Liraglutide and Metformin alone or combined therapy for type 2 diabetes patients complicated with coronary artery disease
Liu et al. Lipids in Health and Disease
Liraglutide and Metformin alone or combined therapy for type 2 diabetes patients complicated with coronary artery disease
Ying Liu 0
Xia Jiang 0
Xin Chen 1
0 Department of Endocrinology, Tianjin First Center Hospital , 24 Fukang Road, Nankai District, Tianjin 300192 , China
1 Department of Cardiovascular Medicine, Tianjin First Center Hospital , Tianjin 300192 , China
Background: This study is to compare the effects of Liraglutide and Metformin alone or combined treatment on the cardiac function in T2DM patients complicated with CAD. Methods: 120 T2DM patients were included at Endocrinology Department of Tianjin First Center Hospital (Tianjin, China) from April 2012 to September 2013. The study contained two sections. Section 1: 30 patients in group 1 was treated with Liraglutide (Novo Nordisk) (1.2 mg/d), and 30 patients in group 2 with Metformin (Shiguibao) (1500 mg/d) for 24 weeks. Section 2: 30 patients in group1 was treated with Liraglutide (1.8 mg/d) and 30 in group 2 with Liraglutide (1.2 mg/d) plus Metformin (1500 mg/d) for 24 weeks. Fasting blood glucose (FBG), postprandial glucose (PPG), glycated hemoglobin (HbA1c), body mass index (BMI), blood pressure (BP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), C reactive protein (CRP), left ventricular end-diastolic diameter (LVEDD), ejection fraction (EF) and the ratio of early (E) to late (A) ventricular filling velocities (E/A ratio) were measured before and after the 24-week treatment. Results: After 24-week treatment, when blood glucose level was controlled in 4 groups, Liraglutide alone treatment showed better improvements than on all measuring except TG in Section 1, however, combined treatment of Liraglutide and Metformin showed better improvements on all measuring except BMI, TG and BP in Section 2. Conclusions: With similar glycemic control, the Liraglutide (1.2 mg/d) monotherapy showed the better effects than either Metformin alone, or combination of Liraglutide and Metformin on lipid metabolism and cardiovascular function. Trial registration: This trial was registered at Chinese Clinical Trial Registry (chictr.org.cn) # ChiCTR-IPR-16008578.
Liraglutide; Metformin; GLP-1; Type 2 diabetes mellitus (T2DM); Coronary artery disease (CAD)
Type 2 diabetes mellitus (T2DM) is commonly
complicated with coronary artery disease (CAD), hypertension,
stroke and heart failure [
]. As a result of small vessel
disease and metabolic disorders, diabetes is associated
with some forms of cardiomyopathy and congestive
heart failure [
]. On the other hand, CAD accounts for
about 80% of deaths in T2DM patients. Besides the
glucose level, other risk factors include hypertension,
dyslipidaemia, obesity and insulin resistance [
glycemic control represents the classical goal of diabetes
therapy, the pathogenesis of the cardiovascular
complications extends beyond hyperglycemia. Thus, from an
individualized perspective, apart from glycemic control,
improvement of cardiovascular function should also be
taken into account for T2DM patients complicated
Glucagon-like peptide-1 (GLP-1) is an endogenous
insulinotropic peptide produced by intestinal epithelial
endocrine L-cells and is considered to potentiate the
incretin effect [
]. GLP-1 receptor agonists (RAs)
improve glucose homeostasis through multifaceted action.
Liraglutide, an analogue of GLP-1, maintains glucose
homeostasis through the regulation of insulin and
glucagon secretion [
]. Liraglutide also regulates
hypertension, left ventricular function, cardiac steatosis,
oxidative stress, and apoptosis both in human and animal
]. Metformin is the first-line medication for
the treatment of type 2 diabetes, and induces muscles to
take up glucose from the blood. Metformin has also
been reported to reduce the multiple CAD risk factors
such as free fatty acid (FFA), triglyceride (TG) and
remnant lipoprotein cholesterol (RLP-C) [
studies also demonstrated a protective role of Metformin
in myocardial dysfunction [
]. Moreover, it was
reported that GLP-1 infusion improves left ventricular
ejection fraction and functional status in patients with
chronic heart failure [
Thus, we investigated the efficacy of alone or
combined therapy of Liraglutide or Metformin on the
cardiovascular function of T2DM patients complicated
We conducted a pilot study with section 1 and 2. In
section 1, 30 patients with T2DM were in Liraglutide
monotherapy (1.2 mg/d) group and 30 patients with
T2DM were in Metformin monotherapy (1500 mg/d)
group. In section 2, 30 patients with T2DM were in
Liraglutide monotherapy (1.8 mg/d) group and 30 patients
with T2DM were in Liraglutide (1.2 mg/d) plus Metformin
(1500 mg/d) group at the Department of Endocrinology of
Tianjin First Center Hospital between April 2012 and
September 2013. The study was approved by Ethics
Committee of Tianjin First Center Hospital (No.
2014N0016LW), and was registered at Chinese Clinical
Trial Registry (chictr.org.cn, No. ChiCTR-IPR-16008578).
All patients provided written informed consent.
The diagnostic criteria for diabetes were: oral glucose
tolerance test, fasting blood glucose ≥7 mmol/L, 2-h
postprandial glucose (PPG) ≥11.1 mmol/L and HbA1c
≥6.5% or 48 mmol/L. According to Clinical Practice
Guidelines by European Society of Cardiology in 2006
(coronary artery stenosis on angiography), the diagnosis
of CAD included one of the following: 1) having the
typical angina symptom and excluding aortic valve
lesion; 2) having history of old myocardial infarction; 3)
having history of acute myocardial infarction; 4)
coronary angiography revealed that > = 70% of coronary artery
stenosis. Exclusion criteria were: 1) Type I diabetes; 2)
history of tuberculosis, viral hemorrhagic fevers, avian
influenza, viral hepatitis, atypical pneumonia, dysentery,
meningococcal meningitis, or any other chronic or acute
infectious diseases that affect carbohydrate metabolism
within the past 6 months; 3) present illness that
interferes with carbohydrate and/or lipids metabolism (such
as hormones); 4) severe heart failure, cardiac
hypertrophy, rheumatic heart disease, valve disorder,
myocarditis or endocarditis, or any other significant
cardiovascular events; 5) not suitable for coronary
angiography; 6) women during pregnancy, lactation, or
planning for pregnancy; 7) taking diet pills within the past
6 months; 8) chronic liver dysfunction (alanine
aminotransferase/aspartate aminotransferase >2.5 ULN)
and/or chronic renal dysfunction (serum creatinine
>150 μmol/L); 9) severe electrolyte disorders; 10)
previous episodes of acute orchronic pancreatitis; 11) history
of tumor or any other severe diseases that are not
suitable to be included as judged by the investigator.
Drugs used in the study included Liraglutid, 18 mg/
3 ml/pen (pre-filled pen), (Novo Nordisk, Beijing, China)
and Metformin (Glucophage) 0.5 mg/pill (Shanghai
Shiguibao pharmaceutical Co. LTD, Shanghai, China).
All patients were instructed by the investigator for
food intake, exercise, drug administration, fingertip
blood glucose (FBG) measurement (Bayer Blood Glucose
Monitoring System), and records of treatment for
hypoglycemia and/or any adverse effects. All preexisting
treatment for hypertension, hypercholesterolemia,
anticoagulant and coronary dilation were maintained
throughout the study. In addition, food intake was
controlled and regular exercise was maintained. No drugs
that potentially interfered with the outcomes were used.
Ultrasound cardiography (UCG) and blood pressure
were measured at the hospital.
Two-drug effects on cardiovascular diseases in T2DM
patients complicated with CAD were compared between
Sections and intra-each Section with glucose and lipid
Thirty patients in Liraglutide group were daily injected
with 0.6 mg of Liraglutide before breakfast. Fasting plasma
glucose (FPG) was measured 7-day later. The dosage was
increased to 1.2 mg/d if FPG > 7.0 mmol/L or 2-h PPG >
11.1 mmol/L, otherwise it was remained at 0.6 mg/d. After
another 7 days, the dosage was increased to 1.8 mg/d if
FPG > 7.0 mmol/L or 2-h PPG > 11.1 mmol/L, otherwise
it remained at 1.2 mg/d. The average dose of Liraglutide
was 1.2 mg/d. 30 patients in Metformin group took orally
Metformin with starting dosage of 500 mg twice daily
before breakfast and supper. The dosage was adjusted every
other day if FPG > 7.0 mmol/L or 2-h PPG > 11.1 mmol/L.
The maximum dose was 2000 mg/d, with the average dose
of 1500 mg/d.
Patients were was daily injected with the 0.6 mg of
Liraglutide before breakfast. FPG was measured 7-day later.
The dosage was increased to 1.2 mg/d if FPG >
7.0 mmol/L, or 2-h PPG >11.1 mmol/L, otherwise the
patients were excluded. After another 7 days, only
patients with FPG > 7.0 mmol/L or 2-h PPG > 11.1 mmol/L
were remained in the study, who were randomized to
either Liraglutide monotherapy (n = 30) or the
combination therapy of Liraglutide and Metformin (n = 30). The
dosage of Liraglutide was increased to 1.8 mg/d in the
monotherapy group, while Liraglutide was maintained in
1.2 mg/d in combined therapy group. The dosage of
Metformin was added to the combined therapy group
according to the same strategy used in Section 1.
For patients with suboptimal glucose control at the
start of the trial, concomitant use of α- glucosidase
inhibitors was permitted at the discretion of the
Patients were randomly grouped according to the
randomization number. The blood test,
echocardiography, and blood pressure were carried out and analyzed
by the technicians, who were blinded to the treatment
The primary outcomes included a total of 8
measurements of FBG (before and 2 h after 3 meals, before
bedtime, and at midnight) taken in the same day once a
week. Other parameters, including FBG, PPG, HbA1c,
blood pressure, body mass index (BMI), TG, total
cholesterol (TC), low-density lipoprotein cholesterol
(LDL-C), C-reactive protein (CRP), left ventricular
enddiastolic diameter (LVEDD), ejection fraction (EF) and
E/A ratio were recorded at baseline before treatment
and at 24-week after treatment. FBG between 5.0–
7.0 mmol/L, PPG between 7.8–11.1 mmol/L and HbAlc
<7.0% were considered normal.
The secondary outcomes were:1) severe hypoglycemia
(requiring assistance from others); 2) moderate
hypoglycemia (showing symptoms of hypoglycemia with
FBG < 3.9 mmol/L, which can be treated with food
intake without need of other’s assistance); 3) mild
hypoglycemia (showing symptoms of hypoglycemia with
FBG >3.9 mmol/L).
The adverse events, like nausea, vomiting, diarrhea,
rash, red/itchy/inflamed skin, and induration or
irritation of injection site skin were recorded.
Data management and statistical analysis
Data were entered into an Excel (Micro-soft office 2000)
database and were proofed for entry errors. The
database was subsequently locked, imported into SPSS for
Windows (IBM SPSS Statistics for Windows, Version
11.0. Armonk, NY: IBM Corp.) formatted and analyzed.
BMI, FBG, TG, TC, LDL-C, PPG, HbA1c, SBP, DBP,
CRP, LVEDD, EF and E/A ratio were normally
distributed as continuous variables, and were analyzed with
Student’s t-test between groups. Independent samples
t-test was performed for the changes from baseline to
week 24 of all parameters. Categorical data were
analyzed by χ2 tests. α was set at 0.05 for all tests.
Once Section 1 analysis was completed, the patients for
Section 2 were recruited. With 76 patients screened for
Section 1, 60 met eligibility criteria and were evenly
grouped into Liraglutide or Metformin monotherapy. Of
the 84 patients screened for Section 2, 60 met eligibility
criteria and were grouped into singled (monotherapy) or
combined (dual) therapy (Fig. 1). Baseline demographic
and clinical characteristics were similar between groups
(Table 1). Patients in Section 1 and 2 were aged between
26 and 88 years (median, 59 years) and between 27 and
82 years (median, 60 years), respectively. The mean
duration of diabetes was 8 ± 5 years in both Sections.
Saction1: Liraglutide vs. Metformin monotherapy
After 24 weeks, Liraglutide monotherapy significantly
decreased the plasma glucose from 13.8 ± 5.1 to 7.9 ±
3.3 mmol/L, HbA1cfrom 9.0 ± 1.3% (or 75 ± 14 mmol/L)
to 6.8 ± 0.8% (or 51 ± 9 mmol/L); while Metformin
significantly decreased the plasma glucose from 13.7 ± 4.8
to 8.2 ± 3.5 mmol/L and HbA1c from 9.1 ± 1.1% (or 96
± 12 mmol/L) to 6.9 ± 0.7% (or 52 ± 8 mmol/L).
Obviously, no significant differences on decreases of the
plasma glucose and HbA1c were seen between two
treatments. Some risk factors for CAD were significantly
decreased with both treatments. Plasma TG was
decreased from 2.8 ± 0.7 to 2.4 ± 0.4 mmol/L, TC from 6.2
± 0.8 to 5.4 ± 0.7 mmol/L, and LDL-C from 4.1 ± 0.8 to
3.5 ± 0.5 mmol/L in Liraglutide group; while plasma TG
was significantly decreased from 2.9 ± 0.6 to 2.6 ±
0.5 mmol/L, TC from 6.3 ± 0.9 to 5.7 ± 0.8 mmol/L,
LDL-C from 4.2 ± 0.7 to 3.8 ± 0.6 mmol/L in Metformin
group (Tables 1 and 2). The two medications showed the
equal efficacy on decreasing plasma glucose. To our
surprise, Liraglutide (1.2 mg/d) alone showed better
improvements on the lipid metabolism and the
cardiovascular function, including TG, LDL-C, CRP, SBP, DBP,
LVEDD, EF and E/A ratio (Tables 2 and 3).
Section 2: Monotherapy vs. combined therapy
Due to a better efficacy of Liraglutide shown in Section
1, higher dose of Liraglutide (1.8 mg/d) alone was
chosen for study in Section 2, and Liraglutide (1.2 mg/d)
plus Metformin was selected for combined therapy.
After 24-week treatment, plasma glucose of 7.9 ±
3.4 mmol/L in monotherapy and 7.7 ± 3.2 mmol/L in
dual therapy, and HbA1c of 6.8 ± 0.9% (or 51 ± 9 mmol/L)
in monotherapy and 6.7 ± 0.7% (or 50 ± 8 mmol/L) in dual
therapy were significantly decreased when compared with
the levels of baseline, in which averages of plasma glucose
and HbA1c from two sections at baseline vs. 24-week
treatment were 9.2 ± 0.2 vs. 6.8 ± 0.1%. However, there
was no significant difference on glycemic control between
groups in Section 2 (Tables 2 and 3).
However, in section 2, combined treatment of
Liraglutide and Metformin showed the better improvements
only on TC, LVEDD and E/A ratio when compared with
Liraglutide (1.8 mg/d) alone treatment (Table 2).
In addition, regarding the adverse events associated
with each treatment, less events such as transient
anorexia, nausea, and vomiting were observed in the dual
therapy than in Liraglutide monotherapy, which were
shown in Table 4.
Both Liraglutide and Metformin have been extensively
studied on the basis of glycemic control. The current
study was focused on the cardiovascular function
analyses with Liraglutide and/or Metformin treatment in
T2DM patients complicated with CAD. We have found
that, with comparable glycemic levels, both Liraglutide
monotherapy and Metformin monotherapy could
significantly improve plasma lipid profile, BMI, CRP, and
cardiac functions. However, Liraglutide (1.2 mg/d)
monotherapy significantly improved the LDL-C, CRP,
BP, LVEDD, EF percentage and E/A ratio, compared with
Metformin monotherapy. Based on the results, we
further compared the higher dose of Liraglutide (1.8 mg/d)
monotherapy with the dual therapy of low dose
Liraglutide (1.2 mg/d) plus Metformin. To our surprise, not
only the dual therapy but also the higher dose of
Liraglutide (1.8 mg/d) monotherapy showed less
improvements on the lipid metabolism and the cardiovascular
function, compared with Liraglutide (1.2 mg/d)
monotherapy. It is understandable that as analogue of GLP-1,
Liraglutide may slow the rate of absorption of nutrients
into the blood stream by reducing gastric emptying and
may directly reduce food intake, including decreasing
lipids intake and absorption. A recent study of
36month LEADER trial revealed that Liraglutide improved
cardiovascular outcomes in T2DM patients [
]. It was
also reported that an addition of 5-week infusion of
GLP-1 to standard therapy in patients with New York
Heart Association class III/IV heart failure significantly
improved cardiac function, as indicated by left
ventricular ejection fraction, maximum myocardial ventilation
oxygen consumption, and 6-min walk distance [
PreDuration of diabetes (year) 8 ± 5
Age at initial visit (year)
Data are mean ± SD, unless otherwise noted; Abbreviations: BMI body mass index, TG triglyceride, TC total cholesterol, LDL-C low-density lipoprotein cholesterol,
PPG postprandial glucose, SBP systolic blood pressure, DBP diastolic blood pressure, CRP C-reactive protein, LVEDD left ventricular end-diastolic diameter, EF
clinical and clinical studies have also revealed the
beneficial effect of Liraglutide on lipid metabolism/profile and
endothelial function in T2DM patients [
underlying mechanisms include alleviated oxidative
stress and cardiomyocytes apoptosis by GLP-1,
prevention of micro-vascular diseases related to diabetes,
protection of cardiac micro-vascular endothelial cells
against hypoxia/re-oxygenation injury, regulation of
calcium homeostasis and electrophysiological activities of
12, 13, 15–19
GLP-1’s actions are mediated through the
G-proteincoupled GLP-1 receptor. GLP-1 or GLP-1 receptor
agonist decreases food intake, slows gastric emptying,
and reduces body weight through its effects on energy
expenditure. As well reviewed, liraglutide has been
demonstrated to reduce food intake, promote weight loss,
and improve indices of metabolic function in both
animal and human studies, and the primary mechanisms
associated with these effects are proposed to be due to
actions of GLP-1 on peripheral and central pathways
that affect food intake and metabolism via hindbrain and
hypothalamic activation, as well as those brain areas
associated with motivation and reward processes [
patients with Type 2 diabetes, well controlled with
metformin monotherapy, addition of liraglutide improves
several cardiovascular risk markers beyond glycaemic
]. These studies, together with our data,
support the effect of Liraglutide on improving the
cardiovascular function of T2DM patients besides glycemic
The ability of Metformin to reduce hepatic glucose
production and increase skeletal muscle glucose uptake
has made it as one of the major first-line therapies for
]. It was also reported that Metformin
could reduce insulin resistance, lower blood pressure,
improve circulating lipid profile, and prevent myocardial
infarction and stroke in patients with diabetes [
In line with these results, the current study also
demonstrated that Metformin improve lipid profile and
cardiovascular function beyond glycemic control. It was
reported that Metformin could inhibit the production of
triglycerides and cholesterol, and stimulates fatty acid
oxidation, preventing the progression of nonalcoholic
fatty liver disease [
]. A recent report demonstrated
a significant association between metformin response
and TG, TC, HDL-C and LDL-C . The
glucoselowering property alone cannot account for
cardiovascular benefit [
]. Accumulating evidences suggest the
inhibition of pro-inflammatory responses, reduction of
smooth muscle cell contractility, or increase of nitric
oxide as possible mechanisms [
Many studies were conducted to investigate the
synergistic effect of different drugs. Liraglutide or Metformin
has previously been studied to combine with other drugs
Transient anorexia, nausea
such as thiazolidinedione (TZD) and sulphonylurea
]. All these dual and triple therapy showed, not
only the more effective on decreasing blood glucose
level, but also on reducing body weight, BP, BMI,
compared with monotherapy. Theoretically, combined
dual or triple drug therapy should produce a
synergetic effect, which must be better than monotherapy.
However, it remains unknown about the mechanism
of the Liraglutide (1.2 mg/d) showed the better
improvements on the lipid profiles and the cardiac
function than either Liraglutide (1.8 mg/d) or dual
therapy, so future studies are needed.
The most common adverse events associated with
GLP-1 RAs were nausea, vomiting, and diarrhea, the
causes of which were thought to be gastric emptying or
the involved central nervous system. [
] To achieve
similar glycemic control, a lower dose of Liraglutide was
needed in the dual therapy. Not surprisingly, with
similar glycemic control in T2DM patients complicated with
CAD, the occurrence of adverse events were significantly
lower in the dual therapy, suggesting underlying
advantage of dual therapy over monotherapy.
The limitation of the study were: 1) the sample size
was relatively small, indicating less statistical power,
lower chance of discovering genuine effects, and the
possible exaggerated estimate [
]; 2) only one time
point (24 weeks after treatment) was assessed, while
T2DM complicated with CAD is a chronic disease, a
longer-term observation would be of good value.
3) Recently, GLP-1 based therapies also have the
potential to be linked to cancer, specifically thyroid
cancer and pancreatic cancer [
]. However, no
cancer risk was found with Liraglutide treatment in the
In summary, the Liraglutide (1.2 mg/d) monotherapy
showed the better effects than either Metformin alone,
or combination of Liraglutide and Metformin on lipid
metabolism and cardiovascular function in patients with
similar glycemic control.
The study was funded by the Endocrinology Department of Tianjin First Center
Hospital. The funder of the study had no role in the study design, data
collection, data analysis, data interpretation, or writing of the manuscript.
Availability of data and materials
The datasets supporting the conclusions of this article are included within
YL contributed to the study design, XJ prepared the manuscript, XC perform
the data analysis, all the authors made the final approval.
Ethics approval and consent to participate
The study protocol was approved by the Ethic Committee of the Tianjin First
Center Hospital and conducted in accordance with Helsinki’s Declaration. All
the patients gave their written information consent.
Consent for publication
The authors declare that they have no competing interests.
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