The Effect of Sitagliptin on Glucagon Counterregulation and Incretin Hormones During Mild Hypoglycemia in Elderly Patients With Metformin-treated Type 2 Diabetes
Phase: PHASE4
Conditions: Type 2 Diabetes
Sponsor: Lund University

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Trial Outline – Protocol 300A 
 
Trial ID: NCT02256189 
 
 
 
The Effect of Sitagliptin on Glucagon Dynamics and Incretin 
Hormones During Mild Hypoglycemia in Elderly Patients with 
Metformin-Treated Type 2 Diabetes (SITACLAMP) 
 
 
 
 
 
 
 
Trial outline originator 
Professor Bo Ahrén 
Department of Clinical Sciences Lund 
Lund University 
B11 BMC 
221 84 LUND 
Sweden 
e-mail Bo.Ahren@med.lu.se 

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Table of contents 
 
 
 
 
page 
 
1. Table of contacts  
 
 
3 
2. Introduction 
 
 
 
 
3 
3. Objective of the study 
 
 
 
4 
4. Study design 
 
 
 
 
5 
5. Study population  
 
 
6 
a. Inclusion criteria 
 
 
6 
b. Exclusion criteria 
 
 
7 
6. Study medication  
 
 
8 
a. Study drug  
 
 
8 
b. Handling of study medication  
8 
7. Study flow and methods 
 
 
8 
a. Study flow  
 
 
8 
b. Methods   
 
 
9 
8. Randomization 
 
 
 
12 
9. Data management and safety registration 
12 
10. Withdrawal criteria 
 
 
 
14 
11. End-points 
 
 
 
 
15 
12. Sample size calculation 
 
 
15 
13. Statistical evaluation 
 
 
 
16 
14. Monitoring, data handling and archiving 
16 
15. Risk-benefit analysis 
 
 
 
16 
16. Insurance 
 
 
 
 
16 
17. Study timeline 
 
 
 
 
17 
18. Publication  
 
 
 
 
17 
19. References  
 
 
 
 
17 

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1. Table of Contacts  
 Sponsor:  Professor Bo Ahrén, Department of Clinical Sciences, Lund University, 
B11, 221 84, Lund, telephone number: +46 46 2220758, fax number: +46 46 222 
07 57, e-mail Bo. Ahrén@med.lu.se 
 
 Co Investigator:  Dr. Johan Farngren, Department of Clinical Sciences, Lund 
University, C11, 221 84, Lund, telephone number: +46 733 823506, e-mail 
Johan.Farngren@skane.se 
 
 Study Nurse:  Margaretha Persson, Research Nurse, Clinical Research Unit, Skåne 
University Hospital, 205 02 Malmö, telephone number: +46 46 332037, e-mail 
Margaretha.M.Persson@skane.se 
 
 Study Monitor :   Lena Liliebladh,   Enheten för Kliniska Prövningar, FoU Centrum 
Skåne, telephone number +46 46 177972, e-mail Lena.Liliebladh@skane.se 
 
 
2. Introduction 
Incretin hormones are important for normal pancreatic islet function and glucose 
homeostasis. While glucagon-like peptide 1 (GLP-1) and glucose dependent 
insulinotropic polypeptide (GIP) both enhance glucose-dependent insulin secretion, 
GLP-1 also suppresses glucagon secretion under hyperglycemic conditions, thereby 
contributing to glucose regulation which is impaired in type 2 diabetes (T2DM) (1). 
Sitagliptin enhances the endogenous levels of both GLP-1 and GIP by inhibiting the 
enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for their inactivation (2). 
Multiple clinical studies with sitagliptin have demonstrated reductions in HbA1c in both 
monotherapy and add-on combination therapy, with durable maintenance of efficacy 
over 52 weeks associated with improvements in islet function (2). Furthermore, 
sitagliptin has been shown to have good tolerability and safety in both monotherapy 

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and combination therapy. A special characteristic of sitagliptin is the low risk for 
hypoglycemia.  
In patients with T2DM there are several defects in α-cell function, including relative 
glucagon hypersecretion at normal and elevated glucose levels, and often an impaired 
response to hypoglycemia (for review see 3). Most of the abnormalities of α-cell 
function seen in T2DM may be considered to reflect an impairment of glucose sensing. It 
has previously been shown that sitagliptin reduces glucagon secretion both during an 
oral glucose tolerance test (4) and after a mixed meal (5). What is importance, however, 
is that sitagliptin should not only reduce glucagon in the context of hyperglycemia but 
also sustain glucagon secretion under condition of hypoglycemia, to avoid 
hypoglycemia. This is important because glucose levels below normal are associated 
with increased cardiovascular risk due to recurrent local release of catecholamines in 
the heart every time glucose levels are reduced below 3.3-3.5 mmol/l (6,7). Preservation 
of α-cell response to severe hypoglycemia (2.5 mmol/l) has previously been 
documented for another DPP-4 inhibitor, vildagliptin (8), but the glucagon dynamics at 
higher, but still low, glucose during DPP-4 inhibition is not known. Therefore, this study 
aims at inducing graded hypoglycemia in patients treated with sitagliptin in combination 
with metformin to examine the glucagon dynamics as well as incretin hormones (GLP-1 
and GIP) and counter-regulatory catecholamine responses and PP (pancreatic 
polypeptide), a marker of the autonomic nervous system, and cortisol. The hypothesis is 
that sitagliptin, in comparison with placebo, will protect the glucagon dynamics and 
counter-regulatory mechanisms at moderate hypoglycemia in metformin-treated 
subjects with T2DM, which will be a mechanism underlying a potential protection of 
moderate hypoglycemia by sitagliptin. 
 
3. Objective of the study  
To assess if sitagliptin can improve the glucagon secretory response to mild 
hypoglycemia in elderly patients with metformin-treated T2DM. 
 

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4. Study design 
 
The study is carried out according to this protocol and in compliance with the 
Declaration of Helsinki and applicable Swedish laws and regulations. The study is a 
single-center, double-blind, placebo controlled, cross-over study. Twenty-eight patients 
with T2DM who are treated with metformin (stable dose > 0.5 g during the preceeding 
three months) and HbA1c 6.0-8.5% (43-67 mmol/mol) will be randomized. Each patient 
will attend one screening visit (Week -4) where the inclusion/exclusion criteria will be 
assessed. Eligible patients will then be randomized at visit 2 (Day 1) and complete two 
treatment periods, receiving a different blinded study medication during each period 
(sitagliptin 100 mg QD and placebo, in random order) in addition to their continued 
metformin regimen. A baseline visit will be performed during each of the two treatment 
periods and the blinded study medication will be dispensed for 4 weeks of outpatient 
treatment. After 4 weeks treatment, a combined meal/hyperinsulinemic hypoglycemic 
clamp (3.5 and 3.0 mmol/l)/meal re-challenge test will be performed. The meal 
preceding the clamp is given to ensure a release of incretin hormones and the meal 
after the clamp to allow glucose to return to baseline in a standardized manner. The 
blinded study medication will then be discontinued and a 4-week washout period will 
occur before the next treatment period is started. Also this treatment is 4 week and end 
with a combined meal/hyperinsulinemic hypoglycemic clamp. The blinded study 
medication will then be discontinued and the subjects continue the regular treatment 
with metformin alone.  
 
 
 
 
 
 
 

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Figure of Study Design 
 
 
* patients will receive two treatments in a randomized, balanced Latin square design: 
A = sitagliptin 100 mg QD; B = placebo;  
# first day of study medication treatment period I;  
## first day of study medication treatment period II 
 
5. Study population 
The study population will consist of male and female patients with metformin-treated 
T2DM and HbA1c 6.0-8.5% (inclusive) (43-67 mmol/mol; inclusive), aged >65 years. It is 
planned to screen approximately 56 patients in order to randomize 28. 
 
5a. Inclusion criteria 
1. Written consent has been given. 
2. Patients with metformin treated T2DM (metformin dose >0.5/day and stable during 
the preceeding 3 months) 
3. Age >65 years. 
4. HbA1c 6.0-8.5% (43-67 mmol/mol; inclusive) at visit 1. 
5. Ability to complete the study 
 

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5b. Exclusion criteria: 
1. Use of other glucose-lowering therapy than metformin within three months 
prior to visit 1. 
2. A history of any secondary forms of diabetes, e.g., Cushing’s syndrome and 
acromegaly. 
3. Type 1 diabetes, positive GAD antibodies 
4. eGFR <60 ml/min 
5. Acute infections which may affect blood glucose control within 4 weeks prior to 
visit 1  
6. Any history of recent (<2 weeks) recurrent or severe hypoglycemic episodes. 
7. Any history of acute pancreatitis 
8. Any history of anaphylaxis, angioedema, and exfoliative skin conditions including 
Stevens-Johnson syndrome. 
9. Liver disease such as cirrhosis or chronic active hepatitis 
10. History of coronary heart disease or heart failure class III or IV 
11. Donation of one unit (500 ml) or more of blood, significant blood loss equaling to 
at least one unit of blood within the past 2 weeks or a blood transfusion within 
the past 8 weeks. 
12. Treatment with growth hormone of chronic oral or parenteral corticosteroid 
treatment (> 7 consecutive days of treatment) within 8 weeks prior to visit 1. 
13. Use of other investigational drugs at visit 1 or within 30 days of visit 1, unsuitable 
for the study 
14. Hypersensitivity to sitagliptin or any compound in the tablet core 
(microcrystalline cellulose (E460), calcium hydrogen phosphate, anhydrous 
(E341), croscarmellose sodium (E468), magnesium stearate (E470b) or sodium 
stearyl fumarate) or in the film coating (poly(vinyl alcohol), macrogol (E3350), 
talc (E553b), titanium dioxide (E171), red iron oxide (E172) or yellow iron oxide 
(E172)) 
 

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6. Study medication 
6a. Study drug  
The study drug sitagliptin is a DPP-4 inhibitor meaning that it inhibits the enzyme DPP-4. 
This enzyme is responsible for the inactivation of the incretin hormones (mainly GLP-1) 
and therefore the study drugs prevent the inactivation of these hormones. This in turn 
results in increased plasma levels of the active form of the incretin hormones which 
through effects on islet hormone secretion result in reduced fasting and postprandial 
glucose and therefore HbA1c in subjects with T2DM. Sitagliptin is a small molecule 
which is taken orally once or twice daily. In terms of adverse events, it has been shown 
to be safe in studies undertaken so far. The study drug was approved by EMA in 2007 
and is a well-established glucose-lowering therapy in T2DM world-wide, including in 
Sweden. 
 
6b. Handling of study medication. 
Sitagliptin and placebo are distributed to the Clinical Research Department from the 
Pharmacy at the University Hospital. Patients will be given a box with 35 tablets (1 tablet 
à 100 mg daily) which covers the 4 week treatment period at the Clinical Research 
Department by the Study Nurse. At randomization, subject will receive a written dosage 
card explaining the dosage of the study medication, i.e., 1 tablet daily. After end of 
treatment period, remaining study medication will be destroyed by the hospital 
pharmacy. 
 
7. Study flow and methods 
7a. Study flow 
Visits are scheduled at Week -4, Day 1, Weeks 4, 8 and 12. On visit days patients should 
have fasted overnight (i.e. no food or drinks, except water, after 10 pm on the day prior 
to the scheduled visit). Study visits should occur before 10 am. Medication 
(sitagliptin/placebo and metformin) should not be taken the morning of study visits. 

9 
 
Table 1 lists all of the assessments and indicates with an “X” the visits when they are 
performed. 
 
Table 1 Assessment schedule 
Visit 
1 
2 
3 
4 
5 
Week 
-4 
Day 1 
4 
8 
12 
Informed Consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
Record concomitant medications 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Anti GAD/fasting C-peptide 
X 
 
 
 
 
Demography, history of diabetes, 
medical history 
X 
 
 
 
 
Hyperinsulinemic hypoglycemic 
clamp (see below) 
 
 
X 
 
X 
Physical examination 
X 
 
 
 
X 
Vital signs, body weight 
X 
X 
X 
X 
X 
ECG, 
X 
 
 
 
X 
Hematology, Liver enzymes, 
creatinine 
X 
X 
X 
X 
X 
HbA1c, fasting glucose 
X 
X 
X 
X 
X 
Adverse events including 
hypoglycemia 
 
 
X 
X 
X 
 
 
7b. Methods 
Hyperinsulinemic hypoglycemic clamps will be performed at Week 4 and Week 12 
following a standardized mixed meal and followed by a standardized meal re-challenge. 
Patients will arrive at the study site in the morning after an overnight fast (from 10 pm). 

10 
 
Patients should be instructed to bring their study medication to these visits. Blinded 
study medication (1 tablet sitagliptin or placebo) and the usual morning dose of 
metformin will be taken 15 minutes before the start of the standardized mixed 
breakfast. The start of the meal will be designated time 0 (t = 0 min).  
 
The standardized mixed breakfast meal must be consumed in 15 minutes, and will 
consist of 524 kcal as rye and wheat bread (67% carbohydrate; 60g), 40% enriched 
margarine (10g), smoked ham from pork with 3% fat (15g), cheese with 17% fat (15g),  
juice (285g), green paprika (40g), light sour milk with 0.5% fat (200g) and mix-muesli 
cereal with fruit (40g) with water and non-sweetened coffee or tea. This breakfast 
consists of 524 kcal with 60% from carbohydrate, 20% from fat and 20% from protein. 
 
After an interval period of 2 hours, in which the patients will rest, the hyperinsulinemic 
hypoglycemic clamp will start. Patients will receive a fixed-rate infusion of insulin.  As 
necessary, glucose will be infused at a rate that results in the desired plasma glucose 
concentration.  Plasma glucose concentrations will be allowed to decrease to 3.5 mmol/l 
during the initial 30 min and will be maintained at this target concentration for 30 min. 
Then, plasma glucose concentrations will be allowed to decrease further to 3.0 mmol/l 
during the subsequent 30 min and will be maintained at this target concentration for 
another 30 min. Then, insulin infusion will then be stopped, and a standardized mixed 
lunch meal (780 kcal) will be served, consisting of meatballs, mashed potatoes, peas, 
beef Bouillon cream sauce, cranberry, one tomato, juice (200g), whitebeard (15g) and 
margarine (3g) (70%) with water and non-sweetened coffee or tea. This meal consists of 
780 kcal 40% from carbohydrate, 45% from fat and 20% from protein. 
 
 
Sampling of plasma glucagon, C-peptide, intact GLP-1, intact GIP, PP, cortisol, adrenaline 
and noradrenaline will be performed at fixed time points as described in Table 2. Blood 

11 
 
glucose concentrations will be determined at the same time points as glucagon until the 
start of the clamp test (test time -20 min to < 120 min), at 5 min intervals during the 
hypoglycemic clamp step, as well as at 15 min intervals during the recovery period (see 
Table 2). 
 
Table 2. Hyperinsulinemic, hypoglycemic clamp schedule 
Time 
(min) 
Procedures 
Period 
Glucagon,  GLP-1, GIP, 
PP and C-peptide 
Cortisol, adrenaline, 
noradrenalilne 
-20 
 
 
X 
 
-15 
Drug intake 
 
 
 
-5 
 
 
X 
X 
0 
Meal served 
 
 
 
15 
 
 
X 
 
30 
 
 
X 
 
45 
 
 
X 
 
60 
 
 
X 
 
90 
 
 
X 
 
120 
Begin insulin/ 
glucose infusion  
Clamp 1; 
3.5 mmol/l 
X 
X 
150 
 
 
X 
X 
165 
 
 
X 
X 
180 
 
Clamp 2; 
3.0 mmol/l 
X 
X 
210 
 
 
X 
X 
225 
 
 
X 
X 
240 
End of infusion/ 
Meal given 
 
X 
X 
255 
 
 
X 
 
270 
 
 
X 
 

12 
 
300 
 
 
X 
 
330 
 
End 
X 
X 
 
For the hyperinsulinemic, hypoglycemic clamp, patients receive a primed, continuous 
infusion of insulin with glucose infused at a variable rate to achieve 3.5 mmol/l. At the 
second hypoglycemic period, glucose infusion rate will be reduced to allow glucose to 
fall to 3.0 mmol/l. The insulin priming is as follows If initial glucose is below 7.5 mmol/l: 
90 ml/h min 0-4, 75 ml/min min 4-7, 60 ml/h min 7-10 and 45 ml/h therafter and If 
initial glucose is 7.5 mmol/l or above: 150 ml/h min 0-4, 125 ml/min min 4-7, 100 ml/h 
min 7-10 and 75 ml/h therafter; insulin concentration 400 pmol/m2). 
 
 
8. Randomization 
Randomization list will be prepared by statistician at Region Skåne and study medication 
will be distributed to the patient according to the randomization. The medication will be 
packed in 1 box per patient with 35 tablets in each box. 
 
9. Data management and safety registration 
Registration. The data are recorded in case and visit notes (hospital records) and 
entered in the CRF containing demographic and medical information, laboratory data, 
electrocardiograms, and the specific study-related results of any other tests or 
assessments. Specific worksheets will be the source documents for the variables derived 
from the hyperinsulinemic hypoglycemic clamps. These will be stored in the CRF. A 
certified study monitor will regularly inspect the CRFs to ensure accuracy with source 
data. 
 
Safety. At first visit, study subjects are informed of the characteristic symptoms of acute 
pancreatitis (persistent and abdominal pain).  Adverse events are acute pancreatitis and 
hypoglycemia and all other symptoms reflecting a change in the health situation 

13 
 
reported by the participating subjects. Adverse events are sought by non-directive 
questioning of the patient at each visit during the study, except directive questioning of 
symptoms of acute pancreatitis and hypoglycemia. Adverse events also may be detected 
when they are volunteered by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. All adverse events, including 
hypoglycemias, are recorded in the clinical case note and CRF and classified as of mild, 
moderate or severe degree, and a judgment whether it is related or unrelated to study 
medication. Hypoglycemia is defined as either a)symptomatic hypoglycemia, 
b)confirmed hypoglycemia (blood glucose <3.1 mmol/l) or c)hypoglycemia episode that 
require assistance for control. 
 
The SmPC will be used for Reference Safety Information (RSI) for expected Serious 
Adverse Events (SAE). These are defined as any untoward medical occurrence that 
- 
Results in death 
- 
Is life threatening (which refers to an event/reaction in which the patient was at risk 
of death at the time of the event/reaction; it does not refer to an event/reaction 
which hypothetically might have caused death if it were more severe), 
- 
Requires inpatient hospitalization or results in prolongation of existing 
hospitalization, 
- 
Results in persistent or significant disability/incapacity, or 
- 
Is a medically important event or reaction. 
Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious, such as important medical events that might 
not be immediately life-threatening or result in death or hospitalization, but might 
jeopardize the patient or might require intervention to prevent one of the other 
outcomes listed in the definition above. 
The investigator informs the sponsor on an SAE within 24 hours and an AE within 7 days 
and the sponsor reports SAE to the sponsor and to MSD (through fax 08-578 13 900) 
within 24 hours. 

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Access to the randomization code during the study. The code must be broken when 
knowledge of the study treatment is essential for patient´s management or if required 
for a regulatory purpose or in case of Serious Unexpected Suspected Adverse Reaction 
(SUSAR). In such cases, the investigator or responsible representative contact the 
hospital pharmacy who has 24h access to a decode envelope. SUSAR will also be 
reported to the health authorities (through the EudraVigilance database) and unblinded 
by the sponsor. Each treatment will be supplied to the local pharmacy with a decoding 
material that contains the name of the treatment. It is the responsibility of the 
pharmacist to ensure that these decoding materials are stored safely, but are readily 
available to relevant staff. If the blind is broken, the investigator will document the date, 
the time of the day, and the reason for code breaking. 
 
10. Withdrawal criteria 
A subject may be withdrawn from the trial at the discretion of the Sponsor if judged 
non-compliant with trial procedures or due to a safety concern. 
A subject must be withdrawn if the following applies: 
1. 
Withdrawal of consent: The subject may withdraw at will at any time.  
2. 
Protocol deviation: If a protocol violation or concurrent illness occurs, 
which, in the clinical judgement of the Sponsor, may invalidate the trial, the subject will 
be withdrawn by the Sponsor. 
3. 
Change in medication: If a subject changes the dose of their existing 
medications during the trial, which, in the clinical judgement the Sponsor, may 
invalidate the trial, the subject will be withdrawn by the Sponsor. 
4. 
If a subject reports symptoms, which are considered unacceptable by the 
subject or the Sponsor, such as acute pancreatitis, the subject will be withdrawn from 
the trial.   
  
 

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11. End-points 
Primary end-point is the effect of sitagliptin on glucagon counter-regulation to 
hypoglycemia measured as ∆glucagon (min 180-150) and ∆glucagon (min 240-210) 
 
Secondary end-points are  
the effect of sitagliptin compared to placebo on the counter-regulatory 
hormones cortisol, adrenaline and noradrenaline at the hypoglycemic clamp steps, 
determined as ∆ for these variables min 180-150 and 240-210, respectively,  
the effect of sitagliptin compared to placebo on the insulin secretory rate 
estimated from the C-peptide responses and GLP-1 and GIP levels at the hypoglycemic 
clamp steps determined as ∆ for these variables min 180-150 and 240-210, respectively. 
. 
  
12. Sample size calculation 
The sample size calculation was based on detecting a difference between sitagliptin and 
placebo in the mean glucagon level of the last 30 min of a hypoglycemic clamp step, 
after 4 weeks of treatment. In our previous study on the effect of the DPP-4 inhibitor 
vildagliptin on the glucagon counter-regulation to hypoglycaemia (8) we found that the 
30 min glucagon response to steady-state hypoglycaemia during a clamp was 34±7 ng/l.  
Based on these data and expecting similar variation in the data in the elderly population 
studied here, a power analysis aiming at showing a 30% difference in glucagon levels by 
sitagliptin with 90% sensitivity results in requirement of 24 subjects when doing paired 
analysis. To allow for even more safe statistics and allow for discontinuation, we will 
recruit four additional subjects; hence we aim at including 28 patients in the study. 
 
13. Statistical evaluation 

16 
 
The variables (glucagon, C-peptide, GLP-1, GIP, PP, cortisol, adrenaline and 
notradrenaline responses to hypoglycemia) will be analyzed using a 2-sided test for 
superiority of sitagliptin versus placebo. The Completers population alone will be used.  
 
14. Monitoring, data handling and archiving 
The study will be monitored by a certified monitor who is not involved in the study. 
Study documentation, including informed consent, CRF and laboratory test results, will 
during the proceeding of the study be kept at the Clinical Research Unit. Sponsor and 
study nurse will have access to these documents. For statistical analysis, anonymous 
data file will be created at the Biomedical Center, Lund University. Sponsor will have 
access to this file. After completion of the study, all documents will be archived at the 
Biomedical Center at Lund University for15 years. 
 
15. Risk-benefit analysis 
This is a study aiming at understanding the glucagon counter-regulation to 
hypoglycemia after treatment with the DPP-4 inhibitor sitagliptin in patients with 
metformin-treated type 2 diabetes. Since the study is a mechanistic study to understand 
whether the low risk of hypoglycemia seen during treatment with sitagliptin is mediated 
by enhanced counter-regulation, the study is of no immediate benefit for the 
participating patients. The results of the study will, however, be beneficial for the 
patient group treated with this therapy since it will provide rationale for future 
treatment by allowing the most efficacious therapy to prevent hypoglycemia to be 
prescribed to elderly subjects with T2DM. The risk for the patients participating in the 
study is minimal since sitagliptin has been shown to be safe with low risk of adverse 
events, even in long-term studies, and the risk with hyperinsulinemic hypoglycemic 
clamp is minimal in view of the extensive experience with this test at the Clinical 
Research Department.  

17 
 
16. Insurance 
Insurance is covered by the regular healthy authorities. 
 
17. Study timeline: 
 - Q4/2014: Obtaining all permissions and planning of the logistics 
 - Q1/2015: Screening of patients 
- Q1-Q4/2015: Performing the study with FPFV planned for January 2015 and LPFV 
planned for October 2015 
 - Q1/2016: Analyses 
18. Publication   
Results will be presented at international meetings and published in international 
scientific journal. 
 
19. References 
1. Drucker DJ (2003) Enhancing incretin action for the treatment of type 2 diabetes. 
Diabetes Care 26:2929-2940. 
2. Ahrén B (2010) Use of DPP-4 inhibitors in type 2 diabetes: focus on sitagliptin. Diabet 
Metab Syndr Obes 3:31-41. 
3. Dunning BE, Foley JE, and Ahrén B (2005) Alpha cell function in health and disease: 
influence of glucagon-peptide-1. Diabetologia 48:1700-1713. 
4. Herman GA et al. (2006) Effect of single oral doses of sitagliptin, a dipeptidyl 
peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose 
tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 9:4612-
4619. 
5. Muscelli E et al. (2012) Mechanisms for the antihyperglycemic effect of sitagliptin in 
patients with type 2 diabetes. J Clin Endocrinol Metab. 97:2818-2826. 
6. Ahrén B (2013) Avoiding hypoglycemia: a key to success for glucose-olowering 
therapy in type 2 diabetes. Vasc Health Risk Manag 9:155-163. 

18 
 
7. Desouza CV, Bolli GB, Fonseca CV (2010) Hypoglycemia, diabetes, and cardiovascular 
events. Diabetes Care 33:1389-1394. 
8. Ahrén B, Schweizer A, Dejager S, et al (2009) Vildagliptin enhances islet 
responsiveness to both hyper- and hypoglycemia in patients with type 2 
diabetes. J Clin Endocrinol Metab; 94;1236-1243. 
 
 
 
Lund, December12, 2015 
 
 
Bo Ahrén, sponsor