Sitagliptin as
combination therapy
in the treatment of
inadequately
controlled type 2
diabetes
Klitsunova Yuliia, PhD State Institution “Zaporizhia Medical
Academy of Post-Graduate Education Ministry of Health of
Ukraine”, Zaporizhzhia, Ukraine
BACKGROUND
• We aimed to assess the efficacy and safety of the DPP-4
inhibitor sitagliptin 100 mg , as adjunct treatments to
metformin, in individuals with type 2 diabetes who did not
achieve adequate glycaemic control with metformin
alone.
ANTI-HYPERGLYCEMIC THERAPY*
• Therapeutic options:
• Oral agents & non-insulin injectables
- Metformin
- Meglitinides
- Sulfonylureas
- Thiazolidinediones
- DPP-4 inhibitors
- SGLT-2 inhibitors
- GLP-1 receptor agonists
- a-glucosidase inhibitors
- Colesevelam
- Dopamine-2 agonists
- Amylin mimetics
Oral Class
Mechanism
Biguanides
• Activates AMPkinase (?other)
•  Hepatic glucose
production
• Extensive
experience
• No hypoglycemia
• Weight neutral
• ?  CVD
• Gastrointestinal
• Lactic acidosis
(rare)
• B-12 deficiency
• Contraindications
Low
Sulfonylure
as
• Closes KATP
channels
•  Insulin secretion
• Extensive
experience
•  Microvascular risk
• Hypoglycemia
•  Weight
• Low durability
• ? Blunts ischemic
preconditioning
Low
Meglitinide
s
• Closes KATP
channels
•  Insulin secretion
•  Postprandial
glucose
• Dosing flexibility
• Hypoglycemia
•  Weight
• ? Blunts ischemic
preconditioning
• Dosing frequency
Mod.
2015;38:140-149;
0125-014-3460-0
Advantages
• PPAR-g activator
• No hypoglycemia
•  Insulin sensitivity • Durability
•  TGs (pio)
•  HDL-C
• ?  CVD events
(pio) agents
Table 1. Properties of anti-hyperglycemic
TZDs
Disadvantages Cost
•  Weight
Low
• Edema/heart
failure
• Bone fractures
•  LDL-C (rosi)
Diabetes Care 2015;38:140-149;
• ?  MI (rosi)
Diabetologia 2015;58:429-442
Oral Class
Mechanism
a• Inhibits aGlucosidase glucosidase
inhibitors
• Slows carbohydrate
digestion / absorption
Advantages
Disadvantages Cost
• No hypoglycemia
• Nonsystemic
•  Postprandial
glucose
• ?  CVD events
• Gastrointestinal
• Dosing
frequency
• Modest  A1c
Mod.
DPP-4
inhibitors
• Inhibits DPP-4
• Increases incretin
(GLP-1, GIP) levels
• No hypoglycemia
• Well tolerated
• Angioedema /
High
urticaria
• ? Pancreatitis
• ?  Heart failure
Bile acid
sequestrant
s
• Bind bile acids
• ?  Hepatic glucose
production
• No hypoglycemia
•  LDL-C
• Gastrointestinal
• Modest  A1c
• Dosing
frequency
High
Dopamine-2
agonists
• Activates DA
receptor
• Alters hypothalamic
control of metabolism
•  insulin sensitivity
• No hypoglyemia
• ?  CVD events
• Modest  A1c
• Dizziness,
fatigue
• Nausea
• Rhinitis
High
• Inhibits SGLT2 in
• Weight
proximal nephron
• No hypoglycemia
• Increases
•  BP
Table 1. Properties
of anti-hyperglycemic
agents at all
glucosuria
• Effective
SGLT2
inhibitors
• GU infections
High
• Polyuria
• Volume
Diabetes Care 2015;38:140-149;
Diabetologia 2015;58:429-442
depletion
METHODS
• In this study, after a screening diet/exercise run-in period, a metformin dose
titration/stabilization period patients (n = 90)(aged 52-72 years) with type 2
diabetes mellitus who had inadequate glycaemic control (glycosylated
haemoglobin (>=1500 mg/day) for >=8 weeks with a A1C >=7.5% and
<=11.0%) and body-mass index of 25-57 kg/m(2) were enrolled and were
assigned to receive sitagliptin 100 mg once-daily for 26 weeks' treatment
• The primary endpoint was change in HbA(1c) from baseline to week 26.
• Patients exceeding specific glycemic limits were provided rescue therapy
(Amaril) until the end of the study. The efficacy analyses were based on an
all-patients-treated population using an ANCOVA and excluded data
obtained after glycemic rescue.
Clinical measurements
• After 12 months of treatment with sitagliptin, changes in
HbA1c, fasting plasma glucose (FPG), blood pressure,
body weight (BW), body mass index (BMI), total
cholesterol (TC), LDL cholesterol (LDL-C), HDL
cholesterol (HDL-C), triglycerides (TG), Liver Funktion
(AST, ALT, Alk ph) albumin/creatinin ratio, GFR were
assessed.
Statistics
• Values are expressed as the mean ± SD. To compare
changes in the values of HbA1c, FPG, BW, BMI, BP,
lipids from baseline to after 12 weeks of treatment, we
used the paired t-test.
• Values of p < 0.05 were considered to be statistically
significant.
Baseline characteristics
• A total of 95 patients agreed to participate in this study.
Of the 95 patients, 5 were excluded due to protocol
violation.
• Therefore, sitagliptin efficacy over 3 months was
evaluated in 90 subjects as efficacy population. The
safety of sitagliptin over 12 months was evaluated in the
89 enrolled subjects as safety population (1 person was
dicontinuadet (creatinine clearance < 30 ml/min).
Study Enrollment
Participants
(95)
Enrolled subjects (N=90)
Excluded for
criteria (N=5)
3 month
Discontinuated subjects (N=1)
creatinine clearance < 30 ml/min
Subjects evaluated
for efficacy (N=90)
12 month
Evaluation of the
safety of
Sitagliptin (N=89)
Baseline characteristics
Enrolled subjects (N=90)
Age (years)
Gender
61.6 ± 6.1
Male: 33% (n = 30),
Female: 67% (n = 60)
BMI
Waist circumference
Obesity (BMI > 25)
Duration of DM (years)
Smoking status
57.23 ± 8.5
89.4 ± 12.8 cm
100%
6.8 ± 6.5
Smoker: 13%
Past smoker: 23%
Never: 64%
Alcohol consumption
Complications
Use of sitagliptin
Yes: 29%
HT: 67%, DL: 55%, HUA: 7%,
Arrhythmia: 5%, CKD 43%
New: 100%
* BMI, Body mass index; DM, diabetes mellitus; HT, hypertension; DL, dyslipidemia; HUA, hyperuricemia;
CKD
Effects of sitagliptin on glycemic
control
• Overall, HbA1c levels decreased in all of the 90
evaluated subjects after 6 months (5.33 % ± 0.6% to
11.67 ± 0.87%, p < 0.001) and 12 months (2.63% ± 0.8%
to 29.48% ± 1.07%, p < 0.001) of sitagliptin treatment
Effects of sitagliptin on glycemic control
10.00
30
25
9.00
20
8.00
<60 yo
15
60-65 yo
>65
10
HbA1C=>
10%
7,6%=>Hb
A1c<10%
HbA1c<7.
9%
5
7.00
0
0m
6m
12 m
0
6
12
Effects of sitagliptin on blood pressure, lipid
profiles
• BW and BMI decreased after 3 months of sitagliptin
treatment (BW: 62.1 ± 14.1 to 61.5 ± 13.8 kg, p = 0.003,
BMI: 25.0 ± 4.5 to 24.8 ± 4.5 kg/m2, p = 0.006). At
12 months, these values had returned to baseline levels
(BW: 62.0 ± 13.7 kg, p = 0.800, BMI: 25.1 ± 4.4 kg/m2,
p = 0.560)
• Systolic (SBP) and diastolic blood pressure (DBP) also
decreased after 3 months (SBP: 135 ± 18 to
131 ± 17 mmHg, p < 0.001, DBP: 75 ± 12 to 71
±11 mmHg, p < 0.001) as did serum levels of TC and TG
(TC: 201 ± 40 to 191 ± 37 mg/dl, p < 0.001; TG: 161 ± 171
to 136 ± 126 mg/dl, p = 0.003)
Effects of sitagliptin on blood
pressure, lipid profiles
FINDINGS:
• Unsuspected finding was significant decreases of the
hepatic safety tests - AST, ALT levels, total and direct
bilirubin, renal failure tests - serum creatinite calculated
using the CKD-EPI formula, urinary albumin/creatinine
ratio were observed after 6 months of treatment with
sitagliptin
CFR
90
FINDINGS:
88
86
140
CFR
84
120
82
100
80
80
Alc Ph
AST
ALT
60
0m
6m
12m
alb/creat
5
4
40
3
20
alb/creat
2
0
0m
6m 12m
1
0
0m
6m
12m
Non-alcoholic fatty liver disease
• Non-alcoholic fatty liver disease (NAFLD) is the most
common liver disorder worldwide. Several lines of
evidence have indicated a pathogenic role of insulin
resistance, and a strong association with type 2 diabetes
(T2MD) and metabolic syndrome. Importantly, NAFLD
appears to enhance the risk for T2MD, as well as worsen
glycemic control and cardiovascular disease in diabetic
patients. In turn, T2MD may promote NAFLD
progression. Liver expresses high DPP-4 levels, [162]
which significantly increase in patients with NAFLD,
compared with healthy subjects [165]. Moreover, serum
DPP-4 activity and hepatic DPP-4 expression are
correlated with NAFLD grading.
Non-alcoholic fatty liver disease
• Recently, Shirakawa et al. [167] studied the effects of sitagliptin in Gck ±
diabetic mice with diet-induced hepatic steatosis. Sitagliptin prevented fatty
liver in both wild-type and Gck ± mice and decreased the expressions of
sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase-1,
and fatty acid synthase, while it increased the expression of peroxisome
proliferator-activated receptor-α in the liver. Further studies conducted in a
mouse model of non-alcoholic steatohepatitis, indicated that linagliptin
improves insulin sensitivity and hepatic steatosis in mice with diet-induced
obesity and may ameliorate liver inflammation.
• Clinical data are very limited, and come from non-randomized trials, all
conducted in small groups of diabetic patients. A case report showed that a
diabetic woman with refractory NAFLD was successfully treated with
sitagliptin 50 mg/day. Glycemic control, ALT levels and liver fat, evaluated
by Magnetic Resonance Imaging (MRI), improved after four months [163].
An open label single arm study [170] evaluated 30 NAFLD patients with
T2DM treated with sitagliptin (50 mg/day) for four months. At the end of
treatment AST, ALT and γ-GTP levels were reduced.
Safety
• Thirty two (35,56%) of the 90 enrolled subjects suffered
adverse events (AEs)
• One subject (1.10%) experienced direct sitagliptinrelated AEs causing them to discontinue sitagliptin
(creatinine clearance < 30 ml/min) and was . Thirty
subjects suffered from fungal infection of the urogenital
tract. These thirty one subjects (34.4%) developed AEs
that were sus-pected to have a causal relationship with
sitagliptin. One patient was non-fatal myocardial
infarction left ventricular posterior wall (initially with high
patient hypertriglyceridemia). Hypoglycemia and loss of
consciousness were not occurred.
Discussion
• Efficacy and safety of sitagliptin
• In our study, the HbA1c and FPG levels were reduced at 6 months
(5.33 % ± 0.6% to 11.67 ± 0.87%, p < 0.001) and 12 months
(2.63% ± 0.8% to 29.48% ± 1.07%, p < 0.001) after treatment with
sitagliptin at a dose of 100 mg/day. Our results are not similar to
those of previous studies reported in the US and Europe. Nathan et
al. reported that the expected percentage decrease in HbA1c levels
is 1.0% to 2.0% with metformin monotherapy, 1.0% to 2.0% with
sulfonylureas (SUs), 0.5% to 1.0% with glinides, 0.5% to 0.8% with
α-glucosidase inhibitors (α-GI), 0.5% to 1.4% with thiazolidinediones
(TZD) and 0.5% to 0.8% with DPP-4 inhibitors. Monotherapy with
metformin or SU exhibits a stronger reduction of HbA1c levels than
a DPP-4 inhibitor alone. However, metformin is associated with side
effects such as GI symptoms and is contraindicated in patients with
renal insufficiency. In our study, renal function even improved after
treatment with the combination of sitagliptin and metformin in all
patients except 1 (98.9%) (with initially low values of glomerular
filtration).
Discussion
• Side effects appear to be more frequently seen with
metformin or SUs than with sitagliptin. The most
common side effects of TZD are weight gain and fluid
retention along with peripheral edema and an increased
risk of congestive heart failure. In our study, body weight
and BMI decreased and there was no evidence of heart
failure during sitagliptin treatment. While metformin,
glinides, and α-GIs are required to be taken three times
daily, sitagliptin is only taken once daily. Therefore,
sitagliptin should be associated with higher adherence
compared to metformin, glinides, and α-GIs.
Discussion
• In our study, AEs after sitagliptin treatment were seen in Thirty two
(35,56%) of the 90 enrolled subjects. In particular, direct sitagliptinrelated AEs such as hypoglycemia and loss of consciousness were
not observed. A previous pooled analysis reported that the overall
incidence of AEs was similar between sitagliptin (100 mg/day) and
other diabetic-comparator agents (except for other DPP-4 inhibitors),
including placebos, pioglitazone, metformin, sulfonylureas,
sulfonylureas + metformin, and metformin + rosiglitazone (overall
side effects: 63.0% vs. 62.8%, hypoglycemia: 3.4% vs. 10.9%).
Therefore, incidence of AEs in this study, including hypoglycemia,
was lower than that reported in the pooled analysis. In previous
studies, sitagliptin did not increase cardiovascular risk in patients
with T2DM and sitagliptin reduced postprandial glucose fluctuation
and stabilized blood glucose levels effectively in combination with
miglitol through continuous glucose monitoring (CGM).
Effects of DPP-4 inhibitors on blood
pressure and lipid profiles
• Systolic and diastolic blood pressure decreased after 6 months of
treatment with sitagliptin. The active isoforms of GLP-1 include GLP-1(7–
36) amide and glycine-extended GLP-1(7–37). GLP-1(7–36) exhibits
vascular actions via GLP-1 receptor signaling. Additionally, GLP-1(9–36),
a metabolite of GLP-1 (7–36), has vasodilator effects independent of the
GLP-1 receptor in a nitrous oxide/cyclic guanosine monophosphate
(cGMP)-dependent manner. DPP-4 inhibitors increase the levels of GLP1, possibly leading to vasodilatation and blood pressure reduction.
• In our study, serum levels of TC and TG also decreased after 6 months
of treatment with sitagliptin. Qin et al. showed that GLP-1 decreases the
intestinal lymph flow and reduces triglyceride absorption and apo B and
apo A-IV production in rats. Another DPP-4 inhibitors, have been shown
to reduce the hepatic expression of genes important for cholesterol
synthesis, including phosphomevalonate kinase and mevalonate
decarboxylase in wild-type mice
Conclusions
• The results of this study show that sitagliptin was safe and
effective in this population; however, further studies are
needed to evaluate the comparison of each DPP-4
inhibitor.
• Given the high likelihood that sitagliptin will be coadministered with renally active drugs and statins in many
diabetic patients, our findings suggest that additional
studies regarding the long-term safety of sitagliptin in renal
insufficiency may be warranted.
• The clinical use of the DPP-4 inhibitor sitagliptin has
beneficial effects not only for glucose control, but also for
improving blood pressure, lipid profiles, and liver enzimes.
• It is suggested that sitagliptin can be administered
effectively and safely to patients with diabetes mellitus
complicated by chronic liver injury.