Received: 31 May 2018 Revised: 5 July 2018 Accepted: 14 July 2018

DOI: 10.1111/dom.13473

ORIGINAL ARTICLE

A randomized clinical trial of the efficacy and safety of

sitagliptin compared with dapagliflozin in patients with type
2 diabetes mellitus and mild renal insufficiency: The
CompoSIT-R study
Russell Scott MD1 | Jerry Morgan BS2 | Zachary Zimmer PhD2 | Raymond L. H. Lam PhD2 |
Edward A. O'Neill PhD2 | Keith D. Kaufman MD2 | Samuel S. Engel MD2 |
Annaswamy Raji MD2

1
Lipid and Diabetes Research Group,
Christchurch School of Medicine, Aim: To compare the efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin with
Christchurch, New Zealand the sodium-glucose transporter-2 inhibitor dapagliflozin in patients with type 2 diabetes and
2
Merck & Co., Inc., Kenilworth, New Jersey mild renal insufficiency.
Correspondence Materials and Methods: Patients with HbA1c ≥7.0 to ≤9.5% (≥53 to ≤80 mmol/mol) and esti-
Annaswamy Raji, MD, Merck & Co., Inc.,
mated glomerular filtration rate ≥60 to <90 mL/min/1.73m2 on metformin (≥1500 mg/d)  sul-
P.O. Box 2000, RY34-A214, Rahway, NJ
07065. fonylurea were randomized to sitagliptin 100 mg (n = 307) or dapagliflozin 5 mg titrated to
Email: [email protected] 10 mg (n = 306) once daily for 24 weeks. A longitudinal data analysis model was used to test
Funding information the primary hypothesis that sitagliptin is non-inferior to dapagliflozin in reducing HbA1c at Week
This study was funded by Merck Sharp & 24, with superiority to be tested if non-inferiority is met. ClinicalTrials.gov NCT02532855.
Dohme Corp., a subsidiary of Merck & Co., Inc.,
Results: Baseline mean HbA1c (% [mmol/mol]) was 7.7 (60.9) and 7.8 (61.2), and mean eGFR
Kenilworth, NJ, USA.
(mL/min/1.73m2) was 79.4 and 76.9 for the sitagliptin and dapagliflozin groups, respectively.
After 24 weeks, the between-group difference in least squares mean (95% CI) changes from
baseline in HbA1c was −0.15% (−0.26, −0.04) (−1.67 mmol/mol [−2.86, −0.48]), P = 0.006,
meeting the prespecified criteria for declaring both non-inferiority and superiority of sitagliptin
versus dapagliflozin. The HbA1c goal of <7% (<53 mmol/mol) was met by 43% (sitagliptin) and
27% (dapagliflozin) of patients. No meaningful between-group difference was observed in a pre-
specified analysis of 2-hour incremental postprandial glucose excursion. A review of adverse
events (AEs) was notable for a lower incidence of drug-related AEs with sitagliptin compared
with dapagliflozin.
Conclusions: In patients with type 2 diabetes, mild renal insufficiency and inadequate glycaemic
control on metformin  sulfonylurea, sitagliptin treatment resulted in greater improvement in
glycaemic control compared with dapagliflozin and was generally well tolerated.

KEYWORDS

clinical trial, dapagliflozin, sitagliptin, type 2 diabetes

1 | I N T RO D UC T I O N (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2,

CKD stages 3-5) in patients with type 2 diabetes has been estimated
Chronic kidney disease (CKD) is a common complication of type 2 dia- at approximately 22%, a larger proportion (38%) have mild renal insuf-
betes. While the prevalence of moderate or severe renal insufficiency ficiency (eGFR ≥60 and <90 mL/min/1.73m2, stage 2).1 These rates

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
2876 wileyonlinelibrary.com/journal/dom Diabetes Obes Metab. 2018;20:2876–2884.
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SCOTT ET AL. 2877

increased in those with type 2 diabetes ≥65 years of age, among Written informed consent was obtained from all study
whom 43% have moderate or severe renal insufficiency and 48% have participants.
mild renal insufficiency.1 While it is widely recognized that the choice
of an antihyperglycaemic agent (AHA) for treatment of type 2 diabetes 2.2 | Study design
should be influenced by renal function, only CKD stages 3-5 are usu-
This was a multinational, randomized, double-blind, active
ally considered relevant to that decision.2 Additionally, clinical studies
comparator-controlled, parallel-group trial, including a 2-week screen-
in patients with CKD are usually focused on patients with eGFR
ing period, a 2-week single-blind placebo run-in period, a 24-week
<60 mL/min/1.73m2. While patients with type 2 diabetes and mild
double-blind treatment period and a post-treatment telephone or in-
renal insufficiency are typically included in Phase III studies of antihy-
person contact 14 days after the last dose of blinded study drug
perglycaemic therapies, the specific impact of mild renal insufficiency (Figure 1).
on the efficacy and safety of most AHAs has not generally been pro- After the run-in period, patients were randomized centrally using
spectively evaluated in clinical trials. an interactive voice response system, in a 1:1 ratio, to sitagliptin
Among the classes of oral AHAs available for treatment of 100 mg/d and placebo matching dapagliflozin or dapagliflozin and pla-
type 2 diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors are con- cebo matching sitagliptin. Dapagliflozin/matching placebo was initi-
sidered both efficacious and well tolerated across the range of ated at 5 mg and titrated up to 10 mg at Week 4, unless, in the
renal function, although dose adjustment to control drug exposure opinion of the investigator, a patient was unable to tolerate uptitra-
is sometimes required.3 In contrast, the sodium/glucose tion to 10 mg, in which case the dose was to remain at 5 mg. Dapagli-
transporter-2 (SGLT-2) inhibitors have reduced efficacy in patients flozin 10 mg/matching placebo was downtitrated to dapagliflozin
with moderate to severe renal insufficiency due to their mecha- 5 mg/matching placebo if the higher dose was not tolerated. Patients
nism of action.4 with eGFR persistently <50 mL/min/1.73m2 (CKD-epi formula) from
The CompoSIT-R (comparison of sitagliptin with dapagliflozin in Visit 3/Day 1 through 1 day prior to Visit 5/Week 10 or persistently
mild renal impairment) study was a prospective, randomized clinical <60 mL/min/1.73m2 (calculated by the CKD-epi formula) from Visit
trial comparing the efficacy and safety of the DPP-4 inhibitor sitaglip- 5/Week 10 through Visit 7/Week 24 were discontinued from study
tin with the SGLT-2 inhibitor dapagliflozin in patients with type 2 dia- medication. Other discontinuation criteria for hyperglycaemia, hypo-
betes and mild renal insufficiency. glycaemia, and liver function are listed in the supporting information
for this article.
A mixed-meal tolerance test (MMTT) was performed at randomi-
2 | METHODS zation (Day 1), prior to the first dose of double-blind study drug and
background medication, and at Week 24 (or discontinuation visit). At
2.1 | Participants Week 24 (or discontinuation visit) patients took study drug and back-
ground medication approximately 1 hour before consuming the stan-
Eligible patients were male or female, ≥25 years of age, with type
dard meal for the MMTT. The MMTT meal consisted of 2 nutrition
2 diabetes and mild renal insufficiency (eGFR ≥60 and <90 mL/
2 bars and 1 nutrition drink and had a nutrient content of 660 kcal
min/1.73m , calculated by the Chronic Kidney Disease Epidemiology
(96 g carbohydrate, 20 g fat and 28 g protein).
Collaboration [CKD-epi] serum creatinine equation5). Eligible patients
This clinical trial (MK-0431-838; ClinicalTrials.gov Identifier:
were on a stable dose of metformin (≥1500 mg/d) alone or in combi-
NCT02532855; EudraCT: 2014-005525-13) was conducted in accor-
nation with a sulfonylurea (SU) (at a dose of ≥50% of the maximum
dance with the principles of Good Clinical Practice and was approved
labelled dose in the country of the investigational site) for ≥8 weeks,
by the appropriate institutional review boards and regulatory
with an HbA1c ≥7.0% and ≤9.5% (≥53 mmol/mol to ≤80 mmol/mol)
agencies.
at screening, and a fasting finger-stick glucose >6.1 mmol/L and
<14.4 mmol/L at randomization.
Patients were excluded from the study if they had type 1 diabetes, 2.3 | Study evaluations
a history of ketoacidosis, active liver disease, significant cardiovascular The primary objectives of this study were: (i) after 24 weeks, to assess
disease, malignancy or haematological disorders, or if, in the opinion the effect of the addition of sitagliptin compared with the addition of
of the investigator, they were at high risk for volume depletion, hypo- dapagliflozin on HbA1c; and (ii) over 24 weeks, to assess the overall
tension and/or electrolyte imbalances. Patients were also excluded if safety and tolerability of sitagliptin in comparison to that of dapagliflo-
they had been previously treated with any AHAs other than metfor- zin. The primary study hypothesis was that after 24 weeks, the
min or, if on dual therapy, metformin in combination with an SU, change from baseline in HbA1c in subjects treated with the addition
within 12 weeks prior to screening. Laboratory exclusion criteria of sitagliptin is non-inferior to that in subjects treated with the addi-
included serum alanine aminotransferase or aspartate aminotransfer- tion of dapagliflozin.
ase levels >2 times the upper limit of normal (ULN), haemoglobin Secondary objectives were assessment of 2-hour incremental
<120 g/L (male) or <110 g/L (female), triglycerides >6.8 mmol/L or postprandial glucose excursion (PPGE), 2-hour postprandial glucose
thyroid-stimulating hormone outside the central laboratory normal (PPG), fasting plasma glucose (FPG), 2-hour postprandial area under
range. the curve (AUC0-120) for insulin and glucagon, the postprandial insulin
 14631326, 2018, 12, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13473 by Sheffield Hallam University, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2878 SCOTT ET AL.

At Visit 1/Screening: Sitagliptin 100 mg q.d. (n = 307)

• ≥ 25years of age with type 2 diabetes and
eGFR ≥60 and <90 mL/min/1.73m2
and on
• Metformin ≥1500 mg/day for ≥8 weeks
with HbA1c ≥7.0 and ≤9.5% R
or on
• Metformin ≥1500 mg/day + an SU (at a Dapagliflozin 10 mg q.d. (n = 306)1
dose of ≥50% of maximum labelled dose)
with HbA1c ≥7.0 and ≤9.5%

At Visit 2/Week -2:

• eGFR ≥60 and <90 mL/min/1.73m2
and
• ≤20 mL/min/1.73m2 different from
the qualifying Visit 1/Screening value

Screening Period Placebo Run-in Double-blind Treatment Period

All subjects remain on their stable regimen of background AHAs (i.e., stable dose(s) of metformin ≥ 1500 mg/day ± SU agent3)

2 weeks2
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7
Screening Week -2 Day 1 Week 4 Week 10 Week 16 Week 24

FIGURE 1 Study design. eGFR, estimated glomerular filtration rate; q.d., once daily; SU, sulfonylurea; R, randomization.1Subjects initiated
dapagliflozin 5 mg q.d. at Randomization/Visit 3/Day 1 and were to uptitrated to dapagliflozin 10 mg q.d. at Visit 4/Week 4. 2The interval
between Visit 1 and Visit 2 for eligible subjects was to be at least 2 weeks and no more than approximately 6 weeks. 3Subjects entering the study
on metformin remained on a stable dose of metformin; subjects entering on metformin + an SU remained on stable doses of both agents

AUC0-120 to glucagon AUC0-120 ratio, and the proportion of subjects 2.6 | Statistical analyses
at the HbA1c goal of <7.0% (<53 mmol/mol) after 24 weeks of treat-
The full analysis set ([FAS], all randomized subjects who received at
ment. An exploratory objective was to assess the effect of the addi-
least one dose of study treatment and had a baseline or a postbaseline
tion of sitagliptin compared with dapagliflozin on medical resource
measurement) served as the primary analysis population for the change
utilization (i.e. unplanned telephone contacts or visits to healthcare
from baseline HbA1c, percentages of individuals at HbA1c goal, 2-hour
providers) during the 24-week treatment period plus the 2-week
incremental PPGE, 2-hour PPG, and FPG. The per protocol
safety follow-up period.
(PP) population (all randomized subjects who received at least one dose
of study treatment and had a baseline and a Week 24 measurement,
without a protocol deviation that would affect or confound the mea-
2.4 | Efficacy endpoints
sure of efficacy) was used as a primary analysis population for glucagon
Glycaemic efficacy endpoints were change from baseline in HbA1c, AUC0-120, insulin AUC0-120, and insulin AUC0-120 to glucagon AUC0-120
2-hour incremental PPGE, 2-hour PPG, FPG, postprandial insulin, glu- ratio. A longitudinal data analysis (LDA) model6 was used to evaluate
cagon, and insulin:glucagon ratio at Week 24, and proportion of the continuous endpoints with fixed effects for treatment, time, back-
patients who achieved an HbA1c goal of <7% (<53 mmol/mol) at ground AHA (metformin alone, or metformin in combination with an
Week 24. SU), the interaction of time by background AHA, and the interaction of
time by treatment, with a constraint that the true mean at baseline is
common to all treatment groups (which is valid due to randomization).
2.5 | Safety endpoints
Data after the last dose of study medication plus an offset of 5 days
Safety endpoints were incidences of adverse events (AEs), percent- was excluded from primary LDA analyses. Missing data were handled
ages of patients meeting predefined limits of change (PDLC) in lab- implicitly by the LDA model.The primary hypothesis regarding the non-
oratory parameters, and change from baseline at Week 24 in inferiority of sitagliptin versus dapagliflozin in decreasing HbA1c was
laboratory parameters, vital signs and body weight. AEs of hypogly- assessed using the estimated between-treatment difference from the
caemia, documented hypoglycaemia and severe hypoglycaemia LDA model. If the upper bound of the two-sided 95% confidence inter-
were predefined AEs of interest. In subjects completing the clinical val (CI) for the mean difference between sitagliptin and dapagliflozin
trial on study medication, safety data were collected from the was less than the non-inferiority margin (δ = 0.3%), then sitagliptin
initiation of treatment until 2 weeks after discontinuation of treat- would be declared non-inferior to dapagliflozin; if the upper bound was
ment. For subjects who discontinued study medication prema- <0.0%, sitagliptin would be declared superior to dapagliflozin. Evalua-
turely, safety data were collected from the initiation of treatment tion of the percentage of individuals at the HbA1c goal of <7.0%
until Week 24. (<53 mmol/mol) at Week 24 was based on estimated rates and CIs for
 14631326, 2018, 12, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13473 by Sheffield Hallam University, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SCOTT ET AL. 2879

between-group rate differences computed using the Miettinen and TABLE 1 Baseline demographic, anthropometric and disease
7
Nurminen method. For this analysis, multiple imputations of missing characteristics of study treatment groups

Week 24 data, using techniques proposed by Rubin,8 were based on Sitagliptin Dapagliflozin
n = 307 n = 306
the LDA model used for analysis of HbA1c. After imputations, patients
Age, years 67.7  8.5 66.6  8.6
were categorized as either at, or not at, the HbA1c goal at Week 24.
Female, n (%) 138 (45.0) 120 (39.2)
Analysis of safety data used the population of all randomized
Race, n (%)
patients who received at least one dose of study treatment. Safety and
White 240 (78.2) 234 (76.5)
tolerability were assessed by clinical review of all relevant parameters,
Multiple 30 (9.8) 39 (12.7)
including AEs, laboratory tests, ECG, vital signs and body weight, during
American Indian/ 18 (5.9) 14 (4.6)
the treatment period and through 14 days after treatment ended. Point Alaska native
estimates with 95% CIs were calculated using the method of Miettinen Asian 11 (3.6) 7 (2.3)
and Nurminen7 for between-group comparisons for AEs with incidence Black or 8 (2.6) 11 (3.6)
of ≥4 patients in either treatment group, and for AEs of hypoglycaemia, African American
Native Hawaiian or 0 (0.0) 1 (0.3)
documented hypoglycaemia and severe hypoglycaemia. Analysis of
other Pacific Islander
hypoglycaemia was performed separately by background AHA,
Ethnicity, n (%)
i.e. metformin alone and metformin in combination with an
Neither Hispanic 195 (63.5) 194 (63.4)
SU. Descriptive statistics were calculated for all other safety endpoints. nor Latino
A sample size of 278 participants per treatment group was esti- Hispanic or Latino 109 (35.5) 109 (35.6)
mated to provide >99% power to establish that sitagliptin is non- Not reported 3 (1.0) 2 (0.7)
inferior to dapagliflozin in lowering HbA1c at an overall one-sided, Unknown 0 (0.0) 1 (0.3)
2.5% α-level, assuming an underlying treatment difference of 0%, and Body weight, kg 87.4  20.2 88.7  18.0

90% power to demonstrate the superiority of sitagliptin versus dapa- BMI, kg/m2 31.8  5.7 31.5  5.3

gliflozin in lowering HbA1c at an overall one-sided, 2.5% α-level, if the HbA1c, % 7.7  0.7 7.8  0.7
(mmol/mol) (60.9  7.9) (61.2  8.0)
underlying treatment difference in HbA1c is −0.2%.
FPGa, mmol/L 9.0  2.2 9.2  2.3
The study-wise type I error rate was controlled using an ordered
eGFR, mL/ 79.4  11.3 76.9  12.3
testing procedure. First, non-inferiority of sitagliptin compared with min/1.73 m2
dapagliflozin for change from baseline in Hba1c was tested. When the Duration of type 2 10.5  7.0 10.7  7.4
success criterion for non-inferiority was met, superiority was diabetes, years
Background medication
assessed. When the test for superiority was successful, the secondary
Metformin alone 212 (69.1) 225 (73.5)
hypothesis for postprandial glucose excursion was tested. All three
Metformin + SU 95 (30.9) 81 (26.5)
tests were conducted at α = 0.025 (one-sided).
Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; SU, sul-
fonylurea. Values are mean  standard deviation unless otherwise noted.
a
To convert to mg/dL multiply mmol/L value by 18.
3 | RESULTS

group initiated treatment at a dose of 5 mg/d; 94.8% (n = 290) upti-

3.1 | Patient disposition and characteristics and
trated to 10 mg/d (Table S3).
dapagliflozin doses
The study was conducted at 185 sites in 24 countries (a list of participat-
3.2 | Efficacy
ing investigators can be found in Table S1). A total of 2770 patients were
screened and 614 were randomized, 307 to sitagliptin and 307 to dapagli- After 24 weeks of treatment, the least squares (LS) mean change from
flozin. The study was initiated on October 21, 2015 and completed on baseline in HbA1c (95% CI) was significantly greater with sitagliptin
October 10, 2017. Of the 614 randomized patients, 595 (96.9%) com- 100 mg (−0.51% [−0.60, −0.43] [−5.58 mmol/mol {−6.52, −4.65}])
pleted the study, and 494 (80.5%) completed on study medication compared with dapagliflozin (−0.36% [−0.45, −0.27] [−3.92 mmol/mol
(Table S2). One patient in the dapagliflozin group, associated with a {−4.88, −2.95}]) (Table 2 and Figure 2A); the between-group differ-
protocol violation, was randomized but did not take a dose of study medi- ence was −0.15% (−0.26, −0.04) (−1.67 mmol/mol [−2.86, −0.48]);
cation; this patient was included in the population of randomized patients P = 0.006, thus meeting the primary efficacy hypothesis that sitaglip-
for the disposition table but was excluded from all efficacy and safety tin is non-inferior to dapagliflozin. In both treatment groups, a near
analyses. maximum reduction in HbA1c was observed by Week 10 (the first on-
Baseline demographics and clinical parameters were similar treatment measurement time-point) and improved glycaemic efficacy
between the treatment groups (Table 1). The mean age of patients in continued through the end of treatment (Figure 2A). At Week 24, the
the study was 67.1 years, approximately 42% were female, mean BMI between-group difference (sitagliptin - dapagliflozin) in patients (95%
2
was 31.6 kg/m , mean HbA1c was 7.7% (61.1 mmol/mol), and mean CI) with HbA1c <7.0% (53 mmol/mol) was 15.5% (7.7, 23.2)
duration of diabetes was 10.6 years. All patients in the dapagliflozin (Figure 2B).
 14631326, 2018, 12, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13473 by Sheffield Hallam University, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2880 SCOTT ET AL.

TABLE 2 Efficacy endpoints at week 24

Parameter Sitagliptin Dapagliflozin

HbA1c, % (mmol/mol) (n = 307) (n = 306)
Baseline 7.7  0.7 (60.9  7.9) 7.8  0.7 (61.2  8.0)
Week 24 7.1  0.7 (54.1  7.7) 7.3  0.6 (56.1  7.0)
Change from baselinea −0.51 (−0.60, −0.43) (−5.58 [−6.52, −4.65]) −0.36 (−0.45, −0.27) (−3.92 [−4.88, −2.95])
* *
Change vs. dapagliflozin b
−0.15 (−0.26, −0.04) (−1.67 [−2.86, −0.48]) -
2 h-incremental PPGEc, mmol/L (n = 295) (n = 290)
Baseline 5.3  3.1 5.3  2.6
Week 24 4.0  2.8 4.3  2.6
Change from baseline a
−1.3 (−1.7, −1.0) −1.0 (−1.4, −0.7)
Change vs. dapagliflozinb −0.3 (−0.7, 0.1) -
2 h PPGc, mmol/L (n = 296) (n = 292)
Baseline 14.3 3.7 14.4 3.6
Week 24 12.0 3.3 12.2 3.1
Change from baselinea −2.4 (−2.8, −2.0) −2.2 (−2.6, −1.8)
Change vs. dapagliflozinb −0.2 (−0.7, 0.3) -
FPGc, mmol/L (n = 307) (n = 306)
Baseline 9.0 2.2 9.2 2.3
Week 24 8.0 1.8 7.8 1.6
Change from baselinea −0.9 (−1.1,-0.7) −1.1 (−1.3, −0.9)
Change vs. dapagliflozinb 0.2 (−0.1, 0.5) -
Insulin AUC0-120, mIU.hr/L (n = 96) (n = 94)
Baseline 158.5  118.8 148.4  98.9
Week 24 132.6  103.8 121.0  80.1
Change from baselinea −23.4 (−36.8, −9.9) −28.2 (−42.1, −14.4)
Change vs. dapagliflozinb 4.9 (−12.2, 22.0) -
Glucagon AUC0-120, pmol.hr/L (n = 85) (n = 88)
Baseline 45.5  18.6 52.3  47.1
Week 24 42.5  16.9 48.0  22.8
Change from baseline a
−4.2 (−8.8, 0.4) 0.2 (−4.4, 4.8)
Change vs. dapagliflozinb −4.4 (−10.1, 1.4) -
Insulin AUC0-120: Glucagon AUC0-120 (n = 83) (n = 81)
Baseline 4.1  3.7 3.7  3.2
Week 24 3.6  3.4 2.8  1.9
Change from baselinea −0.6 (−1.1, −0.0) −1.2 (−1.8, −0.7)
Change vs. dapagliflozinb 0.6 (−0.1, 1.3) -

Abbreviations: AUC, area under the curve; FPG, fasting plasma glucose; PPG, postprandial glucose; PPGE, postprandial glucose excursion. Values are mean
 standard deviation unless otherwise noted.
*P = 0.006.
a
Least squares (LS) mean (95% CI).
b
Difference in LS means (95% CI).
c
To convert to mg/dL multiply mmol/L value by 18.

At Week 24, there were no significant between-group differences percentage of patients with one or more in-person visits associated
in changes from baseline in LS mean 2-hour incremental PPGE, 2-hour with personal health concerns (not scheduled study visits) was similar
PPG, FPG, or in changes from baseline in postmeal glucagon in the sitagliptin and dapagliflozin groups (35.2% and 35.6%, respec-
AUC0-120, insulin AUC0-120, or the ratio of insulin AUC0-120 to gluca- tively); the total number of in-person visits was 247 in the sitagliptin
gon AUC0-120 (Table 2). group and 272 in the dapagliflozin group.
Throughout the trial (the 24-week treatment period plus the
2-week safety follow-up period), a lower percentage of patients in the
3.3 | Safety and tolerability
sitagliptin group had one or more telephone contacts associated with
personal health concerns (not study-scheduled contacts) compared During the study, 48.9% of patients in the sitagliptin group experi-
with the dapagliflozin group (6.8% vs. 11.8%, respectively). The total enced one or more AEs compared with 51.6% in the dapagliflozin
number of telephone contacts was also lower in the sitagliptin group group. No patients died. With the exception of drug-related AEs
than in the dapagliflozin group (30 vs. 58, respectively). The (7.8% in the sitagliptin group and 13.7% in the dapagliflozin group,
 14631326, 2018, 12, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13473 by Sheffield Hallam University, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SCOTT ET AL. 2881

TABLE 3 Adverse events (AEs) summary and AEs of hypoglycaemia

(A)
0.1 Sitagliptin Dapagliflozin
Change from baseline HbA1c, %

Patients, n (%) n = 307 n = 306 Differencea

0.0
With one or more
-0.1 AEs 150 (48.9) 158 (51.6) −2.8 (−10.1, 5.1)
(LS mean ± SE)

Drug-relatedb AEs 24 (7.8) 42 (13.7) −5.9 (−11.0, −1.0)

-0.2
Serious AEs 10 (3.3) 13 (4.2) −1.0 (−4.3, 2.2)
-0.3
Serious drug- 0 (0.0) 1 (0.3) −0.3
-0.4 relatedb AEs
Who died 0 (0.0) 0 (0.0) 0.0
-0.5
Who discontinued
-0.6 due to
An AE 10 (3.3) 10 (3.3) −0.0 (−3.0, 3.0)
-0.7
0 10 16 24 A drug-relatedb AE 5 (1.6) 6 (2.0) −0.3 (−2.8, 2.0)

Week A serious AE 3 (1.0) 3 (1.0) −0.0

A serious drug- 0 (0.0) 1 (0.3) −0.3
(B) relatedb AE
60
Patients on metformin (n = 212) (n = 225)
alone
∆ = 15.5%
(7.7, 23.2) With one or 7 (3.3) 8 (3.6) −0.3 (−4.0, 3.5)
50
more AE of
Percentage at HbA1c goal (%)

42.6 hypoglycaemia
(n =116)
Symptomaticc 5 (2.4) 7 (3.1) −0.8 (−4.2, 2.7)
40
Documentedd 5 (2.4) 7 (3.1) −0.8 (−4.2, 2.7)
Severee 1 (0.5) 2 (0.9) −0.4
27.0 Asymptomaticf 2 (0.9) 2 (0.9) 0.1
30
(n=71)
Patients on metformin (n = 95) (n = 81)
and a sulfonylurea
20 With one or more 15 (15.8) 13 (16.0) −0.3 (−11.6, 10.7)
AE of
hypoglycaemia

10 Sitagliptin Symptomaticc 13 (13.7) 10 (12.3) 1.3 (−9.2, 11.5)

Dapagliflozin Documentedd 13 (13.7) 9 (11.1) 2.6 (−7.8, 12.6)
Severee 0 (0.0) 0 (0.0) 0.0
0 f
Asymptomatic 6 (6.3) 4 (4.9) 1.4 (−6.5, 8.9)

FIGURE 2 HbA1c measures through week 24: A, LS mean  SE a

Difference in % vs. dapagliflozin; estimate (95% CI) was computed only
change from baseline HbA1c (%); black circles = sitagliptin, open for AE summary and hypoglycaemia endpoints with at least 4 patients
circles = dapagliflozin; B, percentage of patients at goal of having events in one or more treatment groups.
b
Assessed by the investigator as related to study drug.
HbA1c <7% at week 24. For both A and B, results were calculated c
Symptomatic hypoglycaemia: episode with clinical symptoms attributed
using the LDA model described in Methods to hypoglycaemia, without regard to glucose level.
d
Documented symptomatic hypoglycaemia: episode with clinical symp-
toms attributed to hypoglycaemia with a documented glucose level of
between-group difference [95% CI] −5.9 [−11.0, −1.0]), summary mea-
≤3.9 mmol/L (≤70 mg/dL).
e
sures of AEs were similar between groups (Table 3). Severe hypoglycaemia: episode that required assistance, either medical
The incidences of AEs and of specific AEs by system organ class or non-medical. Episodes with a markedly depressed level of conscious-
ness, a loss of consciousness, or seizure were classified as having
(SOC) reported for ≥4 patients in at least one treatment group were required medical assistance, whether or not medical assistance was
generally similar between the treatment groups (Table S4). Infections obtained.
f
Asymptomatic hypoglycaemia: finger-stick glucose values ≤3.9 mmol/L
and infestations was the only SOC in which the 95% CI for the (≤70 mg/dL) without symptoms.
between-group difference in incidence excluded 0; in this SOC the
incidence of AEs was higher in the dapagliflozin group (n = 66 sitagliptin n = 5 [1.6%], dapagliflozin n = 0 [0.0%], difference [in %]
[21.6%]) than in the sitagliptin group (n = 46 [15.0%]), between-group = 1.6 [0.4, 3.8]; vomiting: sitagliptin n = 4 [1.3%], dapagliflozin n = 0
difference (in %) = −6.6 [−12.7, −0.5], in part due to a higher observed [0.0%], difference [in %] = 1.3 [0.1, 3.3]) and edema peripheral (higher
incidence of genital mycotic infections in the dapagliflozin group. The in the dapagliflozin group n = 4 [1.3%] than in the sitagliptin group,
incidences of specific AEs were generally similar between the sitaglip- n = 0 [0.0%]; difference [in %] = −1.3 [−3.3, −0.1]).
tin and dapagliflozin groups during the treatment period. The only The incidences of patients with documented symptomatic hypo-
specific AEs that occurred at a higher observed incidence in one group glycaemia, severe hypoglycaemia and asymptomatic hypoglycaemia
compared with the other (95% CI for the between-group difference in were similar between the two treatment groups (Table 3). There were
incidence excluded 0) were abdominal pain and vomiting (higher in higher incidences of patients with AEs of hypoglycaemia in the popu-
the sitagliptin group than in the dapagliflozin group - abdominal pain: lation whose background medication included an SU (15.8% and
 14631326, 2018, 12, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13473 by Sheffield Hallam University, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2882 SCOTT ET AL.

16.0% in the sitagliptin and dapagliflozin groups, respectively) com- peptides which stimulate the release of insulin in a glucose-dependent
pared with the population not using an SU (3.3% and 3.6% in the sita- manner,12 while the mechanism of action of SGLT-2 inhibitors
gliptin and dapagliflozin groups, respectively) (Table 3). depends on renal function.13 However, until now, these two classes
There was a lower incidence of genital mycotic infection-related of AHAs have not been prospectively evaluated in a study limited to a
AEs in the sitagliptin group compared with the dapagliflozin group in population of patients with mild renal insufficiency.
both men (0.6% vs. 4.3%, respectively) and women (0.0% vs. 5.0%, In the current study, 24 weeks of treatment with the DPP-4
respectively). The incidences of volume depletion events were low in inhibitor sitagliptin was associated with greater reduction from base-
both groups (0.7% and 1.3% in the sitagliptin and dapagliflozin groups, line in HbA1c compared with the SGLT-2 inhibitor dapagliflozin; in
respectively). The proportions of participants who met PDLC criteria addition, after 24 weeks, more patients met the HbA1c goal of <7%
for laboratory parameters were similar between the sitagliptin and with sitagliptin than with dapagliflozin. Both treatments resulted in
dapagliflozin groups, and no clinically meaningful between-group dif- reductions from baseline in the 2-hour incremental PPGE and 2-hour
ferences were observed. The proportion of participants with at least PPG. While the reductions with sitagliptin were slightly larger than
one eGFR decrease from baseline >30% was similar between the sita- with dapagliflozin for both of these postprandial glycaemic endpoints,
gliptin and dapagliflozin groups (4.3% and 5.6%, respectively), while there were no significant between-group differences in these
three participants (1.0%) in the sitagliptin group and none in the dapa- parameters.
gliflozin group had at least one eGFR decrease from baseline >50%. Both treatments were generally well tolerated. The treatment
Greater decreases from baseline in mean systolic blood pressure and groups had similarly low rates of hypoglycaemia when the background
body weight were observed in the dapagliflozin group than in the sita- medication was metformin alone. When the background medication
gliptin group through Week 24 (Figure S1). included a sulfonylurea, the rates of hypoglycaemia were higher and
similar in both groups, as expected due to the influence of this class of
agent.14–16 With regard to the small increase in the observed inci-
4 | DISCUSSION dences of abdominal pain and vomiting with sitagliptin compared with
dapagliflozin, and of edema peripheral with dapagliflozin compared
In the clinical trial described here, in subjects with type 2 diabetes and with sitagliptin, imbalances of this type have not previously been
mild renal insufficiency, sitagliptin improved glycaemic control to a noted in pooled safety analyses of either treatment.17,18
greater extent than dapagliflozin. These data provide clinical trial evi- Overall, the incidence of drug-related AEs was higher in the dapa-
dence that can inform patient-centered decisions for the treatment of gliflozin group than in the sitagliptin group. Most of the drug-related
patients with type 2 diabetes and mild renal insufficiency.9 While clini- AEs that occurred at a higher observed incidence with dapagliflozin
cal trials have been conducted to study the safety and efficacy of vari- compared with sitagliptin were in categories of events that have been
ous AHAs in patients with moderate or severe renal insufficiency associated with SGLT-2 inhibitor treatment, in particular, genital
(eGFR <60 mL/min/1.73 m2), there are limited data defining the mycotic infections.19 The increased risk of genital mycotic infections
safety and efficacy profile of these agents in the cohort of patients is typical of the class of SGLT-2 inhibitors and is likely to be related to
with type 2 diabetes and mild renal insufficiency (eGFR ≥60 to the mechanism of action of the class, which results in increased gly-
<90 mL/min/1.73 m2). cosuria. Other between-group differences observed were related to
The overall prevalence of patients with type 2 diabetes and mild blood pressure and body weight. Greater mean decreases from base-
renal insufficiency is estimated to be nearly 40% and prevalence line in systolic blood pressure and body weight were observed in the
increases with age (estimated to be nearly 50% in patients with type dapagliflozin group than in the sitagliptin group, as expected with
2 diabetes ≥65 years of age).1 Improved glycaemic control has been SGLT-2 inhibitors.20 No meaningful changes from baseline in mean
shown to reduce the risk of diabetic complications and to slow blood pressure or body weight were observed in the sitagliptin group.
progression of renal impairment.10 While metformin is the standard The results of this clinical trial may be of particular interest to
first-line pharmacologic intervention for the management of hypergly- physicians treating older patients with type 2 diabetes. Age is associ-
caemia in type 2 diabetes, additional therapies, including oral agents ated with reduction in renal function,21 and together with potentially
such as an SU, a DPP-4 inhibitor, or an SGLT-2 inhibitor are often pre- longer duration of diabetes, older patients are likely to be at increased
scribed in patients with mild renal insufficiency to achieve glycaemic risk of microvascular complications22 including renal impairment and
control. This paper provides data on the efficacy and safety of sitaglip- other co-morbidities.23
tin and dapagliflozin, in combination with other commonly used AHAs, A limitation of this study is that the results are relevant to the
in patients with type 2 diabetes and mild renal insufficiency. population studied and not necessarily to patients at other stages of
DPP-4 inhibitors are often used in patients with type 2 diabetes CKD. Another limitation is that the study evaluated sitagliptin and
and renal disease because these agents maintain efficacy and demon- dapagliflozin, and results cannot be extrapolated to other DPP-4 or
3
strate good tolerability across the spectrum of renal disease. On the SGLT-2 inhibitors. The strengths of this study are: its large sample
other hand, the efficacy of SGLT-2 inhibitors is reduced in patients size, which allowed a robust estimate of between-group differences in
with moderate renal insufficiency and is contraindicated in patients efficacy; the requirement for duplicate eGFR measurements during
with severe renal insufficiency.11 These clinical observations are con- screening that ensured a population with stable renal status; and upti-
sistent with the distinct mechanisms of action of the two classes of tration of dapagliflozin to its maximal approved dose (achieved in
agents. DPP-4 inhibitors stabilize the incretins GLP-1 and GIP, two approximately 95% of patients). Lastly, the CKD-epi formula used to
 14631326, 2018, 12, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13473 by Sheffield Hallam University, Wiley Online Library on [02/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SCOTT ET AL. 2883

estimate GFR in this study is considered more accurate and less likely RE FE RE NC ES
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