REVIEW

Type 2 Diabetes: Assessing the Relative Risks and

Benefits of Glucose-lowering Medications
Richard M. Bergenstal, MD,a Clifford J. Bailey, PhD,b David M. Kendall, MDa
a
International Diabetes Center, Minneapolis, Minn; bDiabetes Research, Life and Health Sciences, Aston University, Birmingham, UK.

ABSTRACT

The selection of appropriate pharmacologic therapy for any disease requires a careful assessment of benefit
and risk. In the case of type 2 diabetes, this decision typically balances the benefits accrued from improved
glycemic control with the risks inherent in glucose-lowering medications. This review is intended to assist
therapeutic decision-making by carefully assessing the potential benefit from improved metabolic control
relative to the potential risks of a wide array of currently prescribed glucose-lowering agents. Wherever
possible, risks and benefits have been expressed in terms of absolute rates (events per 1000 patient-years)
to facilitate cross-study comparisons. The review incorporates data from new studies (Action in Diabetes
and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation, Action to Control
Cardiovascular Risk in Diabetes, and the Veterans Affairs Diabetes Trial), as well as safety issues
associated with newer glucose-lowering medications.
© 2010 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2010) 123,
374.e9-374.e18

KEYWORDS: Diabetes mellitus; Drug toxicity; Risk assessment; Safety; Therapeutics

The safety of blood glucose-lowering medications has been

Funding: This review was supported by funds supplied by Amylin
Pharmaceuticals, Inc.
Conflict of Interest: David M. Kendall, MD and Richard M. Bergen-
stal, MD are clinical investigators and staff at the International Diabetes
Center at Park Nicollet. The institution receives research support or edu-
cational funding, or performs professional or consulting services for the
following organizations: Abbott Diabetes Care, Amylin Pharmaceuticals,
Inc., Bayer Diabetes Care, Daiichi-Sankyo, DexCom, Eli Lilly and Co., Health-
Partners, Hoffman La Roche, Intarcia, LifeScan, MannKind, Merck, MiniMed-
Medtronic, Nektar Therapeutics, Novartis, Novo Nordisk, ResMed, Roche
Diabetes Care, sanofi-aventis, Takeda, and United Health Group. All re-
search activity, advisory/consultancy work, and educational services are
performed under contract to the nonprofit Park Nicollet Institute and the
International Diabetes Center. Dr. Bergenstal and Dr. Kendall receive no
personal compensation for these activities. Dr. Bergenstal has inherited
Merck stock. Clifford J. Bailey, PhD declares no conflict of interest for this
review, but does disclose research support, honoraria, and ad hoc advisory
activities associated with several pharmaceutical companies interested in
antidiabetic and antiobesity treatments.
Authorship: The authors had full and independent editorial control of
the content of this review at all stages of its development.
Requests for reprints should be addressed to Richard M. Bergenstal,
MD, International Diabetes Center, 3800 Park Nicollet Blvd., Minneapolis,
MN 55416.
E-mail address: richard.bergenstal@parknicollet.com
an issue for almost 40 years, ever since the University
Group Diabetes Program study indicated that tolbutamide
therapy increased mortality in patients with type 2 diabetes.1
A recent meta-analysis linking cardiovascular (CV) events
to the use of the thiazolidinedione rosiglitazone is but the
latest issue raised in this ongoing controversy.2 Safety con-
cerns are known to alter how clinicians prescribe diabetes
therapies,3,4 as well as other classes of medications.5-8
Broad media coverage of published safety concerns also
might affect patient adherence to pharmacotherapy,9-11 de-
spite evidence that early and effective glucose control can
reduce the risk of complications in type 2 diabetes.12
According to recent guidelines from the American Dia-
betes Association, the American Heart Association, and the
American College of Cardiology,13 the choice of glycemic
goals and the medications used to achieve them must be
individualized for each patient, balancing the potential for
lowering HbA1c levels and anticipated long-term benefit
with specific safety issues. This review offers a perspective
on this issue. It does not advocate the use or avoidance of
any specific medication, which is a decision that should be
guided by published scientific information, clinical experi-
ence, clinician expertise, and patient preference. Rather, it

0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2009.07.017
374.e10 The American Journal of Medicine, Vol 123, No 4, April 2010

seeks to inform clinical decision-making by comparing the events per 1000 patient-years. Intensive treatment also de-
potential risk of medications, as derived from published creased microvascular complications by 2.8 events per 1000
clinical studies, to the potential benefit of improved glucose patient-years (P ⫽ .010), a reduction from 11.4 to 8.6 events
control. Where possible, risks have been expressed in terms per 1000 patient years. In a subgroup of overweight indi-
of events per 1000 patient-years, an absolute measure of risk viduals weighing ⬎120% of normal, intensive metformin
that is easily comparable between treatment was associated with a re-
studies. This value provides an es- duction
timate of the number of times an in all diabetes-related endpoints,
CLINICAL SIGNIFICANCE all-cause mortality, MI, and diabe-
event might be expected to occur
in 100 patients treated over 10 ● In general, glucose-lowering medica- tes-related deaths by 13.5, 7.1,
years. Due to considerations of tions have a favorable risk-benefit pro- 7.0, and 5.2 events per 1000 pa-
length and clinical significance, file in patients with type 2 diabetes. tient-years, respectively (P ⬍.05
this review focuses on safety is- for all comparisons).21
sues (eg, CV disease, mortality ● The most common drug-associated ad- A recently published post-trial
rates) rather than tolerability issues verse events are hypoglycemic episodes, follow-up of the UKPDS (addi-
(eg, gastrointestinal symptoms). particularly among patients receiving tional 8 years of follow-up)12
sulfonylureas or insulin therapy. demonstrated that a significant re-
duction in risk was observed in the
DIABETES RISK ● Metformin-associated lactic acidosis,
original intensive treatment group
Diabetes is the seventh leading exenatide-associated pancreatitis, and relative to the conventional treat-
cause of mortality in the United sitagliptin-associated hypersensitivity ment group for any diabetes-re-
States, accounting for 72,507 reactions appear to be rare. lated outcome (reduction of 4.1
deaths in 2006 and related directly
● Increased risks of congestive heart fail-
events per 1000 patient-years;
or indirectly to over 250,000 P ⫽ .04) and microvascular com-
deaths in 2005 (Table 1).14 A di- ure and bone fractures in thiazo-
plications (reduction of 3.2 events
agnosis of diabetes at age 40 years lidinedione-treated patients, and re- per 1000 patient-years; P ⫽ 0.001).
has been estimated to reduce ex- ports of increased cardiovascular events In addition, over the longer time
pected life span by approximately in rosiglitazone-treated patients remain frame, events accumulated to re-
12 and 14 years in men and an issue. veal newly emergent statistical
women, respectively (Figure 1).18 significance to the prior trends in
The most important causes of
risk reductions: the risk of diabe-
mortality in diabetes patients are
tes-related death was reduced by
CV and cerebrovascular disease, primarily ischemic heart
16 2.5 events (P ⫽ .01), MI by 2.8 events (P ⫽ .01), and death
disease, heart failure, stroke, and sudden death. Mortality
from any cause by 3.5 events (P ⫽ .007) per 1000 patient-
rates from CV disease have been estimated at 3 deaths per
years. In the overweight subgroup 10 years after trial clo-
1000 patient-years in patients without diabetes and no his-
sure, prior intensive metformin treatment reduced any dia-
tory of prior myocardial infarction (MI). This CV mortality
betes-related endpoint, death from any cause, MI, and
rate increases by an estimated 8-fold in patients with dia-
diabetes-related death by 8.2, 7.2, 6.3, and 4.7 events per
betes (25 deaths per 1000 patient-years) even in the absence
1000 patient-years, respectively (P ⬍.05 for all compari-
of prior CV disease. In those with both diabetes and prior
sons). Similar short- and long-term benefits of intensive
CV disease, mortality rates are even higher (73 deaths per
glycemic control were noted in patients with type 1 diabetes
1000 patient years) (Figure 2).19 These findings are over and
in the Diabetes Control and Complications Trial and the
above the established causal relationship between diabetes
Epidemiology of Diabetes Interventions and Complications
and increased risk of microvascular complications (Table
14 study.22,23
1).
In an observational analysis of 3642 UKPDS patients,
the incidence of macrovascular and microvascular end-
ESTABLISHED BENEFITS OF GLYCEMIC CONTROL points was in each case positively associated with HbA1c
IN DIABETES levels (Figure 3),24 suggesting that more intensive glycemic
The landmark UK Prospective Diabetes Study (UKPDS) control over time may have additional benefit. Three recent
demonstrated the benefit of early intensive glucose control trials—Action in Diabetes and Vascular Disease: Preterax
in type 2 diabetes. In patients with newly diagnosed disease, and Diamicron Modified Release Controlled Evaluation
intensive treatment with sulfonylureas or insulin (or both) (ADVANCE),25 Action to Control Cardiovascular Risk in
for approximately 10 years (median HbA1c, 7.0%) re- 20
Diabetes (ACCORD),26 and the Veterans Affairs Diabetes
duced all diabetes-related endpoints by 5.1 events per 1000 Trial (VADT)27— examined this question more directly by
patient-years (P ⫽ .029) relative to conventional therapy specifically addressing whether even more intensive glyce-
(median HbA1c, 7.9%), a reduction from 46.0 to 40.9 mic control may further reduce the risk of CV disease. A
Bergenstal et al Risks and Benefits of Glucose-lowering Medications
Table 1 Clinical Impact of Diabetes
Diabetes in the United States
Prevalence: 23.6 million children and adults (8% of
population) in 200715
Incidence: 1.6 million new adult cases (ⱖ20 years) in 200715
Most common presentation: type 2 diabetes (90%-95% of
cases)14
Mortality: seventh leading cause in 2006, responsible for
72,507 deaths (⬃65% attributable to cardiovascular disease
and stroke)14,16
Contributing factor to mortality: contributed to 233,619
deaths in 200516
Kidney failure: leading cause, responsible for 44% of new
cases in 2005 (46,739 diabetic patients began treatment for
end-stage renal disease)16
Nontraumatic lower-limb amputations: leading cause,
responsible for ⬎60% of cases (⬃71,000 nontraumatic
lower-limb amputations in 2004)16
Nervous system damage: 60%-70% of diabetic patients have
mild to severe forms of nervous system damage16
Periodontal disease: one-third of patients with diabetes have
severe periodontal disease with loss of attachment of the
gums to the teeth measuring 5 mm or more)16
Sexual dysfunction: significantly increases risk in men and
women16
Total estimated cost of diabetes: $174 billion in 2007 ($116
billion in excess medical expenditures and $58 billion in
reduced national productivity)17
summary of results from these and prior trials is presented
in Table 2.
The ADVANCE study was an international trial
(n ⫽ 11,140; mean age, 66 years; mean duration of diabetes,
8 years) that compared 5 years of standard glucose control
targeting HbA1C values recommended by local national
Figure 1 Life-years lost from diabetes as a function of age at
diagnosis.18
374.e11
Figure 2 Rates of death from cardiovascular (CV) disease
causes per 1000 patient-years in type 2 diabetic and nondia-
betic subjects as a function of MI history.19 Data were from a
7-year population-based Finnish study of 1059 diabetic and
1373 non-diabetic subjects. MI ⫽ myocardial infarction.
guidelines (mean HbA1c, 7.3% at trial end) versus a more
intensive HbA1c goal of ⬍6.5% (mean HbA1c, 6.5% at trial
end); eligibility requirements included a history of prior
macrovascular or microvascular disease or at least one other
risk factor for vascular disease.25 In the study, intensive
treatment reduced the risk of combined macrovascular and
microvascular complications by 3.8 events per 1000 patient-
years (P ⫽ .01) relative to standard control. More intensive
glycemic control reduced the risk of microvascular compli-
cations by an estimated 3.0 events per 1000 patient-years
(P ⫽ .01). However, more intensive control did not statisti-
cally significantly reduce the risk of major macrovascular
events (P ⫽ .32), death from CV causes (P ⫽ .12), or all-
cause mortality (P ⫽ .28), although the statistical power to
assess these latter event rates may have been limited by the
shortened duration of the ADVANCE trial (5.6 years).
In the ACCORD study,26 10,251 patients (mean age,
62.2 years; mean duration of diabetes, 10 years) were as-
signed to either intensive therapy targeting a HbA1c level
below 6.0% or conventional therapy targeting a level from
7.0% to 7.9%. Randomized patients were aged 40-79 years
with a history of CV disease or 55-79 years with evidence
of significant atherosclerosis or other risk factors for CV
disease, including albuminuria, left ventricular hypertrophy,
or 2 risk factors for CV disease. Subjects achieved HbA1c
levels of 6.4% and 7.5% in the intensive and standard
therapy groups, respectively. The intensive therapy group
experienced an unexpected increase in all-cause mortality
and CV mortality of 2.7 and 2.3 events per 1000 patient-
years, respectively (P ⫽ .04 and .02, respectively). Conse-
quently, the intensive glycemia treatment arm of ACCORD
was suspended early in February 2008. Over the 3.5 years of
follow-up, the rate of major CV events and nonfatal MI
were reduced in the intensively treated group (MI reduced
by 3.4 events per 1000 patient-years [P ⫽ .004]). It is im-
portant to note that the overall death rate (5% vs 4%) was
374.e12 The American Journal of Medicine, Vol 123, No 4, April 2010

Figure 3 Incidence rate and 95% confidence intervals for myocardial infarction and
microvascular endpoints (left) and any diabetes-related end point (right) as a function of
HbA1c levels. Data were adjusted for age, sex, and ethnic group and were expressed for
white men 50-54 years of age at diagnosis with mean duration of diabetes of 10 years.24

lower for patients in ACCORD compared with previous benefit may be evident only after an extended period of time
data in patients with diabetes of this age, duration of dis- (perhaps 10 years), and the effect may be sustained for
ease, and these CV risk factors. periods of more than 10 years after the intensive treatment
Most recently, the VADT reported results from a study in intervention is discontinued. Intensive glycemic control
which more than 1791 military veterans with type 2 diabetes with HbA1C targets at or below 6% cannot be supported by
and suboptimal glycemic control (mean age, 60.4 years; these studies, given both the unexpected findings of ACCORD
mean duration of diabetes, 11.5 years) were randomly as- and the lack of benefit on macrovascular disease risk.
signed to either conventional therapy (median HbA1c, 8.4% A recent summary and position statement from the
at end of trial) or intensive glucose control (median HbA1c, American Diabetes Association, American Heart Associa-
6.9% at end of trial).27 Subjects were excluded from the trial tion, and American College of Cardiology clarifies the cur-
by a CV event during the previous 6 months, advanced rent treatment targets.13 The statement indicates that the
congestive heart failure (CHF), or severe angina. In VADT,
other risk factors for CV disease, such as blood pressure and
lipids, were treated aggressively. Over a median follow-up Table 2 Impact of Intensive Therapy in Diabetes: Summary
of 5.6 years, intensive glucose control had no significant of Major Clinical Trials
effect on the rates of major CV events, death, or microvas-
cular complications (except a reduction in worsening of Study Microvascular Macrovascular Mortality
albumin excretion). This observation may reflect, in part, UKPDS 12,20
2 2* — 2* — 2*
the prolonged interval of poor control at enrollment (mean (Type 2)
HbA1c was 9.4% at recruitment with an average duration of DCCT/EDIC22,23 2 2* — 2* — —*
diabetes of 11.5 years), substantial baseline morbidity, or (Type 1)
other factors. Subgroup analyses suggested some benefit of ACCORD26 ? — 1
intense treatment in those individuals with a shorter dura- (Type 2)
tion of diabetes.27 ADVANCE25 2 — —
(Type 2)
While many secondary analyses are underway for these
VADT27 (Type 2) 2 — —
3 trials, the data from the individual trials suggest that very
intensive therapy in patients with long-standing type 2 dia- UKPDS ⫽ UK Prospective Diabetes Study; DCCT ⫽ Diabetes Control
and Complications Trial; EDIC ⫽ Epidemiology of Diabetes Interventions
betes does not significantly reduce the risk of CV disease in and Complications; ACCORD ⫽ Action to Control Cardiovascular Risk in
higher risk patients. As a whole, these data—when com- Diabetes; ADVANCE ⫽ Action in Diabetes and Vascular Disease: Preterax
bined with data from UKPDS and other studies—suggest a and Diamicron Modified Release Controlled Evaluation; VADT ⫽ Veterans
benefit from glucose lowering on CV disease risk that is Affairs Diabetes Trial.
more likely to occur if intensive therapy is initiated earlier 2 ⫽ decreased rate; 1 ⫽ increased rate; — ⫽ no effect.
*Long-term follow up trials.
in the course of the disease.28,29 Moreover, the CV disease
Bergenstal et al Risks and Benefits of Glucose-lowering Medications
lack of reduction of CV events in ADVANCE, ACCORD,
and VADT should not lead clinicians to abandon the general
HbA1c target of ⬍7%, which unambiguously reduces mi-
crovascular complications, but states that there may be an
added mortality risk in normalizing HbA1c levels in high-
risk individuals. This position statement emphasizes the
need for individualized goals for treatment, laying out sev-
eral considerations for less stringent HbA1c treatment tar-
gets and the possibility of some clinical situations where
striving for a lower HbA1c may be inappropriate.
RISKS ASSOCIATED WITH GLUCOSE-LOWERING
MEDICATIONS
CV Risk
As indicated above, a meta-analysis published by Nissen
and Wolski in 2007 concluded that rosiglitazone treatment
was associated with overall increase in the risk of MI as
compared with all other comparator drugs.2 Using data
extracted from the article, the estimated risk with rosiglita-
zone (originally presented as a 43% increase in risk or an
odds ratio [OR] of 1.43; P ⫽ .03) represents an approximate
increase of 1 MI event per 1000 patient-years of rosiglita-
zone treatment versus other therapies. In addition, the meta-
analysis found a potential increase of borderline signifi-
cance in the risk of death from total CV causes (P ⫽ .06).
Since publication, other analyses have been performed
that challenged these findings for a myriad of reasons,
including the substantial heterogeneity among study popu-
lations, the confounding influences of small study effects,
the relatively short time span of most included studies, and
the exclusion of studies with no events.30-33 Other meta-
analyses have reached conflicting results. One found that
rosiglitazone use raised MI risk by 1.2 events per 1000
patient-years among newly diagnosed patients with no his-
tory of unstable or severe angina, by 4.5 events per 1000
patient-years among community-based patients with no
prior history of MI, and by 13.5 events per 1000 patient-
years among community-based patients with prior history of
MI.34 Conversely, a pooled analysis of 3 large rosiglitazone
trials designed to specifically test CV outcomes (A Diabetes
Outcome Progression Trial, Rosiglitazone Evaluated for
Cardiac Outcomes and Regulation of Glycemia in Diabetes,
and Diabetes Reduction Assessment with Ramipril and Ros-
iglitazone Medication) did not reach statistical significance
for either MI (OR 1.29; P ⫽ .12) or death due to CV causes
(OR 0.90; P ⫽ .67).35 Furthermore, a meta-analysis of 86
trials did not find a statistically significant increase in the
overall rate of MI in patients on rosiglitazone.36 It should be
noted that variations in CV exclusion criteria for use of any
thiazolidinedione, including rosiglitazone (eg, New York
Heart Association Class I-IV in Europe and New York
Heart Association Class III-IV outside Europe), also could
confound outcomes.
Unlike rosiglitazone, pioglitazone, the other available
thiazolidinedione, has not been associated with increased
374.e13
risk of either MI or CV mortality.37-39 Both pioglitazone
and rosiglitazone, however, unambiguously increase risk of
CHF, potentially reflecting an inherent proclivity to induce
edema.40 A recent meta-analysis of 7 trials (20,191 patients)
with a mean follow-up of 29.7 months indicated that pa-
tients given thiazolidinediones had increased risk for devel-
oping CHF across a wide background of cardiac risk (rela-
tive risk [RR] 1.72; P ⫽ 0.002).41 These data suggest an
approximate mean increase of 3.8 events per 1000 patient-
years of thiazolidinedione treatment. Rosiglitazone and pio-
glitazone appeared to raise the risk of CHF by similar
amounts, but neither raised the incidence of heart-failure-
associated death.41
Hypoglycemia
Hypoglycemic episodes are the most common complication
occurring in insulin-treated patients.42 They also might oc-
cur in patients taking sulfonylureas, especially older pa-
tients or those with impaired liver or kidney function treated
with long-acting agents such as chlorpropamide or gly-
buride.42 Patients who have experienced hypoglycemic
events report significantly lower treatment satisfaction and
medication adherence rates.43 Hypoglycemia has been re-
ferred to as the limiting factor in achieving glucose targets
in type 1 and type 2 diabetes.44
Clinical trials have consistently shown that intensive
treatment with sulfonylureas or insulin significantly in-
creases the risk of hypoglycemia. In data from UKPDS,
rates of major hypoglycemic episodes requiring third-party
assistance were 7, 10, 14, and 18 events per 1000 patient-
years in the conventional, chlorpropamide, glibenclamide
(glyburide), and insulin treatment groups, respectively.20 In
the Diabetes Control and Complications Trial, the intensive
insulin therapy group had an excess of 430 hypoglycemic
episodes per 1000 patient-years in which assistance was
required in the provision of treatment.22 In ADVANCE, the
intensive-control group (gliclazide [modified release] plus
other drugs) had an excess of 3 severe hypoglycemic epi-
sodes per 1000 patient-years (7 events per 1000 patient-
years in the intensive-control group vs 4 events per 1000
patient-years in the standard-control group). In ACCORD,25
the intensive control group had an excess of 21 hypoglyce-
mic episodes requiring medical assistance per 1000 patient-
years, although in this study the intensive therapy group
received particularly aggressive drug intervention with mul-
tiple classes, including incretin mimetics, metformin, thia-
zolidinediones, and alpha-glucosidase inhibitors.26
Weight Gain
Excess adiposity (body mass index or abdominal obesity) is
associated with exacerbation of hyperglycemia, dyslipide-
mia, hypertension, and increased risk of CV death and
overall mortality in patients with type 2 diabetes.45-47 Con-
versely, intentional weight loss has a favorable impact on
CV risk factors and mortality.48 In a prospective 12-year
study of 4970 overweight individuals with diabetes enrolled
374.e14
in the American Cancer Society’s Cancer Prevention Study
I, intentional weight loss was associated with a 25% reduc-
tion in total mortality (RR ⫽ 0.75) and a 28% reduction in
CV disease and diabetes mortality (RR ⫽ 0.72).
Improvement of glycemic control with insulin, sulfonyl-
ureas, repaglinide, nateglinide, and thiazolidinediones is
often accompanied by weight gain.49,50 In the UKPDS,
weight gain was significantly higher in the intensive treat-
ment group than in the conventional treatment group (mean
difference 2.9 kg; P ⬍.001), and patients assigned insulin
had a greater weight gain (4.0 kg) than those assigned
chlorpropamide (2.6 kg) or glyburide (1.7 kg).20 Calculating
the long-term effect of this pharmacotherapy-induced
weight gain on morbidity and mortality has not been deter-
mined, in part because such calculations are complicated by
the opposing benefits imparted by improved glycemic con-
trol. Nonetheless, it is noteworthy that patients in the inten-
sive treatment arm of ACCORD, which had higher all-cause
and CV mortality rates, had a mean increase in weight of 3.5
kg (28% gained ⬎10 kg), while the standard treatment arm
had a mean increase of 0.4 kg (14% gained ⬎10 kg). By
contrast, the change in body weight was negligible in
ADVANCE, where an increased mortality rate in the inten-
sive treatment arm was not observed.51
Lactic Acidosis
Metformin decreases hepatic glucose production, in-
creases intestinal glucose utilization, and improves pe-
ripheral insulin sensitivity.42 Phenformin, a biguanide
available before metformin, was withdrawn from the
market due to higher risk of lactic acidosis, a rare but
serious metabolic condition with a 50% mortality rate
during use.52,53 This finding and rare case reports of
lactic acidosis with metformin treatment raised concern
over the possibility of metformin-associated lactic acido-
sis, and prompted the inclusion of a “black box warning”
in the metformin package insert.54 Given that many of the
cases of metformin-associated lactic acidosis are seen in
patients with specific risk factors, metformin is contrain-
dicated in renal insufficiency and many chronic hypox-
emic conditions that may be associated with lactic aci-
dosis, such as CV, pulmonary, and hepatic diseases.55
Subsequent studies, however, demonstrated that the in-
cidence of lactic acidosis is very low with metformin. Ac-
cording to one meta-analysis of 274 comparative trials and
cohort studies, no cases of fatal or nonfatal lactic acidosis
were observed after 59,321 patient-years of metformin
use.56 In this study, the upper limit for the true incidence of
lactic acidosis was estimated at 0.051 cases per 1000 pa-
tient-years in the metformin group and 0.058 cases per 1000
patient-years in the non-metformin comparator group. Sim-
ilar conclusions were drawn from a second meta-analysis.57
The metformin package insert estimates the excess rate of
lactic acidosis on the drug at approximately 0.03 cases per
1000 patient-years.54
The American Journal of Medicine, Vol 123, No 4, April 2010
Skeletal Fragility and Fracture
Thiazolidinediones bind to the peroxisome proliferator-acti-
vated receptor-gamma and sensitize peripheral tissues to insu-
lin via transcriptional effects.58 Activation of peroxisome pro-
liferator-activated receptor-gamma can reduce bone formation
by diverting mesenchymal stem cells from the osteogenic to
the adipocytic lineage and may increase bone resorption by
stimulating the development of osteoclasts.59
The previous observations and data from clinical trials
have confirmed that use of thiazolidinediones is associated
with increased risk of bone fractures, possibly more so in
women. In studies of ⬎8100 patients treated with pioglita-
zone and ⬎7400 patients treated with comparators for a
duration of up to 3.5 years, total fracture risk was approx-
imately 2-fold higher with pioglitazone treatment, with an
excess risk of 8 fractures per 1000 patient-years in women
on the drug.60 A nested case-control analysis of 66,696
diabetic patients demonstrated similar bone fracture risk for
rosiglitazone, although the association was independent
of sex (and patient age).61 In the latter study, 12-18 months
of rosiglitazone therapy was associated with a fracture OR of
4.54 at the hip/femur, 2.12 at the humerus, and 2.90 at the
wrist/forearm, relative to nonuse. Recently, a meta-analysis
of 10 randomized controlled trials (n ⫽ 13,715) found that
rosiglitazone and pioglitazone use was associated with a
significantly increased risk of fractures (OR 1.45, 95% CI,
1.18-1.79; P ⬍.001).62 The effect was observed primarily
among women. Bone mineral density in women exposed to
thiazolidinediones was significantly reduced at the lumbar
spine (weighted mean difference ⫺1.11%, 95% CI, ⫺2.08%-
⫺0.14%; P ⫽ .02) and hip (weighted mean difference
⫺1.24%, 95%CI, ⫺2.34%-⫺0.67%; P ⬍.001) in 2 of the
trials.
Pancreatitis
On average, 200,000-300,000 patients are admitted per year
in the US for pancreatitis.63,64 Estimates of the incidence
vary considerably, and the rate seems to be rising for rea-
sons not well understood.64 A study of patients hospitalized
in California with first-time acute pancreatitis found an
age-standardized incidence of 0.44 cases per 1000 adults in
2001.65 Data from the National Hospital Discharge Survey
suggested an incidence of 0.7 hospitalizations per 1000 US
population in 2002.64
Overall, it has been estimated that approximately 2% of
reported pancreatitis cases are drug induced.66 Among the
available glucose-lowering medications, pancreatitis has been
associated most commonly with the incretin-mimetic ex-
enatide67-69 and metformin (especially in patients with renal
dysfunction).70-73 Although postmarketing reports of pancre-
atitis among patients treated with exenatide have been submit-
ted to the Food and Drug Administration’s Adverse Event
Reporting System,67,69 analysis of a health insurance transac-
tion database found that the absolute risk of acute pancreatitis
among exenatide initiators, as identified by International Clas-
sification of Disease, 9th Revision code, was 0.13% (37 cases
Bergenstal et al Risks and Benefits of Glucose-lowering Medications 374.e15

among 27,995 patients followed for up to 1 year), which was
equivalent to the absolute risk in a propensity score-matched
cohort of metformin/glyburide initiators.74
The observation of pancreatitis in patients treated for
diabetes is complicated by a number of factors, including a
likely increase in the risk of pancreatitis in this population
compared with nondiabetes populations. A retrospective
study of type 2 diabetes patients (n ⫽ 337,067) and age- and
sex-matched nondiabetic patients (n ⫽ 337,067) found a
pancreatitis incidence rate of 4.22 cases per 1000 patient-
years in the diabetic cohort versus 1.49 cases per 1000
patient-years in the nondiabetic cohort.75 Pancreatitis risk
also might be increased in the setting of obesity, another
common complication of type 2 diabetes;76 although obe-
sity might correlate more closely with severity of acute
pancreatitis than risk of developing the disease.77,78
Extreme Hypersensitivity Reactions
Extreme hypersensitivity reactions have been reported in
postmarketing surveillance of patients treated with sitaglip-

Figure 4 Events per 1000 patient-years for representative endpoints. Black bars
indicate excess risk of events in diabetes patients relative to nondiabetic subjects;19,75,85,86
gray bars indicate excess risk of events in patients treated with specific glucose-
lowering medications relative to diabetic patients on other agents;2,25,41,54,60,61,74
and white bars indicate the decreased risk of events in patients undergoing
intensive glucose control policies.12 CHF ⫽ congestive heart failure; MI ⫽
myocardial infarction; PVD ⫽ peripheral vascular disease. a ⫽ 85Foley RN et al.
J Am Soc Nephrol. 2005;16(2):489-495; b ⫽ 19Haffner SM et al. N Engl J Med.
1998;339(4)229-234; c ⫽ 75Noel RA et al. Diabetes Care. 2009;32(5):834-838;
d ⫽ 86
Trautner C et al. Diabetes Care. 1997;20(7):1147-1153; e ⫽ 60,61Hampton
T. JAMA. 2007;297(15):1645 and Meier C et al. Arch Intern Med. 2008;168(8):
820-825; f ⫽ 41Lago RM et al. Lancet. 2007;370(9593):1129-1136; g ⫽ 25Patel A
et al. N Engl J Med. 2008;358(24):2560-2572; h ⫽ 2Nissen SE, Wolski K. N Engl
J Med. 2007;356(24)2457-2471; i ⫽ 54Glucophage [package insert]. Princeton,
NJ: Bristol-Myers Squibb Company; 2006; j ⫽ 74Dore DD et al. Curr Med Res
Opin. 2009;25(4)1019-1027; k ⫽ 12Holman RR et al. N Engl J Med.
2008;359(15):1577-1589.
374.e16
tin, a dipeptidyl peptidase-4 (DPP-4) inhibitor,79 and
(rarely) with other diabetes therapies. The reactions reported
with sitagliptin include anaphylaxis, angioedema, and exfo-
liative skin conditions like Stevens-Johnson syndrome.
Overall, the reported events were rare, but data on absolute
rates are not available. Other potential immunologically
mediated events associated with sitagliptin use were iden-
tified in a meta-analysis and included increased rates of
nasopharyngitis (RR 1.2) and urinary tract infections (RR
1.5).80 Sitagliptin improves glucose metabolism in type 2
diabetic patients by raising the levels of incretins, endoge-
nous substrates of DPP-4,81 but DPP-4 is identical to a
T-cell surface antigen (CD26) involved in T-cell activa-
tion82,83 and cleaves other substrates in vivo.84 Some inves-
tigators have postulated that the latter characteristics might
account for the rare immunologic side effects of sitagliptin,
but this has not been confirmed.
CONCLUSIONS
Figure 4 details and compares many of the rates for both
diabetes-related and drug-associated events described in this
review. The data reaffirm the inherently high risk of diabe-
tes-related complications (eg, high rate of CV events as well
as death from CV causes) and the significant benefits im-
parted by improved glycemic control in reducing rates of
some of these complications. Overall, glucose-lowering
agents appear to have a favorable risk-benefit profile. The
most common adverse event is treatment-related hypogly-
cemic episodes, particularly among patients receiving sul-
fonylureas or insulin therapy, or both (only severe events
are shown in Figure 4). There remains significant concern in
many clinicians’ minds over the risk of CHF and bone
fractures in thiazolidinedione-treated patients, and increased
risk of CV events in rosiglitazone-treated patients. Ex-
enatide-associated pancreatitis and metformin-associated
lactic acidosis appear to be rare events, as are the hyper-
sensitivity reactions that occur with DPP-4 inhibitor ther-
apy. Because incretin-based therapies are relatively new,
however, continued careful observation and reporting in
clinical practice will be important to define the true rates of
these possible side effects.
ACKNOWLEDGMENTS
The authors thank David Norris, PhD for editorial assistance
provided during the preparation of this review. This assis-
tance was paid for through funding supplied by Amylin
Pharmaceuticals, Inc. to Ecosse Medical Communications,
LLC (Princeton, NJ).
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