 times more. Outcomes in clinical practice
`may differ from trial results.
`
`OBJEaiVE To compare the rates of hypoglycemia-related emergency department (ED) visits
`or hospital admissions associated with initiation of long-acting insulin analogs vs human NPH
`insulin in patients with type 2 diabetes.
`
`DESIGN. SETIING. AND PARTICIPANTS A retrospective observational study using data from
`Kaiser Permanente of Northern California from January 1, 2006, through September 30,
`2015. Patients with type 2 diabetes who initiated a long-acting insulin analog or NPH insulin
`were included and censored at death, loss of health plan coverage, change in insulin
`treatment. or study end on September 30. 201S.
`
`EXPOSURE Initiation of basal insulin analogs (glargine or detemir) vs NPH insulin.
`
`MAIN OUTCOMES AND MEASURES The primary outcome was the time to a hypoglycemia(cid:173)
`related ED visit or hospital admission and the secondary outcome was the change in
`hemoglobin A1e level within 1 year of insulin initiation.
`
`RESULTS There were 2S 489 patients with type 2 diabetes who initiated basal insulin therapy
`(mean age, 60.2 [SO. 11.8] years; 51.9% white; 46.8% female). During a mean follow-up of 1.7
`years. there were 39 hypoglycemia-related ED visits or hospital admissions among 1928
`patients who initiated insulin analogs (11.9 events [95% Cl. 8.1 to 15.6] per 1000
`person-years) compared with 354 hypoglycemia-related ED visits or hospital admissions
`among 23 561 patients who initiated NPH insulin (8.8 events [95% Cl, 7.9 to 9.8] per 1000
`person-years) (between-group difference. 3.1 events [95% Cl, -1.5 to 7.7] per 1000
`person-years; P = .07). Among 4428 patients matched by propensity score. the adjusted
`hazard ratio was 1.16 (95% Cl, 0.71 to 1.78) for hypoglycemia-related ED visits or hospital
`admissions associated with insulin analog use. Within 1 year of insulin initiation. hemoglobin
`A1e level decreased from 9.4% (95% Cl. 9.3% to 9.5%) to 8.2% (95% Cl. 8.1% to 8.2%) after
`initiation of insulin analogs and from 9.4% (95% Cl. 9.3% to 9.5%) to 7.9% (95% Cl, 7.9% to
`8.0%) after initiation of NPH insulin (adjusted difference-in-differences for glycemic control,
`-0.22% [95% Cl, -0.09% to -0.37%]).
`
`CONCLUSIONS AND RELEVANCE Among patients with type 2 diabetes, initiation of a basal
`insulin analog compared with NPH insulin was not associated with a reduced risk of
`hypoglycemia-related ED visits or hospital admissions or with improved glycemic control.
`These findings suggest that the use of basal insulin analogs in usual practice settings may not
`be associated with clinical advantages for these outcomes.
`
`JAMA. 2018:320(1):53·62. doi: 10.1001/Jama.2018.7993
`Published online June 23. 2018.
`
`t: Editorial page 38
`G Author Aud1o Interview
`
`Author Affiliations: Section of
`Endocrinology. Department of
`Internal Medicine. Yale University
`School of Medicine. New Haven.
`Connecticut (Lipska): Division of
`Research. Kaiser Permanente of
`Northern California, Oakland (Parker.
`Moffet, Karter): Department of
`Medicine, University of Chicago,
`Chicago. Illinois (Huang): Department
`of General Internal Medicine.
`University of California. San Francisco
`(Karter): Department of
`Epidemiology. University of
`Washington. Seattle (Karter):
`Department of Health Services.
`University of Washington. Seattle
`(Karter).
`Corresponding Author: Kasia J.
`Lipska. MD. MHS. Yale School
`of Medicine. PO Box 208020.
`New Haven. CT 06520
`(~aSia ltpsk.1@y.1le edu).
`
`© 2018 American Medical Association. All rights reserved.
`
`53
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`Ex. 1035, p. 1 of 10
`
`

`

`Research Orig1nallnvestigat1on
`
`Association Between Basal Insulin Analog vs NPH Insulin Initiation and Hypoglycemic Events in Type 2 Diabetes
`
`T reatment of type 2 diabetes typically begins with life(cid:173)
`
`style modification and initiation of metformin; how(cid:173)
`ever, 14% to 25% of patients eventually require initia(cid:173)
`tion o f insulin to reach recommended glyce mic targets. 1•2
`The mainstay of insulin treatment has long been human syn(cid:173)
`thetic insulin; however, insulin analogs have become increas(cid:173)
`ingly popular in clinical practice during the past decade.3.4
`lnsulin analogs are molecularly altered forms of insulin that
`more closely mimic the pharmacokinetic profile of endoge(cid:173)
`nous insulin.
`In clinical trials, long-acting insulin analogs modestly re(cid:173)
`duce the risk of nocturnal hypoglycemia compared with hu(cid:173)
`man insulin, but have not been shown to reduce the risk of se(cid:173)
`vere hypoglycemia or to improve glycemic control among
`patients with type 2 diabetes. 5 Discrepancies between trial re(cid:173)
`sults and outcomes in clinical practice are common and high(cid:173)
`light the importance of gathering additional evidence from
`usual care settings.6
`Although human insulin products are still used preferen(cid:173)
`tially within Kaiser Permanente ofNorthern California (KPNC),
`prior work demons trated widespread adoption of insulin
`7
`analogs a mong US patients during the past 2 decades. 3
`·"·
`At the same time, the prices of insulin analogs have increased
`dramatically, 8 ·9 Medicaid payments for insulin ha ve in(cid:173)
`creased substantially,'" and patients' out-of-pocket spending
`on insulin analogs has doubled.'1 In this setting, it is impera(cid:173)
`tive to understand the differences in health outcomes associ(cid:173)
`ated with the use of the more expensive insulin analogs vs the
`more affordable human insulin products.
`This stud y investigated the rates of hypoglyce mia (cid:173)
`related emergency department (ED) visits or hospital admis(cid:173)
`sions and changes in levels of glycemic control after initiation
`of long-acting insulin analogs (glargine or deterriir) compared
`with human neutral protamine Hagedorn (NPH) insulin among
`patients with type 2 diabetes in clinical practice.
`
`Methods
`
`Study Source
`The institutional review boards of the Kaiser Foundation Re(cid:173)
`search Institute and the University of Chicago approved the
`study. Participant informed consent was waived. A large, in(cid:173)
`tegrated health care delivery system, KPNC provides care for
`approximately 30% of the residents in the Northern California
`service area. The KPNC diabetes registry has been main(cid:173)
`tained since 1993. The registry now includes more than
`350 000 adults with diabetes and is updated annually by iden(cid:173)
`tifying all health plan members with diabetes.
`The identification of clinically recognized diabetes
`among health plan me mbers is based on multiple sources
`of data including pharmacy use; laboratory results; a nd
`outpatie nt, emergency department, and hospitalization
`diagnoses of diabetes detailed further in a published algo(cid:173)
`rithm.11 Race/ethnicity was measured because prior studies
`suggest it is associated with both hypoglycemia and glyce(cid:173)
`mic control. 12
`13 Determination of race/ethnicity was based
`•
`on self-reported race/ethnicity captured in the electronic
`
`Key Points
`Question Is initiation of a basal insulin analog compared with
`human neutral protamine Hagedorn (NPH) insulin associated
`with a reduced risk of hypoglycemia-related emergency
`department (ED) visits or hospital admissions in patients with
`type 2 diabetes?
`
`Findings In this retrospective observational study of 25 489
`patients with type 2 diabetes. initiation of basal insulin analogs
`compared with NPH insulin was not associated with a significant
`difference in hypoglycemia-related ED visits or hospital admissions
`among a propensity-score matched cohort of 4428 patients
`(hazard ratio. 1.16).
`
`Meaning Among patients with type 2 diabetes. the use of basal
`insulin analogs compared with NPH insulin was not associated
`with a reduced risk of hypoglycemia-related ED visits
`or hospital admissions.
`
`me dical record according to fixed categories. The study
`methods and a validation study of the KPNC diabetes regis(cid:173)
`try (99% sensitivity for diabetes based on chart review regis(cid:173)
`tration) have been published.H
`
`Study Population
`Using electronic medical records from KPNC, 49190 adults
`(aged 2:19 years) with diabetes were identified. Each patient
`had full health plan and prescription coverage for 24 months
`prior to initiating insulin betwee n Ja nuary 1, 2006, a nd
`December 31, 2014. Patients with type 1 diabetes were ex(cid:173)
`cluded (n = 1838) based on a validated algorithm that uses self(cid:173)
`report or age of diabetes onset and drug treatment history to
`determine diabetes type.15 Clinicians within KPNC can pre(cid:173)
`scribe either NPH insulin or insulin analogs to patients with
`type 2 diabetes without obtaining prior approval; however, cli(cid:173)
`nicians are encouraged to start with NPH insulin.
`The analytic cohort consisted of patients who initiated
`basal insulin therapy and had no insulin prescription fills dur(cid:173)
`ing the prior 12 months (Figure 1). Patients started with either
`NPH insulin or the insulin analog glargine or detemir. Pa(cid:173)
`tients using prandial insulin at baseline were excluded from
`the study. Patients who initiated prandial insulin during the
`study were censored at that time.
`
`Study Outcomes
`The primary outcome was the time to hypoglycemia-related
`ED visit or hospital admission afte r initiation of insulin
`therapy based on a primary or principal discharge diagnosis
`of hypoglycemia using a validated algorithm (any of the fol(cid:173)
`lowing International Classification of Diseases, Ninth Revi(cid:173)
`sion codes: 251.0, 251.1 , 251.2, 962.3, or 250.8 modified by
`259.8, 272 .7, 681, 682, 686.9, 707.1-707.9, 709.3, 730.0-
`730.2, or 731.8). 16
`The secondary outcome was the change in hemoglobin A1c
`level, which is a marker for the clinical effectiveness of insu(cid:173)
`lin. For the baseline hemoglobin A1c level, the last measure
`during the 12 months prior to insulin initiation was used.
`The change from baseline to the last hemoglobin A1c level was
`
`54
`
`JAMA July 3. 2018 Volume 320. Number 1
`
`1ama om
`
`© 2018 American Medical Association. All rights reserved.
`
`PFIZER, INC. v. SANOFI-AVENTIS DEUTSCHLAND GMBH
`
`Ex. 1035, p. 2 of 10
`
`

`

`Association Between Basal Insulin Analog vs NPH Insulin Initiation and Hypoglycemic Events in Type 2 Diabetes
`
`Originallnvestigation Research
`
`assessed prior to censoring and within 3 to 12 months after in(cid:173)
`sulin initiation. A change in hemoglobin A1e level of 0.5% or
`greater is typically considered to be clinically significant. 17
`
`Statistical Analysis
`The analysis involved multiple steps. During the first step, a
`propensity score model was developed, predicting the binary
`outcome of initiating treatment with basal insulin analogs
`(compared with NPH insulin) using a flexible, data-adaptive
`model selection procedure called the deletion, substitution,
`and addition algorithm by Neugebauer and Bullard (available
`in R version 3.1.4; R Foundation for Statistical Computing). 1R
`The deletion, substitution, and addition procedure made use
`of training and test data sets to select the estimator with the
`lowest cross-validated risk among a list of candidate estima(cid:173)
`tors deve loped via machine learning (ie, deletion , substitu(cid:173)
`tion, and addition of potential covariates as well as interac(cid:173)
`tions and higher-order parameters).
`Potential covariates included: demographics, index year,
`clinical and comorbid characteristics, clinician specialty (pri(cid:173)
`mary care, endocrinology, or other specialty), KPNC service
`area, Charlson comorbidity index, chronic kidney disease
`stage, chronic liver disease, visual impairment, history of dia(cid:173)
`betic ketoacidosis, history of depression, glycemic control,
`the number of hypoglycemia-related ED visits or hospita l
`admissions during the year prior to baseline, the number of
`ED visits or inpatient stays (for any reason) during the year
`prior to baseline, medication nonadherence (continuous
`2 0
`measure of medication gaps19
`) , outpatient medical visits
`·
`(ie, the number of face-to-face visits with a clinician) during
`the 2 years prior to baseline, the patient co-pay for index
`insulin dispensed, and indicators of prevalent use for each of
`the diabetes therapeutic drug classes, statins, angiotensin(cid:173)
`converting enzyme inhibitors, and P-blockers.
`Missing data for continuous variables were imputed based
`on the within-group mean. Missing data for categorical vari·
`abies were treated as a separate category. The C statistic (area
`under the receiver operating characteristic curve) for this model
`was 0.81, suggesting good discrimination.
`During the second step, the predicted probability (ie, pro(cid:173)
`pensity score) of initiating treatment with long-acting insulin
`analogs was calculated for each patient. Quintiles of the pro·
`pensity score were created based on the distribution of the
`propensity scores among the exposed patients (ie, patients
`who initiated insulin analogs). Using frequency matching
`(random sampling with replacement), 500 reference patients
`who initiated NPH insulin were selected from each of the
`quintiles defined by the exposed group.
`This frequency matching created a population in which the
`distribution of covariates in the NPH insulin cohort was simi·
`lar to those in the insulin analog cohort, thus minimizing ob(cid:173)
`served confounders. Balance in the covariate distribution in
`each cohort was assessed by visually inspecting box plots and
`cumulative probability distributions of the propensity scores
`between exposed and reference patients and quantitatively
`through the calculation of the standardized difference, which
`compares the difference in means or prevalence ofbaseline co(cid:173)
`variates in units of the pooled SDs. A standardized difference
`
`Figure I. Derivation of the Study Cohort
`
`49120 Adults aged ~ 19 y with clinically recognized I
`
`diabetes who initiated insulin between 2006
`and 2014 and had full health plan and
`prescription coverage for 24 mo prior to
`starting Insulin
`
`I
`
`23 631 Excluded
`1838 Had type 1 diabetes
`14 313 Initiated bolus or premixed insulin
`7480 Had insulin prescription fills
`within prior _12_m_o ____ __.J
`
`25 489 Had newly initiated basal insulin therapy I
`
`(NPH insulin or insulin analog) and were
`included in the analysis
`- - - - - - - - -
`
`Adults with type 2 diabetes and full health plan and prescription coverage were
`included if they began basal insulin therapy (neutral protamine Hagedorn [NPH]
`or insulin analog) between January I. 2006. and December 31. 2014.
`
`with the absolute value ofless than or equal to 0.1 indicates a
`negligible difference in the mean or prevalence of a covariate
`between groups.2 1
`During the third step, a survival analysis was conducted
`for the outcome of hypoglycemia-related ED visits or hospi(cid:173)
`tal admissions. This approach examined time to first event of
`hypoglycemia-related ED visit or hospital admission. Pa·
`tients were censored at the earliest event: death, end of
`KPNC membership, end of prescription drug benefits, dis(cid:173)
`continuation of NPH insulin or long-acting insulin, addition
`of any other insulin subtype, or end of follow-up (September
`30, 2015). The hazard ratios (HRs) and 95% Cis were calcu(cid:173)
`lated from the results of the Cox proportional hazards analy(cid:173)
`ses on 1000 bootstrap samples with replacement, and were
`created using the methods described above.
`The proportional hazard assumption was tested by assess·
`ing independence between the Schoenfeld residuals and
`follow-up time. The primary analysis included the HR after ad(cid:173)
`justing for baseline covariates that remained unbalanced af(cid:173)
`ter propensity score matching (ie, those with the absolute value
`of the standardized difference >0.1), as well as additional ad(cid:173)
`justments for prior hypoglycemia-related ED visits or hospi·
`tal admissions and for time-dependent indicators of diabetes
`medication use. The use of sulfonylureas, metformin, or thia(cid:173)
`zolidinediones was based on dispensing of a given medica(cid:173)
`tion within 6 months prior to the start of insulin; thereafter, it
`was based on monthly fills and days' supply dispensed.
`In a sensitivity analysis, the HR was additionally cal(cid:173)
`culated using traditional regression adjustment for covar(cid:173)
`iates that were significantly different at baseline for prior
`hypoglycemia-related ED visits or hospital admissions and
`for time-dependent indicators of diabetes medication use.
`Based on a post hoc estimate with a sample size of 25 489
`patients, the study had 80% power to detect a HR of 2.1 or
`greater or of 0.5 or less for the outcome of hypoglycemia(cid:173)
`related ED visits or hospital admissions associated with the
`initiation of insulin analogs vs NPH insulin.
`During the fourth step, the change in hemoglobin A1e level
`following insulin initiation was estimated using a difference(cid:173)
`in-differences approach. This approach measured the change
`
`.1rna com
`
`JAMA July 3. 2018 Volume 320. Number 1
`
`55
`
`© 2018 American Medical Association. All rights reserved.
`
`PFIZER, INC. v. SANOFI-AVENTIS DEUTSCHLAND GMBH
`
`Ex. 1035, p. 3 of 10
`
`

`

`Research Ongonal lnvestogatoon
`
`Association Between Basal insulin Analog vs NPH Insulin Initiation and Hypoglycemic Events in Type 2 Diabetes
`
`in glycemic contro l associated with the initiation of long(cid:173)
`acting insulin analogs (first difference) after subtracting the
`background cha nge (second difference [eg, due to secu lar
`trends]) a mong patients who initiated NPH insulin. 22 This
`model was based on the counterfactual assumption that if pa(cid:173)
`tients who initiated insulin analogs had instead initiated NPH
`insulin, their changes in hemoglobin A1e level would be simi(cid:173)
`lar to the changes observed in the NPH insulin reference group,
`who were frequency matched based on the propensity score
`quintile. The model was adjusted for baseline covariates that
`re mained unbalanced after propensity score matching.
`In the main secondary outcome analysis, participants with
`missing data for hemoglobin A1e level at baseline and those who
`were censored within 90 days ofbaseline were excluded . In a
`sensitivity analysis, patients also were excluded if the use of
`any class of diabetes medications changed from baseline un(cid:173)
`til they were censored or until12 months after initiation ofin(cid:173)
`sulin, whichever occurred first. The purpose of this analysis
`was to isolate the relationship between insulin initiation and
`change in hemoglobin A1e levels.
`The difference-in-differences estimates and 95% Cis we re
`calculated from the results of a least-squares regression analy(cid:173)
`sis on 1000 bootstrap samples with replacement. 23 We used
`R version 3.3.1 and SAS version 9.3 (SAS Institute Inc) statis(cid:173)
`tical software for all analyses. A P value <.OS was considered
`statistically significant and all testing was 2-sided.
`
`Results
`
`Patient Characteristics at Baseline
`Between 2006 and 2014, a total of25 489 patients with type
`2 diabetes initiated basal insulin therapy (Table 1). The mean
`age was 60.2 years (SD, 11.8 years) and 46.8% were female. The
`racial/ethnic makeup ofthe cohort consisted of5l.9% who were
`white, 9.2% who were black, 17.6% who were Hispanic, and
`15.3% who were Asian. The Charlson comorbidi ty index value
`was 0 among 28.1%, 1 among 28.5%, 2 among 11.3%, and 3 or
`greater among 32.1%.
`In t his cohort, data were missing for race/ethnicity
`(n = 280), chronic kidney disease stage (n = 213), duration of
`d iabetes (n = 6641), age at diabetes onset (n = 6641), body mass
`index (n = 1429), elevated serum creatinine level (n = 33),
`neighborhood deprivation index (n = 242), hemoglobin A1e
`level (n = 402), KPNC service area (n = 61), and medication non(cid:173)
`adherence (n = 5474).
`Among the patients who initiated insulin, 23 561 (92%)
`started with NPH insulin and 1928 (8%) started with insulin
`analogs. Patients who initiated insulin analogs were more likely
`to have a greater number of comorbid conditions and had more
`ED or hospital use events (for any cause) within the prior year,
`but the magnitude of the differences was small (Table 1). One
`substantive difference was that the median co-payments for
`insulin a nalogs ($20) were significantly higher than for NPH
`insulin ($10). The mean baseline hemoglobin A1e levels for the
`2 groups were 9.41% [SO, 2.0%] among patients who started
`insulin analogs and 9.40% [SD, 1.8%] among patients who
`s tarted NPH insulin.
`
`ln the propensity score-matched cohort (n = 4428), the dif(cid:173)
`ferences in the characteristics of patients who initiated insu(cid:173)
`lin analog vs NPH insulin were minimized; however, statisti(cid:173)
`cal differences persisted for outpatient medical visits, KPNC
`service area, and year of index prescription. These differ(cid:173)
`ences were not substantive.
`
`Primary Outcome
`Among patients who initiated insulin analogs (n = 1928; 3289.8
`person-years), there were 32 ED visits and 7 hospital admis(cid:173)
`sions related to hypoglycemia (11.9 events [95% CI, 8.1 to 15.6]
`per 1000 person-years) during a mean follow-up ofl.71 years
`(95% Cl, 1.62 to 1.79) and a med ian follow-up ofl.03 years (i n(cid:173)
`terquartile range, 0.36 to 2.37). Among patients who initiated
`NPH insulin (n = 23561; 40060.0 person-years), there were
`309 ED visits and 45 hospital admissions related to hypogly(cid:173)
`cemia (8.8 events [95% Cl, 7.9 to 9.8] per 1000 person-years)
`during a mean follow-up ofl.70 years (95% CI, 1.68 to 1.72) and
`a median follow-up of 1.09 years (interquartile range, 0.41 to
`2.38). The between-group difference was 3.1 events (95% CI,
`- 1.5 to 7.7) per 1000 person-years (P = .07).
`The Kaplan-Meier curve a ppears in Figure 2. Amo ng all
`censoring events, 2.8% were due to death, 31.9% were due to
`discontinuation of insulin, and 31.6% were due to initiation of
`an additional type ofinsulin. The proportional hazard assump(cid:173)
`tion was met because the Schoenfeld residuals for the expo(cid:173)
`sure were independent of time (Pearson correlation coeffi(cid:173)
`cient, 0.06; P = .20 ).
`After frequency matching the patients who initiated in(cid:173)
`sulin analogs with those who initiated NPH insulin, and after
`additional adjustment for unbalanced covariates, prior hypo(cid:173)
`glycemia-related ED visits or hospital admissions, and t ime(cid:173)
`dependent indicators of diabetes medication use, there was
`no significant difference in hypoglycemia-related ED visits or
`hospital admissions (HR, 1.16 [95% CI, 0.71 to 1.78]; Table 2).
`
`Secondary Outcome
`In the main secondary outcome analysis of change in glyce(cid:173)
`mic control, participants with missing data for hemoglobin A1e
`level at baseline (n = 402) and those who were censored within
`90 daysofbaseline (n = 3665) were excluded (n = 4067). Within
`1 year of initiation of insulin analogs, hemoglobin A1e level de(cid:173)
`creased by 1.26 percentage points (95% CI, l.l6 to 1.36 per(cid:173)
`centage points) from 9.41% (95% C1, 9.34% to 9.50%) to 8.16%
`(95% CI, 8.09% to 8.24%).
`Within 1 year ofinitiation ofNPH insulin, hemoglobin A1e
`level decreased by 1.48 percentage points (95% Cl, 1.39 to 1.57
`percentage points) from 9.39% (95% CI, 9.32% to 9.47%) to
`7.92% (95% CI, 7.85% to 7.99%). Between the baseline and post(cid:173)
`baseline measures, the mean number of days was 298 (SD, 103
`days) among patients who initiated ins ulin a nalogs and
`288 days (SO, 98 days) among patients who initiated NPH
`(standard ized difference, 0.10). After adjustment, the differ(cid:173)
`ence-in-differences for glycemic control was - 0 .22% (95% CI,
`-0.09% to - 0.37%), indicating that the use ofNPH insulin was
`associated with a statistically significant greater decrease in
`hemoglobin A1c level (Table 3). However, this difference is not
`considered clinically significant.17
`
`56
`
`JAMA July 3. 2016 Volume 320. Number 1
`
`Jl•n 1 com
`
`© 2018 American Medical Association. All rights reserved.
`
`PFIZER, INC. v. SANOFI-AVENTIS DEUTSCHLAND GMBH
`
`Ex. 1035, p. 4 of 10
`
`

`

`Association Between Basal Insulin Analog vs NPH Insulin Initiation and Hypoglycemic Events in Type 2 Diabetes
`
`Ongtnal lnvesugatton Research
`
`Table 1. Baseline Characteristics o f 25 489 Patients With Type 2 Diabet es
`
`Characteristic
`Age, mean (SO), y
`Female sex, No. (%)
`Race/ethnicity, No. (%)0
`Asian
`Black
`White
`Hispanic
`Other
`Neighborhood deprivation index by quartile, No. (%)0
`First (least deprived)
`Second
`Third
`Fourth (most deprived)
`Comorbidities, No. (%)
`Charlson comorbidity index'
`0
`1
`2
`
`·•
`
`~3
`Chronic kidney disease stage"
`0
`
`3A
`3B
`4
`5 or dialysis
`Elevated serum creatinine level, No0•9
`Chronic liver disease
`Depression
`Visual impairment or blindness
`Health Care Use, No. (%)
`Emergency department visit for any cause in prior year
`Inpatient hospitalization for any cause in prior year
`No. of outpatient medical visits in prior 2 y by quartile
`0·6
`7·11
`12·19
`
`~20
`Diabetic ketoacidosis in prior year
`Emergency department or inpatient hospitalization
`for hypoglycemia within prior year
`No. of hypoglycemic events resulting in emergency department
`or inpatient stay in prior year. median (IQR)
`Kaiser Permanente or Northern California service area"
`A
`B
`c
`D
`
`F
`G
`H
`
`K
`
`M
`
`1Jfl1,] (\}111
`
`Insulin Anal og
`(n = 1928)
`60.6 (12.8)
`912 {47)
`
`Before Frequency Matching
`Standardized
`NPH Insulin
`(n = 23 561)
`Oifferenceb
`60.2 (ll.8)
`0.04
`11105 (47)
`0.01
`
`After Frequency Matching•
`Standardized
`NPH Insulin
`(n = 2500)'
`Oifferenceb
`60.8 (11.8)
`-O.Dl
`1140 (46)
`0.03
`
`332 (17)
`214(11)
`957 (SO)
`293 (lS)
`114 (6)
`
`374 (20)
`538 (28)
`572 (30)
`423 (22)
`
`501 (26)
`533 (28)
`228 (l2)
`666 (35)
`
`202 (11)
`468 (25)
`656 (35)
`297 ( 15)
`179 (9)
`77 (4)
`28 (1)
`266 (14)
`103 (5)
`395 (20)
`95 (5)
`
`649 (34)
`379 (20)
`
`423(22)
`435 (23)
`480 (25)
`590 (31)
`31 (2)
`16 (l)
`
`3534 (15)
`2109 (9)
`12136 (52)
`4130 (l8)
`1390 (6)
`
`4643 (20)
`6695 (29)
`7030 (30)
`4972 (21)
`
`6654 (28)
`6736 (29)
`2652 (11)
`7519 (32)
`
`3121 (13)
`6024 (26)
`8348 (36)
`3064 (13)
`2088 (9)
`627 (3)
`115 (l)
`2664 (11)
`1392 (6)
`5266 (22)
`618 (3)
`
`6822 (29)
`3069 (13)
`
`5931 (25)
`6148 (26)
`5769 (24)
`5713 (24)
`206 (1)
`115 (1)
`
`0 (0 to 2)
`
`0 (0 to 3)
`
`114 (6)
`209 (11)
`123 (6)
`144 (7)
`128 (7)
`71 (4)
`253 (13)
`139 (7)
`97 (5)
`143 (7)
`65 (3)
`139 (7)
`272 (14)
`
`1989 (8)
`2392 ( 10)
`1631 (7)
`740 (3)
`1870 (8)
`1513 (6)
`2080 (9)
`38 10 (l6)
`1981 (8)
`581 (2)
`1831 (8)
`1600 (7)
`1513 (6)
`
`0.06
`0.07
`- 0.04
`-0.06
`-0.04
`
`- O.Dl
`-0.01
`-0.004
`0.02
`
`- 0.05
`-0.02
`0.02
`0.06
`
`-0.09
`- 0.03
`-0.03
`0.04
`0.01
`0.07
`0.10
`0.08
`- 0.02
`- 0.05
`0.12
`
`0.10
`0.18
`
`-0.08
`-0.08
`0.01
`- 0. 14
`0.07
`0.04
`
`0.04
`
`-0.10
`0.02
`- 0.02
`0.19
`- 0.05
`-0.13
`- 0. 14
`- 0.28
`- 0.14
`0.23
`-0.19
`0.02
`0.26
`
`383 (15)
`23 1 (9)
`1265 (5 1)
`446 (18)
`133 (5)
`
`486 (19)
`702 (28)
`760 (30)
`532 (21)
`
`690 (28)
`735 (29)
`256 (10)
`819 (33)
`
`337 (14)
`597 (24)
`883 (35)
`316 (13)
`237 (9)
`82 (3)
`19 (1)
`334 (l3)
`14 1 (6)
`527 (21)
`93 (4)
`
`780 (31)
`421 (17)
`
`613 (25)
`609 (24)
`631 (25)
`647 (26)
`46 (2)
`22 (1)
`
`0.05
`0.06
`-0.02
`- 0.07
`-0.04
`
`-0.002
`-0.004
`-0.02
`0.02
`
`-0.04
`-0.04
`0.05
`0.04
`
`-0.09
`0.0 1
`-O.D3
`0.05
`-O.Dl
`0.04
`0.07
`0.01
`-0.01
`-0.01
`0.06
`
`0.05
`0.07
`
`-0.06
`-0.04
`-0.01
`
`0.11
`-0.02
`-0.01
`
`0 (0 to 3)
`
`-0.0002
`
`196 (8)
`224 (9)
`121 (5)
`172 (7)
`164 (7)
`123 (5)
`272 (ll)
`244 (10)
`166 (7)
`135 (5)
`175 (7)
`129 (5)
`354 (l4)
`
`-0.08
`0.06
`0.07
`0.02
`0.004
`-0.06
`0.07
`-0.09
`-0.07
`0.08
`-0.16
`0.09
`-0.001
`
`© 2018 American Medical Association. All rights reserved.
`
`(continued)
`
`JAMA July 3. 2018 Volume 320. Number 1
`
`57
`
`PFIZER, INC. v. SANOFI-AVENTIS DEUTSCHLAND GMBH
`
`Ex. 1035, p. 5 of 10
`
`

`

`Research Ongmal lnvestogation
`
`Association Between Basal Insulin Analog vs NPH Insulin Initiation and Hypoglycemic Events in Type 2 Diabetes
`
`Table 1. Baseline Characteristics of 25 489 Patients With Type 2 Diabetes (continued)
`
`Characteristic
`Prescribing clinician specialty
`Primary care
`Endocrinologist
`Other specialist
`Clinical Characteristics of Diabetes
`Duration of diabetes. mean (SO), 'I'
`Age at diabetes onset, mean (SO), y•
`Body mass index, mean (So)•
`Hemoglobin A1, level, mean (SO), %•
`Type of diabetes medication, No. (%)
`None
`Metformin
`Sulfonylurea
`Thiazolidinedione
`Dipeptidyl peptidase 4 inhibitors
`Glucagon-like peptide 1 receptor agonists
`Other"
`Types of cardiometabolic medications, No. (%)
`Stat ins
`Angiotensin-converting enzyme inhibitors
`P-Biockers
`Medication nonadherence, %0 ·1
`Year of index insulin prescription, No. (%)
`2006
`2007
`2008
`2009
`2010
`2011
`2012
`2013
`2014
`Patient co-pay for index insulin dispensed, median (IQR), $
`
`Insulin Analog
`(n = 1928)
`
`Before Frequency Matching
`NPH Insulin
`Standardized
`(n = 23 561)
`Difference•
`
`After Frequency Matching•
`NPH Insulin
`Standardized
`(n = 2SOO)'
`Difference•
`
`1631 (85)
`74 (4)
`223 (12)
`
`21595 (92)
`667 (3)
`1299 (6)
`
`11.6 (7.9)
`49.2 (11.2)
`32.2 (7 .5)
`9.41 (2.0)
`
`10.6 (6.4)
`50.0 (10.8)
`33.3 (7.5)
`9.40 ( 1.8)
`
`166 (9)
`1330 (69)
`1590 (82)
`540 (28)
`38 (2)
`23 (1)
`54 (3)
`
`1409 (73)
`912 (47)
`828 (43)
`432 (22)
`
`289 (15)
`310 (16)
`280 (15)
`243 (13)
`104 (5)
`169 (9)
`211 (11)
`214 (11)
`108 (6)
`20 (10 to 35)
`
`1142 (5)
`17915 (76)
`20 648 (88)
`5533 (23 )
`248 (1)
`71 (<1)
`322 (1)
`
`18 553 (79)
`11185 (47)
`9951 (42)
`5473 (23)
`
`1683 (7)
`3277 (14)
`2357 (10)
`1947 (B)
`2072 (9)
`2667(ll)
`3l20 (13)
`3227 (14)
`3211 (14)
`10 (5 to 10)
`
`-0.22
`0.05
`0.22
`
`0.18
`- 0.08
`-0.1S
`O.Ol
`
`0.15
`-0.16
`- 0.1S
`0.10
`0.08
`0.10
`0.10
`
`- 0.13
`- 0.003
`0.01
`0.15
`
`0.25
`0.06
`0.14
`0.14
`- 0.13
`-0.09
`-0.07
`- 0.08
`- 0.27
`0.67
`
`2120(85)
`90 (4)
`290 (12)
`
`- 0.002
`0.01
`-O.Dl
`
`11.7 (7 .4)
`49.0 (9.3)
`32.7 (7.2)
`9.39 (1.8)
`
`172 (7)
`1805 (72)
`2142 (86)
`668 (27)
`40 (2)
`12 (1)
`44 (2)
`
`1922 (77)
`ll92 (48)
`1056 (42)
`591 (24)
`
`313 (13)
`354 (14)
`373 (15)
`294 (12)
`176 (7)
`212 (8)
`289 (12)
`247 (10)
`242 (10)
`15 (10 to 45)
`
`-O.Dl
`0.03
`-0.06
`0.02
`
`0.06
`-0.07
`-0.09
`0.03
`0.03
`0.07
`0.07
`
`-0.09
`-0.01
`O.Dl
`- 0.03
`
`0.07
`0.06
`-0.01
`0.03
`-O.D7
`O.Dl
`-0.02
`0.04
`-0.15
`0.05
`
`Abbreviations: IQR. interquartile range: NPH. neutral protamine Hagedorn.
`• Patients who initiated NPH insulin were frequency matched with patients
`initiating insulin analogs based on propensity score quintile.
`• compares characteristics for patients who initiated insulin analogs vs NPH
`insulin. An absolute value :50.1 indicates a negligible difference in the mean or
`prevalence of a covariate between groups.2 '
`'The number of patients in each category for the bootstrapped analysis (1000
`samples of 2500 each) calculated based on the distributions in the 2.5 million
`observations and then applied to the 2500. Numbers reflect average across
`the 1000 samples.
`• Missing data: race/ethnicity (n = 280). neighborhood deprivation index
`(n = 242), chronic kidney disease stage (n = 213). elevated serum creatinine
`(n = 33). Kaiser Permanente of Northern California service area (n = 61).
`duration of diabetes (n = 6641). age at diabetes onset (n = 6641). body mass
`index (n = 1429). hemoglobin Ale (n = 402). and medication nonadherence
`(n = 5474).
`
`c Created by a principal components analysis of 8 census·derived variables at
`the census tract level(% of men in management and professional
`occupations. living in crowded housing. households in poverty, female· headed
`households with dependents. households receiving public assistance.
`households earning <$30 000/year. individuals with less than a high school
`education. and unemployment). 24·25 Negative scores = less deprivation.
`1 Based on the modified version of the Deyo Charlson Score. 26 Possible scores
`ranged from 0 ·17 and represent t he number of s