Editorial
Heart Failure, Diabetes Mellitus, and Chronic
Kidney Disease
A Clinical Conundrum
David Aguilar, MD
T ype 2 diabetes mellitus and heart failure (HF) commonly
coexist, with diabetes mellitus occurring in ≈25% of patients
with chronic HF and ~40% in those hospitalized with acute HF.1
Importantly, the presence of diabetes mellitus in HF is associ-
ated with reduced survival and increased rates of hospitalization
compared with HF patients without diabetes mellitus.1 Despite
the common and dangerous coexistence of diabetes mellitus and
HF, the optimal management of diabetes mellitus in patients
with established HF is not well defined, and the presence of HF
complicates the pharmacological treatment of hyperglycemia.2
For example, thiazolidinediones are associated with greater rates
of HF hospitalization and should be avoided in symptomatic HF
patients.3 Additionally, the risk of hypoglycemia with sulfonyl-
ureas and insulin may be particularly relevant.
See Article by Patel et al
The presence of chronic kidney disease (CKD) further
complicates the treatment of diabetes mellitus in HF patients.
Approximately 40% to 50% of HF patients have CKD,4 and
the severity of renal dysfunction is associated with a graded
increased risk of death.4,5 Similar to HF, pharmacological
treatment of hyperglycemia in patients with CKD is challeng-
ing, with few studies to guide treatment in this population. As
CKD progresses, most of the oral antihyperglycemic medi-
cations must be reduced or discontinued depending on renal
clearance.6,7 Metformin is contraindicated in patients with
advanced CKD (eGFR <30 mL/min per 1.73 m2), although
the absolute renal threshold for discontinuation of metformin
varies per guidelines.3,6,7 With moderate or severe CKD, most
sulfonylureas should be avoided because of decreased renal
clearance and risk of hypoglycemia.6,7 Further challenging
the cardiologist is the growing number of available antihy-
perglycemic medications. These newer medications include
the incretin-based therapies, such as dipeptidyl peptidase-4
inhibitors and glucagon-like peptide 1 receptor agonists and
the sodium–glucose co-transporter 2 inhibitors. Medications
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Section of Cardiology, Department of Medicine, Baylor
College of Medicine, Houston, TX.
Correspondence to David Aguilar, MD, Cardiovascular Division,
Baylor College of Medicine, 6620 Main St: BCM 620, Houston, TX
77030. E-mail daguilar@bcm.edu.
(Circ Heart Fail. 2016;9:e003316.
DOI: 10.1161/CIRCHEARTFAILURE.116.003316.)
© 2016 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
DOI: 10.1161/CIRCHEARTFAILURE.116.003316
1
within each of these classes may require dose adjustment or
discontinuation in patients with worsening CKD.7
In this issue of Circulation: Heart Failure, Patel et al bring
much needed attention to the complicated conundrum regard-
ing the treatment of hyperglycemia in older patients with HF,
diabetes mellitus, and CKD.8 Using the Get With the Guidelines-
Heart Failure (GWTG-HF) program and linking the program to
Medicare Part D Claims data, the authors describe the pattern of
antihyperglycemic medication use in diabetic patients discharged
with HF and CKD. The GWTG-HF patients with diabetes mel-
litus selected for the analysis were older (median age, 77 years)
and had a high prevalence of CKD (17.2% with eGFR<30 mL/
min per 1.73 m2 and 49.1% with eGFR 30–60 mL/min per 1.73
m2), findings that confirm the common existence of advanced
renal dysfunction in older HF patients with diabetes mellitus.
Multiple observations of the study highlight treatment challenges
in this population. Despite being discharged with HF, 6.6% of
patients were treated with thiazolidinediones. Moreover, the use
of antihyperglycemic medications that may be contraindicated
occurred in 35% of patients with advanced CKD (eGFR<30 mL/
min per 1.73 m2). Temporal trends demonstrated improvements
in prescribing patterns over the study (2006–2011), with reduc-
tions in the use of thiazolidinediones and potentially renal con-
traindicated antihyperglycemic medications, but the use of other
medications that should be cautiously used or avoided, such as
dipeptidyl peptidase-4 inhibitors, increased.
The challenges of treating diabetes mellitus in HF patients,
particularly in the presence of CKD, highlighted in the study
by Patel et al8 reflect a historical gap in knowledge and data
regarding the optimal treatment of these high-risk patients.
Indeed, this need for further safety data regarding antihyper-
glycemic therapy in high cardiovascular-risk patients was
reflected in the US Food and Drug Administration require-
ments,9 which has led to multiple large-scale cardiovascu-
lar outcome studies of new antihyperglycemic medications.
Several of these cardiovascular outcome trials of antihyper-
glycemic medications have now been completed (Table)10–15
and provide observations relevant to the population studied
by Patel et al.8 As demonstrated in Table, the cardiovascular
outcome studies have included larger number of patients with
established HF and baseline CKD, although several studies
excluded patients with an eGFR <30 mL/min per 1.73 m2 if
the medication was contraindicated.10,12,15 Studies also required
treatment dose reductions based on renal function.10,13,14
The outcomes of these studies have also provided important
data. By meeting their primary noninferiority major adverse
cardiovascular event outcome, the studies have provided reas-
suring safety data in high-risk cardiovascular patients. Even
2   Aguilar   Heart Failure, Diabetes, and CKD
Table.  Key Characteristics and Outcomes of Cardiovascular Outcome Trials Evaluating Antihyperglycemic Medications
Number of Patients With HF
CV Outcome Trial Intervention Patients at Baseline, %
SAVOR-TIMI 5313 Saxagliptin 16 492 12.8%
EXAMINE 14,16
Alogliptin 5380 28.5%
TECOS10 Sitagliptin 14 671 18.0%
ELIXA12 Lixisenatide 6068 22.4%
LEADER 11
Liraglutide 9340 14.0%
EMPA-REG Empagliflozin 7020 10.0%
Outcome15
CI indicates confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate (mL/min per 1.73 m2); ELIXA, The Evaluation of Lixisenatide in Acute
Coronary Syndrome trial; EXAMINE, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care trial; HF, heart failure; LEADER, Liraglutide Effect
and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial; MACE, major adverse cardiovascular events; SAVOR-TIMI 53, the Saxagliptin Assessment
of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 trial; and TECOS, Trial Evaluating Cardiovascular Outcomes
with Sitagliptin trial.
*MACE outcome=CV death, MI, and stroke.
†MACE included unstable angina hospitalization.
‡Excluded patients with eGFR<30 mL/min per 1.73 m2.
more promising, recent studies with liraglutide11 and empa-
glifozin15 have demonstrated cardiovascular benefit when com-
pared with placebo. Importantly, the cardiovascular outcome
studies have demonstrated no heterogeneity in the primary out-
come in those with and without HF at baseline. Although most
studies have also not demonstrated heterogeneity for the pri-
mary outcome in patients with baseline CKD,10,12,13,15 liraglutide
was shown to reduce the major adverse cardiovascular events
to a greater degree in patients with an eGFR <60 mL/min per
1.73 m2 (hazard ratio 0.69, 95% confidence interval 0.57–0.85)
compared with those with eGFR ≥60 mL/min per 1.73 m2 (haz-
ard ratio 0.94, 95% confidence interval 0.83–1.07; P interaction
=0.01).11 On the contrary, alogliptin was associated with nomi-
nally increased rates of major adverse cardiovascular events in
those with eGFR <60 mL/min per 1.73 m2 (hazard ratio 1.15,
95% confidence interval 0.91–1.46) compared with those with
eGFR ≥60 mL/min per 1.73 m2 (hazard ratio 0.84, 95% con-
fidence interval 0.68–1.04; P interaction =0.046).14 Finally,
although most studies have shown no difference in HF hos-
pitalization with active therapy,4,11,12,16 HF hospitalization was
increased with saxagliptin13 and reduced with empagliflozin.15
In aggregate, these cardiovascular trials provide welcome
data regarding the treatment of hyperglycemia in diabetic
patients with high cardiovascular risk, including patients with HF
and CKD. Nonetheless, more information is needed regarding
the treatment of diabetic patients who have both HF and CKD.
In the Saxagliptin Assessment of Vascular Outcomes Recorded
in Patients with Diabetes Mellitus-Thrombolysis in Myocardial
Infarction 53 trial (SAVOR-TIMI 53), 56.5% of patients with HF
at baseline had an eGFR <60 mL/min per 1.73 m2,17 and despite
being in a clinical trial, 3.5% of these HF patients were treated
with thiazolidinediones,17 and nearly 20% of patients with an
eGFR <30 mL/min per 1.73 m2 at baseline were treated with
metformin.18 These findings, coupled with GWTG-HF data,8
highlight the need for increasing awareness regarding the use of
antihyperglycemic medications in patients with HF and CKD,
Renal Dysfunction at Hazard Ratio for Primary MACE Hazard Ratio for HF
Baseline, % Outcome (95% CI)* Hospitalization (95% CI)
eGFR 30–50: 13.6% 1.00 (0.89–1.12) 1.27 (1.07–1.51)
eGFR<30: 2.0%
eGFR<60: 29.1% 0.96 (upper 95% CI 1.16) 1.07 (0.79–1.46)
eGFR<60: 22.7% 0.98 (0.88–1.09)† 1.00 (0.83–1.20)
eGFR<60: 23.2%‡ 1.02 (0.89–1.17)† 0.96 (0.75–1.23)
eGFR 30–59: 20.7% 0.87 (0.78–0.97) 0.87 (0.73–1.05)
eGFR <30: 2.4%
eGFR<60: 25.6‡ 0.86 (0.74–0.99) 0.65 (0.50–0.85)
implementing appropriate dose reductions based on renal func-
tion and avoiding medications that are potentially harmful.
Disclosures
Dr Aguilar has received consulting fees from Bristol-Myers Squibb
and is a research investigator in the Exenatide Study of Cardiovascular
Event Lowering Trial (EXSCEL) trial.
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Key Words: Editorials ■ chronic kidney disease ■ diabetes mellitus
■ heart failure ■ hyperglycemia ■ insulin