1. 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

2. 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.

3. ANTI-HYPERGLYCEMIC THERAPY*
Therapeutic options:
Oral agents & non-insulin injectables
Metformin
Sulfonylureas
Thiazolidinediones
DPP-4 inhibitors
SGLT-2 inhibitors
GLP-1 receptor agonists
Meglitinides
a-glucosidase inhibitors
Colesevelam
Dopamine-2 agonists
Amylin mimetics

4. Oral Class Mechanism Advantages Disadvantages Cost
Biguanides
Activates AMP-kinase (?other)
 Hepatic glucose production
Extensive experience
No hypoglycemia
Weight neutral
?  CVD
Gastrointestinal
Lactic acidosis (rare)
B-12 deficiency
Contraindications
Low
Sulfonylureas
Closes KATP channels
 Insulin secretion
 Microvascular risk
Hypoglycemia
 Weight
Low durability
? Blunts ischemic preconditioning
Meglitinides
 Postprandial glucose
Dosing flexibility
Dosing frequency
Mod.
TZDs
PPAR-g activator
 Insulin sensitivity
Durability
 TGs (pio)
 HDL-C
?  CVD events (pio)
Edema/heart failure
Bone fractures
 LDL-C (rosi)
?  MI (rosi)
Diabetes Care 2015;38: ;
Diabetologia 2015; /s
Here are some of the older oral drug classes used in T2DM. The table describes the mechanism of action of each class, its advantages, disadvantages and cost. Less commonly used classes are denoted in grey font.
Table 1. Properties of anti-hyperglycemic agents
Diabetes Care 2015;38: ;
Diabetologia 2015;58:

5. Oral Class Mechanism Advantages Disadvantages Cost
a-Glucosidase inhibitors
Inhibits a-glucosidase
Slows carbohydrate digestion / absorption
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
Well tolerated
Angioedema / urticaria
? Pancreatitis
?  Heart failure
High
Bile acid sequestrants
Bind bile acids
?  Hepatic glucose production
 LDL-C
Dopamine-2
agonists
Activates DA receptor
Alters hypothalamic control of metabolism
 insulin sensitivity
No hypoglyemia
Dizziness, fatigue
Nausea
Rhinitis
SGLT2 inhibitors
Inhibits SGLT2 in proximal nephron
Increases glucosuria
 Weight
 BP
Effective at all stages
GU infections
Polyuria
Volume depletion
 LDL-C
Cr (transient)
Additional oral agent classes used in T2DM are included on this slide. The table describes the mechanism of action of each class, its advantages, disadvantages and cost. Less commonly used classes are denoted in grey font.
Table 1. Properties of anti-hyperglycemic agents
Diabetes Care 2015;38: ;
Diabetologia 2015;58:

6. METHODS
In this study, after a screening diet/exercise run-in period, a metformin dose titration/stabilization period patients (n = 90)(aged 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 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.

7. 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.

8. 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.

9. 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).

10. Study Enrollment Participants (95) 3 month 12 month
Enrolled subjects (N=90)
Discontinuated subjects (N=1)
creatinine clearance < 30 ml/min
Subjects evaluated for efficacy (N=90)
Evaluation of the safety of Sitagliptin (N=89)
Excluded for criteria (N=5)
3 month
12 month

11. Baseline characteristics
Enrolled subjects (N=90)
Age (years)
61.6 ± 6.1
Gender
Male: 33% (n = 30),
Female: 67% (n = 60)
BMI
57.23 ± 8.5
Waist circumference
89.4 ± 12.8 cm
Obesity (BMI > 25)
100%
Duration of DM (years)
6.8 ± 6.5
Smoking status
Smoker: 13%
Past smoker: 23%
Never: 64%
Alcohol consumption
Yes: 29%
Complications
HT: 67%, DL: 55%, HUA: 7%, Arrhythmia: 5%, CKD 43%
Use of sitagliptin
New: 100%
* BMI, Body mass index; DM, diabetes mellitus; HT, hypertension; DL, dyslipidemia; HUA, hyperuricemia; CKD

12. 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 ± 0.87%, p < 0.001) and 12 months (2.63% ± 0.8% to 29.48% ± 1.07%, p < 0.001) of sitagliptin treatment

13. Effects of sitagliptin on glycemic control

14. 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)

15. Effects of sitagliptin on blood pressure, lipid profiles

16. 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

17. FINDINGS:

18. 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.

19. 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.

20. Safety
Thirty two (35,56%) of the 90 enrolled subjects suffered adverse events (AEs)
One subject (1.10%) experienced direct sitagliptin-related 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.

21. Discussion Efficacy and safety of sitagliptin
In our study, the HbA1c and FPG levels were reduced at 6 months (5.33 % ± 0.6% to ± 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).

23. 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.

24. Discussion
In our study, AEs after sitagliptin treatment were seen in Thirty two (35,56%) of the 90 enrolled subjects. In particular, direct sitagliptin-related 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).

25. 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 GLP-1, 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

26. 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 co-administered 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.