Insulin is the most effective therapy for achieving optimal glycemic control; however, many patients with type 2 diabetes on an intensified treatment regimen fail to achieve the recommended HbA1c target (1,2) and face the risk of adverse effects such as hypoglycemia and weight gain (3). The addition of sodium–glucose cotransporter 2 (SGLT2) inhibitors to a regimen of insulin therapy in this patient population has the potential to mitigate insulin-related weight gain and risk of hypoglycemia, with the added benefit of insulin dose reduction (4). Randomized controlled trials (RCTs) have shown improved clinical outcomes of SGLT2 inhibitors as monotherapy and as an add-on to oral and insulin therapy, but there is a paucity of real-world (RW) studies evaluating similar outcomes.

Data extracted from WebDR (5) was used to evaluate the RW clinical impact of SGLT2 inhibitors (initiation of canagliflozin or dapagliflozin between February 2014 and December 2016) as an add-on to insulin therapy in patients with type 2 diabetes not achieving glycemic targets (those with HbA1c >7% [>53 mmol/mol]). Empagliflozin was excluded because of inadequate sample size. Ethical approval was obtained from Western University’s Research Ethics Board.

A total of 411 patients met the study criteria. The study population had a mean age of 57 years, diabetes duration of 15 years, HbA1c of 9.01% (75 mmol/mol), BMI of 36.3 kg/m2, and median baseline insulin dose of 75 IU/day, with 33.4% on >100 IU/day and 71.8% presenting with one or more diabetes-related complications. Multiple regression analysis, adjusted for age, sex, and duration of diabetes, showed that both drugs were associated with a significant reduction in HbA1c, blood pressure, weight, and insulin dose at 3 and 6 months postinitiation (Table 1). Of particular interest in our research was the substantial insulin dose reduction observed in patients on a high insulin regimen (>100 IU/day). Canagliflozin use resulted in a reduction of the insulin dose by 17 IU at 3 and 6 months in patients on 101–200 IU/day. Patients on >200 IU of insulin/day experienced a reduction of 21 and 23 IU at 3 and 6 months, respectively, with canagliflozin and 77 and 71 IU at 3 and 6 months, respectively, with dapagliflozin. Despite these positive clinical outcomes and benefits, a relatively small percentage of patients achieved the glycemic target after SGLT2 addition.

Table 1

Baseline characteristics of study patients at the time of canagliflozin or dapagliflozin initiation and mean change from baseline in clinical outcomes at 3 and 6 months

ParametersCanagliflozin (N = 290)Dapagliflozin (N = 121)
BaselineΔ BL-3MP valueΔ BL-6MP valueBaselineΔ BL-3MP valueΔ BL-6MP value
HbA1c, % 9.03 ± 1.5 −0.69 <0.00 −0.88 <0.00 9.13 ± 1.5 −0.59 <0.00 −0.71 <0.00 
HbA1c, mmol/mol 75.2 ± 15.9 −7.00 <0.00 −9.00 <0.00 76.3 ± 15.9 −6.00 <0.00 −8.00 <0.00 
HbA1c at target,* % 0.0 15.5 <0.00 21.1 <0.00 0.0 13.3 0.00 10.0 0.00 
Weight, kg 107.2 ± 27.8 −1.40 0.00 −2.99 <0.00 102.2 ± 22.9 −0.96 0.00 −1.60 <0.00 
SBP, mmHg 131.7 ± 16.1 −5.10 <0.00 −6.40 <0.00 128.8 ± 14.2 −7.97 <0.00 −4.70 0.00 
DBP, mmHg 76.4 ± 9.4 −3.35 <0.00 −2.30 0.00 76.9 ± 9.9 −5.79 <0.00 −1.43 0.21 
LDL-C, mmol/L 1.9 ± 0.7 −0.01 0.70 −0.01 0.87 1.9 ± 0.8 −0.12 0.07 −0.15 0.03 
HDL-C, mmol/L 1.1 ± 0.3 0.02 0.05 0.02 0.07 1.1 ± 0.3 −0.00 0.65 0.01 0.18 
TC, mmol/L 3.9 ± 1.1 −0.01 0.84 0.00 0.94 4.2 ± 1.5 −0.12 0.11 −0.15 0.05 
TG, mmol/L 2.3 ± 2.4 −0.06 0.26 −0.08 0.14 3.1 ± 4.0 −0.14 0.14 −0.15 0.09 
ACR, mg/mmol 15.3 ± 59.8 −3.20 0.31 −0.56 0.85 11.0 ± 23.6 0.30 0.82 −0.03 0.97 
eGFR, mL/min 87.5 ± 16.4 −3.39 <0.00 −2.90 0.00 89.5 ± 16.4 −0.46 0.74 −0.91 0.51 
SCr, µmol/L 68.2 ± 16.4 3.64 <0.00 3.24 <0.00 69.4 ± 15.7 2.19 0.07 2.60 0.03 
K, mmol/L 4.4 ± 0.4 0.08 0.00 0.07 0.01 4.5 ± 0.5 0.03 0.38 0.03 0.34 
Insulin/day, IU 98.2 ± 83.8 −5.19 0.05 −5.80 0.03 90.1 ± 67.8 −3.40 0.36 −5.44 0.20 
 Basal 228 (78.6)     96 (79.2)     
 Prandial 56 (19.5)     25 (20.8)     
 Premixed 6 (1.9)     0 (0)     
Insulin/day, IU           
 0–100 190 (65.5) 1.53 0.55 0.76 0.77 85 (70.2) 0.22 0.94 −0.36 0.90 
 101–200 73 (25.2) −17.22 <0.00 −17.0 0.00 29 (23.8) 2.4 0.84 −4.05 0.05 
 >200 27 (9.4) −21.38 0.29 −23.1 0.26 7 (5.9) −77.4 0.02 −71.0 0.03 
Insulin/weight/day, IU/kg/day           
 0.1–0.4 80 (27.5) 0.03 0.25 0.06 0.00 27 (22.6) 0.07 0.18 0.08 0.12 
 0.5–1.0 111 (38.2) −0.06 0.09 −0.02 0.60 59 (48.4) 0.04 0.44 0.01 0.79 
 1.1–2.0 77 (26.4) −0.15 0.00 −0.13 0.01 27 (22.6) −0.05 0.69 −0.10 0.42 
 >2.0 23 (7.9) −0.34 0.28 −0.39 0.20 8 (6.5) −0.57 0.01 −0.55 0.01 
ParametersCanagliflozin (N = 290)Dapagliflozin (N = 121)
BaselineΔ BL-3MP valueΔ BL-6MP valueBaselineΔ BL-3MP valueΔ BL-6MP value
HbA1c, % 9.03 ± 1.5 −0.69 <0.00 −0.88 <0.00 9.13 ± 1.5 −0.59 <0.00 −0.71 <0.00 
HbA1c, mmol/mol 75.2 ± 15.9 −7.00 <0.00 −9.00 <0.00 76.3 ± 15.9 −6.00 <0.00 −8.00 <0.00 
HbA1c at target,* % 0.0 15.5 <0.00 21.1 <0.00 0.0 13.3 0.00 10.0 0.00 
Weight, kg 107.2 ± 27.8 −1.40 0.00 −2.99 <0.00 102.2 ± 22.9 −0.96 0.00 −1.60 <0.00 
SBP, mmHg 131.7 ± 16.1 −5.10 <0.00 −6.40 <0.00 128.8 ± 14.2 −7.97 <0.00 −4.70 0.00 
DBP, mmHg 76.4 ± 9.4 −3.35 <0.00 −2.30 0.00 76.9 ± 9.9 −5.79 <0.00 −1.43 0.21 
LDL-C, mmol/L 1.9 ± 0.7 −0.01 0.70 −0.01 0.87 1.9 ± 0.8 −0.12 0.07 −0.15 0.03 
HDL-C, mmol/L 1.1 ± 0.3 0.02 0.05 0.02 0.07 1.1 ± 0.3 −0.00 0.65 0.01 0.18 
TC, mmol/L 3.9 ± 1.1 −0.01 0.84 0.00 0.94 4.2 ± 1.5 −0.12 0.11 −0.15 0.05 
TG, mmol/L 2.3 ± 2.4 −0.06 0.26 −0.08 0.14 3.1 ± 4.0 −0.14 0.14 −0.15 0.09 
ACR, mg/mmol 15.3 ± 59.8 −3.20 0.31 −0.56 0.85 11.0 ± 23.6 0.30 0.82 −0.03 0.97 
eGFR, mL/min 87.5 ± 16.4 −3.39 <0.00 −2.90 0.00 89.5 ± 16.4 −0.46 0.74 −0.91 0.51 
SCr, µmol/L 68.2 ± 16.4 3.64 <0.00 3.24 <0.00 69.4 ± 15.7 2.19 0.07 2.60 0.03 
K, mmol/L 4.4 ± 0.4 0.08 0.00 0.07 0.01 4.5 ± 0.5 0.03 0.38 0.03 0.34 
Insulin/day, IU 98.2 ± 83.8 −5.19 0.05 −5.80 0.03 90.1 ± 67.8 −3.40 0.36 −5.44 0.20 
 Basal 228 (78.6)     96 (79.2)     
 Prandial 56 (19.5)     25 (20.8)     
 Premixed 6 (1.9)     0 (0)     
Insulin/day, IU           
 0–100 190 (65.5) 1.53 0.55 0.76 0.77 85 (70.2) 0.22 0.94 −0.36 0.90 
 101–200 73 (25.2) −17.22 <0.00 −17.0 0.00 29 (23.8) 2.4 0.84 −4.05 0.05 
 >200 27 (9.4) −21.38 0.29 −23.1 0.26 7 (5.9) −77.4 0.02 −71.0 0.03 
Insulin/weight/day, IU/kg/day           
 0.1–0.4 80 (27.5) 0.03 0.25 0.06 0.00 27 (22.6) 0.07 0.18 0.08 0.12 
 0.5–1.0 111 (38.2) −0.06 0.09 −0.02 0.60 59 (48.4) 0.04 0.44 0.01 0.79 
 1.1–2.0 77 (26.4) −0.15 0.00 −0.13 0.01 27 (22.6) −0.05 0.69 −0.10 0.42 
 >2.0 23 (7.9) −0.34 0.28 −0.39 0.20 8 (6.5) −0.57 0.01 −0.55 0.01 

Baseline values are mean ± SD or n (%) unless otherwise indicated. Δ BL-3M, mean change from baseline in clinical outcomes at 3 months; Δ BL-6M, mean change from baseline in clinical outcomes at 6 months; ACR, albumin-to-creatinine ratio; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL-C, HDL cholesterol; K, potassium; LDL-C, LDL cholesterol; SBP, systolic blood pressure; SCr, serum creatinine; TC, total cholesterol; TG, triglycerides.

*

HbA1c <7% (<53 mmol/mol).

View Large

Unique aspects of our RW research include the high proportion of patients on an intensified insulin regimen with suboptimal glycemic control, high BMI, and high rate of complications, reflecting a population typically excluded from RCTs. Despite the fact that hypoglycemia has been identified as a concern in patients using SGLT2 inhibitors in combination with insulin, we were unable to report hypoglycemia events because of inconsistent documentation in WebDR. This RW study plays an important role in the evaluation of treatment patterns and health outcomes and can supplement knowledge gained from RCTs. This research is the first in North America to exclusively examine the RW impact of SGLT2 inhibitors in patients with type 2 diabetes treated with insulin and highlights the advantage of adding an SGLT2 inhibitor to improve glycemic control, blood pressure, and weight and to reduce insulin dose.

Acknowledgments. The authors acknowledge the editorial assistance of Jordan Tompkins of the Centre for Studies in Family Medicine.

Funding. This study was supported by an investigator-initiated research grant from Janssen Canada and AstraZeneca Canada.

Duality of Interest. S.B.H. has served on advisory panels and as a consultant for Abbott Diabetes Care, AstraZeneca, Merck Canada, Janssen Pharmaceuticals, Boehringer Ingelheim, Sanofi, Eli Lilly Canada, and Novo Nordisk A/S. S.B.H. received research grants for this study and other studies from Boehringer Ingelheim, Janssen Pharmaceuticals, AstraZeneca, Novo Nordisk A/S, Sanofi, and Abbott. S.M.R. has served on advisory panels for and has spoken at scientific meetings sponsored by Sanofi, Novo Nordisk, Abbott, AstraZeneca, Servier, Boehringer Ingelheim, Eli Lilly Canada, Merck Canada, and Janssen Pharmaceuticals. T.S. has served as a consultant for Sanofi Canada and Eli Lilly Canada and holds research grants from Lexicon Pharmaceuticals, Novo Nordisk, AstraZeneca, and Janssen Research & Development. T.S. has spoken at scientific meetings sponsored by Boehringer Ingelheim, Novo Nordisk, and Eli Lilly Canada. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. S.B.H., S.M.R., and T.S. contributed to the design and conduct of the study and the interpretation of the data and reviewed and approved the manuscript. S.M. contributed to the design and conduct of the study and the acquisition, analysis, and interpretation of data; wrote the first draft of the manuscript; and reviewed and approved the manuscript. K.M. contributed to the conduct of the study, the acquisition and analysis of data, and the first draft of the manuscript and reviewed and approved the manuscript. S.B.H. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Results obtained from the canagliflozin and dapagliflozin data were presented as posters at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017.

1.
Dalal
 
MR
,
Grabner
 
M
,
Bonine
 
N
,
Stephenson
 
JJ
,
DiGenio
 
A
,
Bieszk
 
N
.
Are patients on basal insulin attaining glycemic targets? Characteristics and goal achievement of patients with type 2 diabetes mellitus treated with basal insulin and physician-perceived barriers to achieving glycemic targets
.
Diabetes Res Clin Pract
 
2016
;
121
:
17
–
26
Google Scholar
Crossref
Search ADS
 
2.
Holman
 
RR
,
Farmer
 
AJ
,
Davies
 
MJ
, et al.;
4-T Study Group
.
Three-year efficacy of complex insulin regimens in type 2 diabetes
.
N Engl J Med
 
2009
;
361
:
1736
–
1747
Google Scholar
Crossref
Search ADS
 
3.
Roumie
 
CL
,
Greevy
 
RA
,
Grijalva
 
CG
,
Hung
 
AM
,
Liu
 
X
,
Griffin
 
MR
.
Diabetes treatment intensification and associated changes in HbA1c and body mass index: a cohort study
.
BMC Endocr Disord
 
2016
;
16
:
32
Google Scholar
Crossref
Search ADS
 
4.
John
 
M
,
Gopinath
 
D
,
Jagesh
 
R
.
Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: clinical perspectives
.
Indian J Endocrinol Metab
 
2016
;
20
:
22
–
31
Google Scholar
Crossref
Search ADS
 
5.
Liu
 
SL
,
Spaic
 
T
,
Mequanint
 
S
, et al.
Use of WebDR, a web-based diabetes electronic medical record, as a researchable database to identify and define a cohort of patients with type 1 diabetes on insulin pump therapy
.
Can J Diabetes
 
2013
;
37
(
Suppl. 4
):
S76
Google Scholar
Crossref
Search ADS
 
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