Oral Hypoglycemics in Patients with Type 2
Diabetes and Peripheral Artery Disease
Luke Rannelli MD, MSc, Eric Kaplovitch MD, Sonia S. Anand MD, PhD
About the Authors:
Luke Rannelli MD, MSc, is with the Department of Medicine, Division of General Internal Medicine, University of Calgary, Calgary,
Alberta, Canada.
Eric Kaplovitch MD, is with the Department of Medicine, University of Toronto, ON, Canada.
Sonia S. Anand MD PhD
is with the Population Health Research Institute and Department of Medicine, McMaster University and
Hamilton Health Sciences, ON, Canada.
Corresponding Author: larannel@ucalgary.ca
Submitted: April 18, 2018. Accepted: September 16, 2018. Published: May 21, 2019. DOI:10.22374/cjgim.v14i2.282
Worldwide, in 2010, 202 million people were living with peripheral artery disease (PAD), with a
prevalence between 3–12%. The prevalence of PAD is 3 times greater in diabetic patients compared
to those with normal glycemia. PAD of the limbs is associated with increased cardiovascular
morbidity and mortality, as well as major adverse limb events including acute limb ischemia
and amputation. These risks are particularly high in patients who smoke and/or have type 2
diabetes. The goal of treatment in diabetic patients with PAD is to prevent cardiovascular events
and prevent further peripheral artery stenosis leading to limb ischemia, and amputation. Poor
glycemic control contributes to atherosclerotic progression; however, no randomized control
trial evidence exists that demonstrates improved glycemic control reduces the risk of PAD. Oral
diabetic medications are designed to lower glucose levels, reduce symptoms and the microvascular
complications of diabetes without the inconvenience of daily injections. However, the data
supporting the benefit of these medications in diabetic populations with concurrent PAD are
limited. We review the evidence for oral hypoglycemic agents in the treatment of patients with
concurrent PAD and diabetes.
En 2010, 202 millions de personnes dans le monde vivaient avec une maladie artérielle périphérique
(MAP), avec une prévalence comprise entre 3 et 12 %. La prévalence de la MAP est 3 fois plus
élevée chez les patients diabétiques que chez ceux dont la glycémie est normale. La MAP des
membres est associée à une augmentation de la morbidité et de la mortalité cardiovasculaires,
ainsi qu’à des événements indésirables majeurs des membres, dont l’ischémie aiguë des membres
et lamputation. Ces risques sont particulièrement élevés chez les patients qui fument et/ou qui
souffrent de diabète de type 2. Lobjectif du traitement chez les patients diabétiques atteints
de MAP est de prévenir les événements cardiovasculaires et de prévenir dautres sténoses des
artères périphériques entraînant une ischémie des membres et lamputation. Un mauvais contrôle
glycémique contribue à la progression de lathérosclérose ; cependant, il nexiste aucune preuve
dessai clinique comparatif randomisé qui démontre qu’un meilleur contrôle glycémique réduit le
Canadian Journal of General Internal Medicine
Volume 14, Issue 2, 2019 13
R a n n e l l i e t a l .
risque de MAP. Les médicaments oraux pour diabétiques sont conçus pour abaisser la glycémie,
réduire les symptômes et les complications microvasculaires du diabète sans les inconvénients des
injections quotidiennes. Toutefois, les données à l’appui des bienfaits de ces médicaments chez
les populations diabétiques présentant une MAP concomitante sont limitées. Nous examinons
les données probantes sur les hypoglycémiants oraux dans le traitement des patients atteints de
MAP et de diabète concomitants.
Keywords: hemoglobin A1c, peripheral arterial disease, diabetes, oral hypoglycemic agents
A 57-year-old-female with type 2 diabetes for the last 5-years
presented to her primary care physician complaining of pain in
her legs with walking, but not at rest. She was a smoker with a
body mass index of 21. She had palpable posterior tibial pulses.
After being sent for peripheral artery disease (PAD) testing, a
new diagnosis of intermittent claudication was made based on
her symptoms and low ankle-brachial indices of 0.72 and 0.80
in the right and left legs respectively. The patient was treated
with metformin, rosuvastatin, and ramipril and was placed on
low dose aspirin following the diagnosis of symptomatic PAD.
Smoking cessation and nicotine replacement therapy were offered
to the patient. Despite maximal titration of her metformin, her
most recent hemoglobin A1c remained elevated at 8.3%, and
her primary care physician was concerned that her sub-optimal
hemoglobin A1c may have contributed to her development of
PAD, and considered adding a second oral hypoglycemic agent.
In light of the results of the EMPA-REG outcome trial and
Diabetes Canada Guidelines, a SGLT-2 inhibitor (empagliflozin)
was prescribed.
The pharmacist filling prescription pointed
out that a similar SGLT-2 inhibitor has a United States-FDA
warning for increased risk of limb amputation.
What is the Risk of Developing PAD in Patients
with Type 2 Diabetes? What is the Impact of PAD
on Cardiovascular Health and Risk of Amputation
in Diabetic Patients?
Worldwide, in 2010, 202 million people were living with PAD,
with a prevalence between 3 and 12%.
PAD of the lower
extremities is usually characterized by flow-limiting artery
stenosis resulting in a reduction of blood supply to the limbs.
This can manifest as symptoms of intermittent claudication and
pain with ambulation in the legs, persistent rest pain, or limb
ulceration/gangrene. However, a large percentage of patients
remain asymptomatic. PAD of the limbs is associated with
increased cardiovascular morbidity and mortality, as well as
major adverse limb events including acute limb ischemia and
amputation. These risks are particularly high in patients who
smoke and/or have type 2 diabetes.
Diabetes causes endovascular
dysfunction, accelerating atherosclerosis of the vessels.
The prevalence of PAD is 3 times greater in diabetic patients
compared to those with normal glycemia,
and is a common
initial presentation of vascular disease in diabetic patients,
occurring in 16.2% of the first manifestation of cardiovascular
The duration and control of a patient’s diabetes are
associated with an increased risk in the development of PAD.
For example, a 1% increase in hemoglobin A1c is associated
with a 28% increased risk of PAD development over an 18 year
Patients with diabetes and concurrent PAD have a 3-4
fold increase in mortality,
and amputation rates are 5 times
higher than non-diabetic patients with PAD.
What is the Impact of Glycemic Control On PAD?
The goal of treatment in diabetic patients with PAD is to prevent
cardiovascular events and prevent further peripheral artery stenosis
leading to limb ischemia, and amputation. Poor glycemic control
contributes to atherosclerotic progression; however, no randomized
control trial evidence exists that demonstrates improved glycemic
control reduces the risk of PAD.
A prospective cohort study
of 1,637 patients with PAD reported that diabetic patients who
were not treated with glucose-lowering medications had a higher
mortality and increased rates of peripheral artery interventions
compared to patients treated with oral hypoglycemic agents.
Two meta-analyses of the effect of intensive glucose-lowering
treatment on mortality, myocardial infarction, stroke, peripheral
vascular events (i.e., leg revascularization, PAD or claudication)
and amputation, concluded that there was minimal mortality,
myocardial infarction or stroke benefit from tight hemoglobin
A1c control.
However, the 2 meta-analyses did differ in their
conclusions on amputations and peripheral vascular events.
The initial publication in 2011 did not show an impact of tight
glucose control on peripheral vascular events (RR 0.98; 95%
CI: 0.84–1.13) or amputations (RR 0.84; 95 %CI: 0.54–1.29),
whereas the more recent 2016 publication suggests a reduction
in diabetic-related amputations (RR 0.65, 95%CI: 0.45–0.94).
Of note, the 2016 meta-analysis did not demonstrate a difference
between intensive glycemic control and liberal control in
peripheral ischemic outcomes (i.e., gangrene, ischemic ulcer,
new-onset claudication, new diagnosis of PAD) (RR 0.92 95%
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14 Volume 14, Issue 2, 2019
Clinical Medicine: The Art and Science
CI: 0.67–1.26).
The discrepancy between the 2 meta-analyses
conclusion on amputation outcomes may be due to different
methodology. The 2016 study included multiple studies that
utilized multifactorial interventions, which were excluded from
the 2011 meta-analysis.
More recently, in a retrospective cohort
study of PAD patients awaiting revascularization (endovascular
repair, open surgical repair and hybrid) a lower pre-operative
hemoglobin A1c level was associated with a lower risk of adverse
limb outcomes/amputations after a 3.5-year follow-up period
(i.e., hemoglobin A1c 6.1–7%; HR 1.03 CI 0.95–1.12; hemoglobin
A1c 7.1–8%; HR 1.15 CI 1.05–1.26; hemoglobin A1c >8%; 1.27
CI 1.16–1.38) compared to PAD patients without diabetes).
As hyperglycemia contributes to atherosclerosis progression,
achievement of intensive glycemic control, defined as a hemoglobin
A1c ≤7, is a logical approach in the management of a patient with
diabetes and PAD. However, no randomized controlled trials of
the effect of tight glycemic control on cardiovascular outcomes
and amputation rates have been completed.
Diabetic Agents and PAD
The majority of patients in the US with diabetes are managed
with oral hypoglycemic medications (56.9%) compared to the use
of insulin alone (14%), or the combination of oral medications
and insulin (14.7%).
Similar prescription use is seen in Canada,
where the majority of diabetic patients (~61%) between 30 and
90 years of age are prescribed at least one oral hypoglycemic.
Oral diabetic medications are designed to lower blood glucose
levels, reduce symptoms and the microvascular complications of
diabetes without the inconvenience of daily injections. However,
the data supporting benefit of these medications in diabetic
populations with concurrent PAD are limited.
The development of metformin, a biguanide has become a
mainstay of therapy for patients with type 2 diabetes. Much of the
cardiovascular benefit for metformin is derived from the initial
UKPDS trial and subsequent 10-year follow-up that demonstrated
a mortality and myocardial infractions benefit.
the impact on mortality and PAD has been controversial.
A meta-analysis of randomized trials among patients with
type 2 diabetes examined the impact of metformin on major
cardiovascular outcomes, and suggested a non-significant 16%
reduction in all-cause mortality (HR 0.96 95%: CI 0.84–1.09)
and 25% reduction in myocardial infarction (HR 0.89 95%: CI
2079 patients were included in the meta-analysis
with duration of follow-up ranging from 6 to 212 months, with
much of the data driven by the UKPDS data. Subset analyses
of diabetic patients on metformin showed a non-significant
19% reduction in the risk of developing PAD (RR 0.81 95%: CI
The diagnosis of PAD varied widely among the 4
papers included, from a new diagnosis of PAD after angiographic
demonstration, to PAD resulting in amputation or death. The
10-year follow-up UKPDS study failed to demonstrate any
advantage of metformin to sulphonylureas or insulin in the
prevention of PAD in diabetic patients.
To date, there has been
no randomized controlled trial data supporting a reduction in
cardiovascular death, development of PAD or amputation from
PAD in diabetic patients with PAD with metformin.
Sulfonylurea drugs promote insulin secretion through its
effect on ATP channels. The UKPDS trial showed microvascular
benefit of sulfonylureas and a trend towards macrovascular
benefit; however, no data has shown a reduction in PAD in type
2 diabetic patients.
Furthermore, there are concerns about an
increased risk of significant hypoglycemic episodes.
the benefit of these medications may not outweigh the risks
in the PAD patient population that often have higher rates of
cardiovascular disease.
The forthcoming CAROLINA study
will study the potential cardiovascular benefits of glimepiride
versus linagliptin in the diabetic population.
The effect of thiazolidinediones in improving insulin
sensitivity in peripheral tissues made this class of medications an
attractive option in patients with high cardiovascular risk. The
overall cardiovascular benefit of these medications and possible
risk of congestive heart failure in patients with diabetes has been
hotly debated.
In the PROACTIVE randomized, placebo-
controlled trial, treatment with pioglitazone demonstrated a
non-significant reduction in the primary outcome of all-cause
mortality, myocardial infarction, stroke, amputation and leg
revascularization (HR 0.90 CI 0.80–1.02, P=0.095).
The secondary
composite endpoint of all-cause mortality, non-fatal myocardial
infarction, and stroke was significantly reduced compared
to placebo (HR 0.84, CI 0.72–0.98, P = 0.027).
However, in
the subgroup of diabetic patients with pre-established PAD,
pioglitazone did not demonstrate improvement in any major
cardiovascular outcomes and was associated with an increase in
leg revascularizations (surgical bypass/atherectomy/angioplasty/
thrombolysis) (HR 1.68, CI 1.15–2.47, P=0.008). There was no
significant increase in lower limb amputations (HR 1.58 CI
0.81–3.12, P=0.18). The beneficial effects of pioglitazone were
only seen in patients without PAD, as the P-values for interaction
between PAD and non-PAD patients were P=0.04 for primary
outcome, P=0.03 for acute coronary syndrome, P=0.007 for leg
revascularization, and P=0.03 for amputation rates. No other
thiazolidinediones class medication have studied diabetic patients
in PAD with regards to vascular outcomes.
Animal and observational studies in human populations
suggest that the incretin-based oral selective inhibitors of dipeptidyl
peptidase 4 (DPP-4) medications may reduce cardiovascular
For example, a large population-based observational
cohort study from Taiwan of 82,169 patients started on DPP-4
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Rannelli et al.
medication demonstrated a 16% decrease in the risk of developing
PAD and a 35% reduced risk of amputation.
However, these
findings have not been confirmed in randomized trials of DPP-4
inhibitors as no reduction in the major cardiovascular events
(MACE) outcome or PAD outcomes have been observed.
In contrast, the incretin modulator GLP-1 agonists have
demonstrated a significant reduction in cardiovascular events
in both the large LEADER trial and SUSTAIN-6 trial.
Liraglutide an injectable agent reduced the risk of cardiovascular
death, myocardial infarction and stroke by 13% in patients
with a baseline elevated cardiovascular risk.
A similar trend
was observed in semaglutide, with a 26% reduced in combined
primary outcome of cardiovascular death, non-fatal myocardial
infarction and nonfatal stroke.
A significant reduction in
nephropathy has also been demonstrated with both liraglutide
and semaglutide.
Though the mechanism remains unclear,
the weight, blood pressure and lipid reductions with GLP-1
inhibitors may explain the improvement in cardiovascular
events but this remains unclear. However, the effect of GLP-1
agonists on PAD development, progression, revascularization
procedure rates and amputations secondary to PAD have not
been well studied.
The newest and most promising class of hypoglycemic
agents are the SGLT-2 inhibitors, which along with liraglutide,
are recommended as a second-line agent for patients with
documented clinical cardiovascular disease.
SGLT-2 inhibitors
block sodium-glucose cotransport in the renal tubules, increasing
urinary glucose exertion. The CDA recommendation came
primarily from the EMPA-REG OUTCOME trial in which the
novel SGLT-2 inhibitor, empagliflozin, demonstrated a 14%
(HR 0.86; 95% CI 0.74–0.99) relative risk reduction in MACE
and a 32% (HR 0.68 95% CI 0.57–0.82) reduction in all-cause
among the 7,020 patients randomized. In addition,
empagliflozin slowed progression in kidney disease by 6% and
risk of macroalbuminuria by 5% (nephropathy HR 0.61 CI
0.53–0.70; macroalbuminuria HR 0.62 95% CI 0.54–0.72).
In a
recent subgroup analysis of 1461 patients with PAD included in
the EMPA-REG OUTCOME trial, empagliflozin demonstrated a
38% reduction in all-cause mortality (HR 0.62 95% CI 0.44–0.88)
and a 43% reduction in cardiovascular deaths (HR 0.57 95% CI
0.37–0.88) with no increased rate of limb amputations (HR 0.84
95% CI 0.54–1.32).
The other SGLT-2 inhibitor approved in
Canada is canagliflozin, which in the CANVAS trial, demonstrated
similar reductions in MACE (HR 0.86 95% CI 0.75–0.97).
However, in contrast to empagliflozin, an unexpected two-fold
increase in the risk of lower limb amputations was observed
with canagliflozin, with the majority (71% HR 1.97 95% CI
1.41–2.75) of amputations occurring at the toe or metatarsal
The highest risk of amputation occurred among patients
with previous amputation or PAD and tended to occur later
in the trial (1.5 years) after drug initiation. This observation
underlies canagliflozins black box warning from the US FDA for
amputation risk.
The exact mechanism by which amputations
are increased remains unclear. In unpublished subgroup data
on etiologies of amputations in patients on canagliflozin, acute
limb ischemia, a precursor to amputation, was also increased by
two-fold increase compared to placebo (12.9% canagliflozin vs.
6.4% placebo).
To date there has been no reported increased
risk of amputation rates in other SGLT-2 inhibitors thus far
(dapagliflozin or empagliflozin).
Furthermore the prevalence
of PAD (20%) between CANVAS and EMPA-REG OUTCOME
were similar, suggesting that clinical characteristics of the studies
do not explain the increased amputation rates.
Recently, an
observational cohort study conducted by the pharmaceutical
company responsible for canagliflozin, did not demonstrate an
increased risk of amputation in 63,845 new users of canagliflozin
with and without established cardiovascular disease (20% and
8% of whom had PAD).
Further randomized clinical studies
with canagliflozin and its impact of amputation rates and
PAD are required. It should be noted that since this report,
the DECLARE trial with dapagliflozin is now required by the
European Medicines Agency to report amputation events.
Case Revisited
After a discussion regarding risks and benefits and importance
of lifestyle changes (smoking cessation and regular walking, and
foot care), the primary care physician prescribed empagliflozin
at 10-mg daily given its cardiovascular benefit and reduction in
all-cause mortality. While it would also have been reasonable
to recommend liraglutide, empagliflozins benefit in reducing
nephropathy and renal impairment may make it the preferred
agent in patients at risk or with documented kidney dysfunction.
We now have second line hypoglycemic agents with proven
benefit to diabetic patients with PAD.
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