Download Non-TNF-Targeted Therapy in Unresponsive RA More Effective than

OUTCOMES RESEARCH IN REVIEW
Non-TNF-Targeted Therapy in Unresponsive RA More Effective
than a Second Anti-TNF Drug
Gottenberg JE, Brocq O, Perdriger A, et al. Non-TNF-targeted biologic vs a second anti-TNF drug to treat
rheumatoid arthritis in patients with insufficient response to a first anti-TNF drug: a randomized clinical trial.
JAMA 2016;316:1172–80.
Study Overview
Objective. To determine whether a non–tumor necrosis
factor (TNF)-targeted drug is more effective than a second anti-TNF drug in rheumatoid arthritis (RA) patients
who have had an inadequate response to a first anti-TNF
drug.
Design. 52-week pragmatic, multicenter, open-label,
parallel-group, randomized clinical trial (the “Rotation
or Change” trial).
Setting and participants. 300 patients who were at least
18 years old were recruited from December 2009 to
August 2012 from 47 French clinical centers. These
patients had to have a diagnosis of RA according to the
1987 American College of Rheumatology criteria, presence of erosions, a DAS28-ESR (a measure of disease burden using patient global health, tender and swollen joint
counts, and the erythrocyte sedimentation rate) of 3.2 or
more, and insufficient response to an anti-TNF according
to the physician (based on 1 or more of: persistent tender
and swollen joints, persistent disease activity according to
patient global assessment, elevated levels of acute-phase
reactants, and dependence on analgesics, nonsteroidal
anti-inflammatory drugs, or corticosteroids). In addition,
patients had to have a stable dose of oral corticosteroids of
15 mg/d or less of equivalent prednisone within 4 weeks
before enrollment, a stable dose of synthetic diseasemodifying antirheumatic drugs (DMARDs) within 4
weeks of enrollment, and informed written consent. Exclusion criteria included cessation of the first anti-TNF
agent due only to an adverse event, previous treatment
with 2 or more anti-TNF agents, previous treatment with
abatacept, rituximab, or tocilizumab, a contraindication to
all anti-TNF agents and other biologics such as an infection or cancer, pregnancy and breastfeeding.
Intervention. Patients were randomly assigned in equal
proportions to receive either a non-TNF biologic (abatacept, rituximab, or tocilizumab) or a second anti-TNF
agent (adalimumab, certolizumab, etanercept, infliximab,
or golimumab); the choice of agent after randomization
was decided by the physician. The starting dose and frequency of treatment was predetermined. Golimumab was
not available for use at the time of this study. The choice
of future dosing and frequency of the treatment was left
up to the treating physician in both groups. The assigned
drug treatments continued for 12 months but were
Outcomes Research in Review Section Editors
Kristina Lewis, MD, MPH
Wake Forest School of Medicine
Winston-Salem, NC
William Hung, MD, MPH
Mount Sinai School of Medicine
New York, NY
Katrina F. Mateo, MPH
CUNY School of Public Health
New York, NY
536 JCOM December 2016 Vol. 23, No. 12
Gordon Ngai, MD, MPH
Mount Sinai School of Medicine
New York, NY
Karen Roush, PhD, RN
Lehman College
Bronx, NY
www.jcomjournal.com
OUTCOMES RESEARCH IN REVIEW
allowed to be discontinued for adverse events, patient
choice, or inefficacy. Treatment and dose adjustments
for oral corticosteroids and glucocorticoid intra-articular
injections were allowed for both treatment groups.
Main outcome measures. The primary outcome was the
proportion of patients at week 24 with a good or moderate European League Against Rheumatism (EULAR)
response. A good EULAR response is defined as a
decrease in DAS28-ESR of more than 1.2 points leading to a score of 3.2 or lower while a moderate EULAR
response is defined as a decrease of more than 0.6 and
resulting in a score of 5.1 points or lower. Secondary
end points were EULAR response at weeks 12 and 52,
DAS28-ESR at weeks 12, 24, and 52, low disease activity
(DAS28-ESR < 3.2) and remission (DAS28-ESR < 2.6)
at weeks 12, 24, and 52, mean oral corticosteroid use at
weeks 24 and 52, therapeutic maintenance (defined as
the proportion of patients who did not discontinue the
assigned biologic treatment) at weeks 24 and 52, and
health assessment questionnaire (HAQ) score (range,
0–3 with 0 representing the best and 3 the worst outcomes) at weeks 12, 24, and 52. Safety including serious
adverse events as well as serious infections was also evaluated throughout the study.
Main results. 300 patients were randomized. The 2 groups
were not different with regard to demographic and disease
characteristics. In the non-TNF group of 150 patients,
33 of 146 patients (23%) received abatacept, 41 (28%)
rituximab, and 70 (48%) tocilizumab; 2 patients (1%) did
not receive the intervention as planned, 1 patient received
adalimumab and 1 patient received no treatment. For
the anti-TNF group, 57 of 146 patients (39%) received
adalimumab, 23 (16%) certolizumab, 53 (36%) etanercept,
and 8 (5%) infliximab. Five patients (3%) did not receive
the intervention assigned as 2 patients received rituximab,
1 patient received tocilizumab, and 2 patients received no
treatment. About two-thirds of patients in each group
received concomitant methotrexate and about half in each
group received oral corticosteroids.
With regard to the primary outcome, at week 24 101
of 146 patients (69%) in the non-TNF group and 76
(52%) in the second anti-TNF group achieved a good
or moderate EULAR response, with 39% with a good
response and 30% with a moderate response in the nonTNF group and 21% with a good response and 31%
with a moderate response in the second anti-TNF group
www.jcomjournal.com
(odds ratio [OR], 2.06; 95% confidence interval [CI],
1.27 to 3.37; P = 0.004, with imputation of missing data;
absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The
DAS28-ESR was lower in the non-TNF group (mean
difference adjusted for baseline differences, −0.43; 95%
CI, −0.72 to −0.14; P = 0.004). More patients in the
non-TNF group vs the second anti-TNF group showed
low disease activity at week 24 (45% vs 28%; OR, 2.09;
95% CI, 1.27 to 3.43; P = 0.004) and at week 52 (41%
vs 23%; OR, 2.26; 95% CI, 1.33 to 3.86; P = 0.003).
The mean DAS28-ESR change from baseline was
greater for patients in the non-TNF group than for
patients in the second anti-TNF group with a 24-week
mean difference of −0.43 (95% CI,−0.72 to −0.14;
P = 0.004) and 52-week mean difference of −0.38 (95%
CI, −0.69 to −0.08; P = 0.01).
The proportion of EULAR good and moderate
responders at week 24 did not significantly differ with
abatacept, rituximab, and tocilizumab treatment. The
therapeutic maintenance rate, defined as the proportion
of patients who continued the biologic treatment, was
found to be significantly higher at weeks 24 and 52
in the non-TNF group than in the second anti-TNF
group. The mean change from baseline to weeks 24 and
52 in the level of prednisone doses was not significantly
different between patients between treatment groups.
With respect to safety, 16 patients (11%) in the nonTNF group experienced 18 serious adverse events and 8
patients (5%) in the second anti-TNF group experienced
13 events (P = 0.10) with 7 patients (5%) in each group
developing serious infections.
Conclusion. In patients with RA previously treated with
an anti-TNF drug with an inadequate response, the use
of a non-TNF biologic agent was found to be more effective in achieving a good or moderate disease activity
response at 24 weeks compared with a second anti-TNF
medication.
Commentary
In patients with RA who have shown an inadequate
response to methotrexate, TNF-α inhibitors have been
shown to improve quality of life. However, it has been
shown that almost one-third of patients have an insufficient and inadequate response to anti-TNF agents and
continue to have persistent disease activity [1–3]. Alternative treatments are therefore needed, but there is currently
little guidance available for choosing the next treatment.
Vol. 23, No. 12 December 2016 JCOM 537
OUTCOMES RESEARCH IN REVIEW
There are 3 placebo-controlled trials that have shown
that switching to a non–TNF-targeted therapy may
be appropriate [4–6]. The most commonly used nonTNF agents are abatacept, rituximab, and tocilizumab.
However, there is evidence that switching to another
anti-TNF agent after failure of a first can also be a good
choice, as the molecular structure of TNF-inhibitors
and their affinity for membrane and TNF-α vary. There
were 2 randomized placebo-controlled trials that reported that approximately half of patients with R A with
insufficient response to a TNF-α inhibitor responded to
a second anti-TNF drug [7,8].
Although there have been observational studies
addressing this question, this is the first randomized
controlled trial to evaluate the efficacy of a non-TNFtargeted biologic compared to a second anti-TNF drug
to treat R A in patients with an insufficient response to
a first anti-TNF drug. Data showed that at week 24,
69% in the non-TNF group and 52% in the anti-TNF
group achieved a good or moderate EULAR response.
The non-TNF treatment was also associated with a better EULAR response than a second anti-TNF drug at
weeks 12 and 52. The DAS28-ESR and the number
of patients achieving low disease activity status were
found to be greater at months 6 and 12 in the nonTNF group than in the second anti-TNF group. One
strength of the study is its pragmatic design—the study
evaluated the effectiveness of interventions under reallife, routine practice conditions where physicians often
choose one drug over another for reasons based on
the habits or characteristics of the patient. The comparison of strategies and not individual drugs more
appropriately addresses the questions that physicians
face in daily practice. However, there were some limitations including the lack of blinding by participants, the
exclusion of some biologic agents such as golimunab,
the lack of assessment of individual drug efficacy, and
the fact that approximately 40% of patients in each
group did not have concomitant treatment with methotrexate, an agent known to improve the efficacy of most
biologic agents.
Applications for Clinical Practice
This is the first randomized controlled trial to evaluate
the efficacy of a non-TNF-targeted biologic vs. a second
538 JCOM December 2016 Vol. 23, No. 12
anti-TNF in patients with RA who have an insufficient response to a first anti-TNF drug. Further studies
addressing the limitations identified in this study are
needed before physicians can employ these findings in
clinical practice.
—Anita Laloo, MD
References
1. Hyrich KL, Lunt M, Watson KD, et al; British Society for
Rheumatology Biologics Register. Outcomes after switching
from one antitumor necrosis factor alpha agent to a second
anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort
study. Arthritis Rheum 2007;56:13–20.
2. Hetland ML, Christensen IJ, Tarp U, et al; All Departments of Rheumatology in Denmark. Direct comparison of
treatment responses, remission rates, and drug adherence in
patients with rheumatoid arthritis treated with adalimumab,
etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO
registry. Arthritis Rheum 2010;62:22–32.
3. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis
with synthetic and biological disease-modifying antirheumatic
drugs. Ann Rheum Dis 2010;69:964–75.
4. Cohen SB, Emery P, Greenwald MW, et al; REFLEX
Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase
3 trial evaluating primary efficacy and safety at twenty-four
weeks. Arthritis Rheum 2006;54:2793–806.
5. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in
patients with rheumatoid arthritis refractory to anti-tumour
necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis
2008;67:1516–23.
6. Genovese MC, Becker JC, Schiff M, et al. Abatacept for
rheumatoid arthritis refractory to tumor necrosis factor alpha
inhibition. N Engl J Med 2005;353:1114–23.
7. Smolen JS, Kay J, Doyle MK, et al; GO-AFTER study investigators. Golimumab in patients with active rheumatoid
arthritis after treatment with tumour necrosis factor alpha
inhibitors (GO-AFTER study): a multicentre, randomised,
double-blind, placebo-controlled, phase III trial. Lancet
2009;374:210–21.
8. Schiff MH, von Kempis J, Goldblum R, et al. Rheumatoid
arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol:
a phase IV, randomised, multicentre, double-blind, 12-week
study, followed by a 12-week open-label phase. Ann Rheum
Dis 2014;73:2174–7.
www.jcomjournal.com
OUTCOMES RESEARCH IN REVIEW
Combination Therapy with Ribociclib Improves Progression-Free
Survival in Advanced Breast Cancer
Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced
breast cancer. N Engl J Med 2016;375:1738–48.
Study Overview
Objective. To evaluate the efficacy and safety of the
CDK4/6 inhibitor ribociclib in combination with letrozole as initial therapy in patients with hormone-receptor
(HR)–positive, human epidermal growth factor receptor
2 (HER-2)–negative advanced breast cancer.
Design. Pre-planned interim analysis of a randomized,
double-blind, phase 3 clinical trial.
Setting and participants. This study enrolled patients in
29 countries at 223 centers. A total of 668 postmenopausal women underwent randomization, with 334
assigned to receive ribociclib plus letrozole and 334
assigned to receive placebo plus letrozole. All women had
HR-positive, HER-2 negative recurrent or metastatic
breast cancer and had not received prior systemic therapy.
Enrolled patients had either measurable disease on imaging or at least 1 lytic bone lesion. All patients were
required to have an Eastern Cooperative Oncology
Group performance status of 0 or 1. Patients were
excluded if they had received prior therapy with a CDK4/6
inhibitor, previous systemic chemotherapy or endocrine
therapy. If a patient received an aromatase inhibitor
for neoadjuvant or adjuvant therapy, the disease-free interval needed to be more than 12 months to be included
in the study. Patients with inflammatory breast cancer or
central nervous system involvement were also excluded.
Normal cardiac function (normal QT interval) was
required for enrollment. The randomization was stratified by presence of liver or lung metastases.
Intervention. The patients were randomized to oral
ribociclib 600 mg per day 3 weeks on, 1 week off in a
28-day treatment cycle plus letrozole 2.5 mg daily or
placebo plus letrozole. The dosing of ribociclib was based
on a prior phase 1 study [1]. Treatment was continued
until disease progression, unacceptable toxicity, discontinuation, or death. Dose reductions of ribociclib were
www.jcomjournal.com
allowed; however, dose reductions of letrozole were not
permitted. Crossover between treatment arms was not
allowed. Patients were assessed with computed tomography at the time of randomization, every 8 weeks
for the first 18 months and every 12 weeks thereafter. Patients were monitored for hematological toxicity
each cycle. Electrocardiographic assessment was done at
screening, on day 15 of cycle 1 and on day 1 of all subsequent cycles to monitor for QT prolongation.
Main outcome measures. The primary outcome was
progression-free survival. The secondary outcomes were
overall survival, overall response rate (complete or partial
response), clinical benefit rate, and safety. Clinical benefit
rate was defined as overall response plus stable disease
lasting 24 weeks or more. A prespecified interim analysis was planned after disease progression or death was
reported in 211 of 302 patients (70%).
Results. The baseline characteristics were balanced
between the 2 groups. Visceral disease was present in
58.8% and bone-only disease in 22% of the patients. The
median duration of therapy exposure was 13 months
in the ribociclib group and 12.4 months in the placebo group. The median duration of follow-up was 15.3
months. After 18 months, progression-free survival was
63% (95% confidence interval [CI], 54.6 to 70.3) in the
ribociclib/letrozole group versus 42.2% (95% CI, 34.8
to 49.5) in the placebo group (P < 0.001). The median
progression-free survival was not met in the combination group (95% CI, 19.3 to not reached) versus 14.7
months (95% CI, 13.0 to 16.5) in the placebo group.
The improved progression-free survival was seen across
all subgroups. The overall response rate was higher in
the combination arm (52.7% vs. 37.1%) as was the clinical benefit rate (80.1% vs. 71.8%). Serious adverse events
occurred in 21.3% of patients in the ribociclib group and
11.8% in the placebo group. Serious adverse events were
attributed to the study drug in 7.5% of the ribociclib
Vol. 23, No. 12 December 2016 JCOM 539
OUTCOMES RESEARCH IN REVIEW
group and 1.5% of the placebo group. The most common
adverse events were myelosuppression, nausea, fatigue
and diarrhea. Grade 3 and 4 neutropenia was noted in
59.3% in the ribociclib group versus < 1% in the placebo
arm. The discontinuation rate due to adverse events in
the ribociclib and placebo groups was 7.5% versus 2.1%,
respectively. The most common reason for discontinuation was disease progression in 26% in the ribociclib
group and 43.7% in the placebo group. Three deaths
occurred in the ribociclib group and one in the placebo
group. Interruptions in ribociclib occurred in 76.9% of
patients. Dose reductions occurred in 53.9% of patients
in the ribociclib group versus 7% in the placebo group.
The most common reason a dose reduction occurred was
neutropenia.
Conclusion. First-line treatment with ribociclib plus
letrozole in postmenopausal women with HR-positive,
HER-2 negative advanced breast cancer was associated with significantly longer progression-free survival
compared with letrozole plus placebo. The improved
progression-free survival was seen across all subgroups.
Commentary
Nearly 80% of all breast cancers express hormone receptor positivity. Hormonal therapy has been an important
component of treatment for women with hormonepositive breast cancer in both the local and metastatic
setting. Many tumors will eventually develop resistance to such therapy with the median progression-free
survival with first-line endocrine therapy alone being
around 9 months [2]. Cyclin dependent kinases 4 and 6
(CDK4/6) play an important role in estrogen-receptor
signaling and cell cycle progression. CDK 4/6 mediates
progression through the cell cycle from G1 to S phase
via phosphorylation and inactivation of the retinoblastoma tumor suppressor protein [3]. Overexpression of
CDK 4/6 in hormone receptor positive breast cancer is
thought to play an important role in the development of
endocrine therapy resistance [4].
The previously published PALOMA-2 trial, which
compared treatment with the CDK 4/6 inhibitor palbociclib plus letrozole with letrozole alone, reported a
significant improvement in progression-free survival with
the addition of palbociclib (24.8 months vs. 14.5 months)
in the front-line setting for women with advanced,
hormone-positive breast cancer [5]. The improved
progression-free survival with palbociclib was seen across
540 JCOM December 2016 Vol. 23, No. 12
all subgroups with a favorable toxicity profile. The current study represents the second randomized trial to show
that the addition of CDK4/6 inhibitor to endocrinebased therapy significantly improves progression-free
survival. This benefit was also seen across all patient subgroups including those with liver and lung metastases. In
addition, the combination of ribociclib and letrozole also
show significantly higher rates of overall response compared with placebo. In general, the addition of ribociclib
to letrozole was well tolerated with a very low rate (7.5%)
of discontinuation of therapy. Although neutropenia was
a frequent complication in the ribociclib group febrile
neutropenia occurred in only 1.5% of patients.
The incorporation of CDK4/6 inhibitors to
endocrine-based therapy in the front-line setting has
proven effective with an impressive early separation of the
progression-free survival curves. Both the PALOMA-2
trial and the current MONALEESA-2 trial have shown
similar results with approximately 40% improvement in
progression-free survival. Whether the results seen in
these trials will translate into an improvement in overall
survival is yet to be determined. The results of these 2
trial suggest that CDK4/6 inhibitors have activity in
both patients who have not received previous treatment
with endocrine therapy and in those who received adjuvant endocrine therapy with late (> 12 months) relapse.
Further determination of the subset of women who
would benefit from the addition of CDK4/6 inhibitors
remains an important clinical question. There are currently no clinical biomarkers that can be used to predict
whether a patient would benefit from the addition of
these medications.
Applications for Clinical Practice
The results of the current trial represent an exciting
step forward in the treatment of advanced breast cancer.
Palbociclib in combination with endocrine therapy is
currently incorporated into clinical practice. The cost of
these agents remains a concern; however, most insurance
policies will cover them. Clinical trials are ongoing in the
neoadjuvant and adjuvant setting for early breast cancer.
—Daniel Isaac, DO, MS
References
1. Infante JR, Cassier PA, Gerecitano JF, et al. A phase 1 study
of cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011)
in patients with advanced solid tumors and lymphomas. Clin
Cancer Res 2016.
2. Mouridse H, Gershanovich M, Sun Y, et al. Phase III study
www.jcomjournal.com
OUTCOMES RESEARCH IN REVIEW
of letrozole versus tamoxifen as first-line therapy of advanced
breast cancer in post-menopausal women: analysis of survival
and update of efficacy from the international letrozole breast
cancer group. J Clin Oncol 2003 21:2101–9.
3. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995;81:323–30.
4. Zavardas D, Baselga J, Piccart M. Emerging targeted
agents in metastatic breast cancer. Nature Rev Clin Oncol
2013;10:191–210.
5. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: primary results from a phase III trial of palbociclib with letrozole compared with letrozole alone in women with ER+/
HER2- advanced breast cancer. J Clin Oncol 2016;34(Supp).
Abst 507.
Does Higher BMI Directly Increase Risk of Cardiovascular
Disease? Maybe Not . . .
Nordström P, Pedersen NL, Gustafson Y, et al. Risks of myocardial infarction, death, and diabetes in identical
twin pairs with different body mass indexes. JAMA Intern Med 2016;176:1522–9.
Study Overview
Objective. To evaluate whether higher BMI alone contributes to risk of cardiovascular disease (CVD) and
death.
Study design. Cohort study of weight-discordant monozygotic twin pairs
Setting and participants. This study took place in Sweden, using a subset of data from the Swedish Twin Registry and the Screening Across Lifespan Twin (SALT)
study, which aimed to screen Swedish twins born prior
to 1958 for the development of “common complex diseases.” From a total of 44,820 individuals, the current
study limited to a subset of 4046 monozygotic twin pairs
where both twins had self-reported height and weight
data, and where calculated body mass index (BMI) was
discordant between the twins, defined as a difference
> 0.01 kg/m2. No other inclusion or exclusion criteria
are mentioned. Data for the study were collected from
several different sources, including telephone interviews
(eg, height and weight, behaviors such as physical activity
and smoking), national registries on health conditions
(eg, myocardial infarction [MI], stroke, diabetes) or prescriptions (eg, diabetes medications), the national causes
of death register, and a nationwide database containing
socioeconomic variables (eg, income and education). The
primary exposure of interest for this study was weight status, categorized as “leaner” or “heavier,” depending on
the relative BMI of each twin in a given pair. “Leaner”
twins were assumed to have lower adiposity than their
www.jcomjournal.com
“heavier” counterparts, and yet to have identical genetic
makeup, thereby allowing the authors to eliminate the
contribution of genetic confounding in evaluating the
relationship between weight status and CVD risk. The
classification system could mean that one person with a
BMI of 26 kg/m2 would be placed in the “leaner” category if their twin had a BMI of 28, while someone else
in another twin pair but also with a BMI of 26 kg/m2
might be classified in the “heavier” category if their twin
had a BMI of 22. Twin pairs were followed for up to 15
years to assess for incident outcomes of interest, with
baseline data collected between 1998 and 2002, and
follow-up through 2013.
Main outcome measures. The primary outcome of interest was the occurrence of incident MI or death from
any cause. As above, these outcomes were assessed using
national disease and death registries spanning 1987-2013,
and ICD-9 or -10 codes of interest. A secondary outcome
of incident diabetes was also specified, presumably limited to development of type 2 diabetes mellitus, and
identified using the same datasets, as well as the national
prescription registry. Kaplan-Meier curves for incident
MI and death were constructed comparing all “leaner”
twins against all “heavier” twins, and Cox proportional
hazards modeling was used to compare the hazard of the
primary composite outcome between groups. Logistic
regression was used to evaluate the odds of each outcome including diabetes incidence, and several models
were built, ranging from an unadjusted model to one
adjusting for a number of lifestyle factors (eg, smoking
Vol. 23, No. 12 December 2016 JCOM 541
OUTCOMES RESEARCH IN REVIEW
status, physical activity), baseline health conditions, and
sociodemographic factors.
The authors separately examined risk of MI/death in
the subgroup of twins where the “heavier” twin had a
BMI ≤ 24.9 kg/m2 at baseline (ie, despite being labeled
“heavier” they still had a technically normal BMI), and
examined the impact of weight trajectory prior to the
defined baseline (eg, they were able to incorporate into
models whether someone had been actively gaining or
losing weight over time prior to the baseline exposure
categorization). The authors also conducted several
sensitivity analyses, including running models excluding
twins with < 1 year of follow-up in an effort to insure that
results of the main analysis were not biased due to differential loss to follow-up between exposure categories.
Results. Of the 4046 twin pairs in this study, 56% (2283
pairs) were female, and mean (SD) age at baseline was
57.6 (9.5) years. Race/ethnicity was not reported but
presumably the vast majority, if not all, are non-Hispanic
white, based on the country of origin. In comparing
the group of “heavier” twins to “leaner” twins, several
important baseline differences were found. By design, the
“heavier” twins had significantly higher mean (SD) BMI
at study baseline (25.9 [3.6] kg/m2 vs. 23.9 [3.1] kg/m2)
and reported greater increases in BMI over the 15–20
years preceding baseline (change since 1973 was +4.3
[2.9] BMI units for “heavier” twins, vs. +2.6 [2.6] for
“leaner” twins). Smoking status differed significantly
between groups, with 15% of “heavier” twins reporting
they were current smokers versus ~21% of “leaner” twins.
“Leaner” twins were also slightly more active than their
“heavier” counterparts (50.4% reported getting “rather
much or very much” exercise versus 46.5%). The groups
were otherwise very similar with respect to marital status,
educational level, income, and baseline diagnoses of MI,
stroke, diabetes, cancer or alcohol abuse.
In fully adjusted models over a mean (SD) 12.4
(2.5)-year follow-up, “heavier” twins had a significantly
lower odds of MI or death (combined) than “leaner”
twins (odds ratio [OR] 0.75, 95% CI 0.63–0.91).
Because the “heavier” vs. “leaner” dichotomy did not
map to clinical definitions of overweight or obesity, the
investigators also examined this primary outcome among
subgroups with more clinical relevance. Being “heavier”
actually had the greatest protective effect against MI/
death (OR 0.61, 95% CI 0.46–0.80) among pairs
where the so-called “heavier” twin had a normal BMI
542 JCOM December 2016 Vol. 23, No. 12
(< 25.0 kg/m 2), and this subgroup appeared to be
driving the overall finding of lower odds of MI/death
in the “heavier” group as a whole. This pattern was
underscored when examining the subgroup of twin
pairs where the “heavier” twin had a BMI ≥ 30 kg/m 2
at baseline – in this group the protective effect of being
“heavier” disappeared (OR 0.92, 95% CI 0.60 to 1.42).
Besides not always reflecting clinically relevant weight
categories, the “heavier” vs. “leaner” twin dichotomy
could, in some cases, amount to a very small difference
in BMI between twins (anything > 0.01 unit counted as
discordant). As such, the investigators sought to examine whether their results held up when looking at pairs
with a higher threshold for BMI discordance (1.0 to 7.0
units or more difference between twins), finding that
risk of MI or death did not increase among the “heavier” group in these more widely split twin pairs, even
when adjusting for smoking status and physical activity.
In contrast to the MI/mortality analyses, “heavier”
twins did have significantly greater odds of developing
diabetes during follow-up compared to their “leaner”
counterparts (OR 1.94, 95% CI 1.51 to 2.48, adjusted
for smoking and physical activity). Also unlike the MI/
death analyses, this relationship of increased diabetes
risk among “heavier” twins was enhanced by increasing BMI dissimilarity between twins, and among twins
who had been gaining weight prior to baseline BMI
measurement.
Sensitivity analyses excluding twins with less than 1
year of follow-up did not result in changes to the main
findings—“heavier” twins still had similar odds of MI/
death as “leaner” twins.
Conclusion. The authors conclude that among monozygotic twin pairs, where the possibility for genetic
confounding has been eliminated, obesity is not causally
associated with increased risk of MI or death, although
the results do support an increased risk of developing
incident diabetes among individuals with higher BMI.
Commentary
Obesity is a known risk factor for many chronic conditions, including diabetes, osteoarthritis, sleep apnea,
and hypertension [1]. However, the relationship between obesity and cardiovascular outcomes, particularly
coronary artery disease and death from heart disease,
has been more controversial. Some epidemiologic studies have demonstrated reduced mortality risk among
www.jcomjournal.com
OUTCOMES RESEARCH IN REVIEW
patients with obesity and heart failure, and even among
those with established coronary artery disease—the socalled “obesity paradox” [2]. Others have observed that
overweight older adults may have lower overall mortality
compared to their normal weight counterparts [3]. On
the other hand, it is known that obesity increases risk for
diabetes, which is itself a clear and proven risk factor for
CVD and death.
As the authors of the current study point out, genetic
confounding may be a potential reason for the conflicting results produced in studies of the obesity–CVD
risk relationship. In other words, patients who have
genes that promote weight gain may also have genes
that promote CVD, through pathways independent of
excess adipose tissue, with these hidden pathways acting as confounders of the obesity–CVD relationship. By
studying monozygotic twin pairs, who have identical
genetic makeup but have developed differential weight
status due to different environmental exposures, the
investigators designed a study that would eliminate any
genetic confounding and allow them to better isolate
the relationship between higher BMI and CVD. This is
an important topic area because, at a population level,
we are faced with an immense number of adults who
have obesity. Treatment of this condition is resource
intense and it is critical that patients and health care
systems understand the potential risk reduction that will
be achieved with sustained weight loss.
The strengths of this study include the use of a very
unique dataset with longitudinal measures on a large
number of monozygotic twin pairs, and the authors’
ability to link this dataset with nationwide comprehensive datasets on health conditions, health care use
(pharmacy), sociodemographics, and death. Sweden’s
national registries are quite impressive and permit these
types of studies in a way that would be very difficult
to achieve in the United States, with its innumerable
separate health care systems and few data sources that
contain information on all citizens. Because of these
multiple data sources, the authors were able to adjust
for some important lifestyle factors that could easily confound the weight status-MI/death relationship,
such as smoking and physical activity. Additionally, their
models were able to factor in trajectory of weight on
some individuals prior to baseline, rather than viewing
baseline weight only as a “snapshot” which could risk
missing an important trend of weight gain or loss over
time, with important health implications.
www.jcomjournal.com
There are several limitations of the study that are
worth reviewing. First, and most importantly, as pointed
out in a commentary associated with the article, the categorization of “leaner” and “heavier” can be somewhat
misleading if the true question is whether or not excess
adiposity is an independent driver of cardiovascular risk
[4]. BMI, at the individual level, is not an ideal measure
of adiposity and it does not speak to distribution of fat tissue, which is critically important in evaluating CVD risk
[5]. For example, 2 siblings could have identical BMIs,
but one might have significantly more lean mass in their
legs and buttocks, and the other could have more central
adipose tissue, translating to a much higher cardiovascular risk. Measures such as waist circumference are critical
factors in addition to BMI to better understand an individual’s adipose tissue volume and distribution.
Although the authors did adjust for some selfreported behaviors that are important predictors of
CVD (smoking, exercise), there is still potential for
confounding due to unscreened or unreported exposures that differ systematically between “leaner” and
“heavier” twins. Of note, smoking status—probably
the single most important risk factor for CVD—was
missing in 13% of the cohort, and no imputation techniques were used for missing data. Another limitation
of this study is that its generalizability to more racial/
ethnically diverse populations may be limited. Presumably, the patients in this study were non-Hispanic white
Swedes, and whether or not these findings would be
replicated in other groups, such as those of African or
Asian ancestry, is not known.
Finally, the finding that “heavier” twins had greater
odds of developing diabetes during follow-up is certainly consistent with existing literature. However, it is
also known that diabetes is a strong risk factor for the
development of CVD, including MI, and for death [6].
This raises the question of why the authors observed an
increased diabetes risk yet no change in MI/death rates
among heavier twins. Most likely the discrepancy is due
to inadequate follow-up time of incident diabetes cases.
Complications of diabetes can take a number of years to
materialize, and, with an average of 12 years’ total followup in this study, there simply may not have been time to
observe an increased risk of MI/death in heavier twins.
Applications for Clinical Practice
For patients interested in weight loss as a way of reducing
CVD risk, this paper does not support the notion that
Vol. 23, No. 12 December 2016 JCOM 543
OUTCOMES RESEARCH IN REVIEW
lower body weight alone exerts direct influence on this
endpoint. However, it reinforces the link between higher
body weight and diabetes, which is a clear risk factor
for CVD. Therefore, it still seems reasonable to advise
patients who are at risk of diabetes that improving dietary
quality, increasing cardiorespiratory fitness, and losing
weight can reduce their long-term risk of CVD, even if
indirectly so.
—Kristina Lewis, MD, MPH
References
1. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/
ACC/TOS guideline for the management of overweight and
obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines and The Obesity Society. Circulation 2014;129(25
Suppl 2):S102–138.
2. Antonopoulos AS, Oikonomou EK, Antoniades C, Tousoulis D. From the BMI paradox to the obesity paradox: the
obesity-mortality association in coronary heart disease. Obes
Rev 2016;17:989–1000.
3. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of
all-cause mortality with overweight and obesity using standard
body mass index categories: a systematic review and metaanalysis. JAMA 2013;309:71–82.
4. Davidson DJ, Davidson MH. Using discordance in monozygotic twins to understand causality of cardiovascular disease
risk factors. JAMA Intern Med 2016;176:1530.
5. Amato MC, Guarnotta V, Giordano C. Body composition
assessment for the definition of cardiometabolic risk. J Endocrinol Invest 2013;36:537–43.
6. The Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, et al. Diabetes mellitus, fasting glucose, and risk of
cause-specific death. N Engl J Med 2011;364:829–41.
Copyright 2016 by Turner White Communications Inc., Wayne, PA. All rights reserved.
544 JCOM December 2016 Vol. 23, No. 12
www.jcomjournal.com