21 / 24
the treatment of nonalcoholic steatohepati-
tis (NASH).
2
Nonalcoholic fatty liver disease
(NAFLD) and the more serious NASH are
two of the more common complications
of obesity, insulin resistance, and type 2
diabetes. There is evidence that treat-
ment with TZDs decreases hepatic lipid
stores, while increasing subcutaneous
fat. Cusi and colleagues randomized 101
patients with prediabetes or type 2 diabe-
tes mellitus and biopsy-proven NASH to
pioglitazone, 45 mg/day, or placebo and
observed them for 18 months. This was fol-
lowed by an 18-month open-label phase
with pioglitazone treatment. They found a
decrease of 41 percentage points (95% CI,
23–59 percentage points; P < 0.001) in the
primary outcome (a reduction of at least 2
points in the NAFLD activity score in two
histologic categories without worsening
of fibrosis) in pioglitazone-treated patients
compared with controls. Remarkably,
51% of patients treated with pioglitazone
had resolution of NASH (P < 0.001). Pio-
glitazone treatment also was associated
with reduced hepatic triglyceride content,
from 19% to 7% (treatment difference, −7
percentage points; 95% CI, −10 to −4 per-
centage points; P < 0.001) and improved
hepatic and peripheral insulin sensitivity, as
expected. This study is important because
NAFLD and NASH are highly prevalent
among patients with type 2 diabetes and
are associated with significant long-term
risks for cirrhosis and hepatocellular carci-
noma. Until this study, there were no highly
effective medications for these conditions.
These data suggest that, in addition to
weight loss, treatment with pioglitazone
can be considered for patients with NASH.
Further larger and longer-term studies will
be required before this can become a gen-
eral treatment recommendation, however.
The second paper featured in
Prac-
ticeUpdate
also explored the use of
pioglitazone for a novel indication. Kernan
and colleagues studied pioglitazone for
the prevention of fatal or nonfatal stroke
or myocardial infarction in patients with
insulin resistance (but not diabetes) who
had previously experienced an ischemic
stroke or transient ischemic attack (TIA).
3
Such patients are known to be at high risk
for subsequent cardiovascular events.
Current preventive therapies addressing
lipids, blood pressure, and the coagulation
system do not address insulin resistance,
which has been identified as an independ-
ent risk factor for stroke and myocardial
infarction. Thus, the investigators asked
whether treatment with the insulin sensi-
tizer pioglitazone would prevent further
cardiovascular events. They conducted a
multicenter, double-blind trial (called the
IRAS study), in which 3876 patients who
had had a recent ischemic stroke or TIA
were randomized to receive either pio-
glitazone (45 mg/day) or placebo. After a
mean follow-up of 4.8 years, they observed
that the primary outcome had occurred in
175 of 1939 patients (9.0%) in the piogli-
tazone-treated group and in 228 of 1937
patients (11.8%) in the placebo-treated
group (HR for pioglitazone, 0.76; 95% CI,
0.62–0.93; P = 0.007). They also noted
that pioglitazone was associated with sig-
nificantly less progression to diabetes
(HR, 0.48; 95% CI, 0.33–0.69; P< 0.001).
As expected, pioglitazone was associated
with more weight gain (52.2% vs 33.7%
gained >4.5 kg; P < 0.0001) and edema
(reported in 35.6% vs 24.9%; P < 0.001).
Also, significantly more bone fractures
requiring surgery or hospitalization were
noted with pioglitazone compared with pla-
cebo (5.1% vs 3.2%; P = 0.003).
Collectively, these two trials demonstrate
that insulin sensitization with pioglitazone
can have beneficial effects beyond glu-
cose control. In both trials, pioglitazone was
generally well-tolerated, with a side-effect
profile consistent with that seen in patients
with diabetes. Since NAFLD/NASH and
cardiovascular disease are common com-
plications of type 2 diabetes, these results
suggest that we should rethink the role of
pioglitazone as we seek to improve global
outcomes in patients with type 2 diabetes.
References
1. Nissen S, Wolski K. Effect of rosiglitazone on
the risk of myocardial infarction and death
from cardiovascular causes.
N Engl J Med
2007;356(24):2457
-2471.
2. Cusi K, Orsak B, Bril F, et al. Long-term
pioglitazone treatment for patients with
nonalcoholic steatohepatitis and prediabetes or
type 2 diabetes mellitus: a randomized trial.
Ann
Intern Med
2016;165(5):305-315.
3. Kernan WC, Viscoli CM, Furie KL, et al.
Pioglitazone after ischemic stroke or
transient ischemic attack.
N Engl J Med
2016;374(14):1321-1331.
Collectively, these two trials
demonstrate that insulin
sensitization with
pioglitazone can have
beneficial effects beyond
glucose control. In both trials,
pioglitazone was generally
well-tolerated, with a side-
effect profile consistent
with that seen in patients
with diabetes.
MY PERSPECTIVE
21
VOL. 1 • NO. 1 • 2017