Abstract
Aims
The duration of type 2 diabetes mellitus (T2DM) is an important determinant of diabetes severity. The EMPA‐HEART CardioLink‐6 trial reported significant left ventricular (LV) mass indexed to body surface area (LVMi) regression in patients treated with the sodium‐glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin for 6 months. This exploratory sub‐analysis of the same trial investigated the association between T2DM duration and LVMi regression.
Methods and results
A total of 97 individuals with T2DM and coronary artery disease (CAD) were randomly assigned to receive empagliflozin 10 mg daily or placebo. LVMi was measured at the baseline and 6 month visit using cardiac magnetic resonance imaging. The study population was divided into those with a baseline T2DM duration <10 years (n = 40) or ≥10 years (n = 57). A linear model adjusting for baseline values in each of the subgroups (ANCOVA) was used to assess the treatment effect of 6 month change in LVMi, LV end systolic volume indexed to body surface area, LV end diastolic volume indexed to body surface area and LV ejection fraction. Patients in the T2DM duration <10 years group (38 males [95.0%], median age 63 [IQR: 55 years to 70 years]) had a median T2DM duration of 4 years (IQR: 2.0 years to 7.0 years). Those in the T2DM duration ≥10 years group (52 males [91.2%], median age 65 [IQR: 57 years to 71 years]) had a median duration of 15 years (IQR: 12 years to 20 years). There was no significant difference in baseline LVMi according to T2DM duration (median 62 g/m2 [IQR: 53.1 g/m2 to 70.0 g/m2] for T2DM duration <10 years; median 57.5 g/m2 [IQR: 52.1 g/m2 to 66.2 g/m2] for T2DM duration ≥10 years; P = 0.11). Empagliflozin was associated with reductions in LVMi irrespective of duration of T2DM above and below 10 years (T2DM duration <10 years group, mean adjusted difference −2.90 g/m2 [95% CI: −6.64 g/m2 to 0.84 g/m2]; T2DM duration ≥10 years group, mean adjusted difference −3.69 g/m2 [95% CI: −0.14 g/m2 to −7.24 g/m2]; P interaction = 0.07).
Conclusions
In the EMPA‐HEART CardioLink‐6 trial, empagliflozin treatment was associated with reductions in LVMi in people with T2DM and CAD irrespective of the duration of diabetes assessed categorically above and below 10 years.
Keywords: Diabetes duration, Diabetes severity, SGLT2 inhibitor, Left ventricular reverse remodelling, Diabetes
Background
The Effect of Empagliflozin on Left Ventricular Mass in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease (EMPA‐HEART CardioLink‐6) trial 1 was a 6 month double‐blind, placebo‐controlled trial of individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) randomized to receive empagliflozin or placebo. This trial showed a significant decrease among the empagliflozin‐assigned group in its primary endpoint of a 6 month change in left ventricular (LV) mass indexed (LVMi) to baseline body surface area (adjusted difference −3.35 g/m2; 95% confidence interval [CI]: −5.9 g/m2 to −0.81 g/m2, P = 0.01), when compared with placebo. Although these findings offered some insights into how the cardiovascular benefits reported in large outcome studies with sodium‐glucose cotransporter 2 inhibitors (SGLT2i) may have arisen, 2 , 3 , 4 , 5 , 6 , 7 the exact mechanisms underlying SGLT2i‐associated LV mass regression remains unclear although it has been speculated that osmotic diuresis, reductions in preload or afterload and improved glycaemic control may have a role. 8 , 9 , 10
Longer diabetes duration is a well‐recognized determinant of disease severity and studies have shown that people with long‐standing T2DM have a higher incidence of macrovascular and microvascular complications. 11 , 12 , 13 Chronicity of diabetes is also associated with a higher risk of heart failure. 14 In addition, there is evidence suggesting T2DM is associated with left ventricular hypertrophy. 15 , 16 , 17 Previous studies have shown consistent benefit in the use of SGLT2i across the population living with T2DM. 18 , 19 The efficacy of SGLT2i to promote cardiac remodelling as a function of diabetes duration has not been previously reported.
Aims
This exploratory sub‐analysis of the EMPA‐HEART CardioLink‐6 trial sought to evaluate the relationship between T2DM duration and LVMi regression in empagliflozin‐ vs. placebo‐treated patients who have CAD.
Methods
The design of the EMPA‐HEART CardioLink‐6 trial, as well as the primary results and full study protocol have previously been published. 1 Briefly, this trial included 97 individuals with T2DM and CAD who received either empagliflozin 10 mg once daily (n = 49) or placebo (n = 48) for 6 months. The primary outcome was the 6 month change in LVMi measured using cardiac magnetic resonance imaging (cMRI). All cMRI readers were blinded to the end point clinical data, treatment regimen and timing of scans. Medical history pertaining to T2DM duration was taken at screening.
The subgroups for T2DM duration were defined by T2DM duration at baseline, namely, <10 years and ≥10 years. This cut‐off was selected based on evidence that the risk of adverse cardiovascular events increases for each decade of diabetes duration. 13
Normality of continuous variables was tested with the Skewness and Kurtosis test and examined with visual inspection of histogram. Baseline characteristics with continuous variables are reported as median with interquartile ranges (IQR) or mean ± SD as appropriate, while frequencies and percentages are used to describe categorical data. For non‐parametric continuous variables, the Mann–Whitney U‐test was used. A χ 2 test was used to compute categorical variables and if appropriate, the Fisher's exact test was used.
To assess the treatment effect on 6 month change in LVMi in each of the sub‐groups, a linear model adjusting for baseline differences in LVMi (ANCOVA) that included an interaction term between each of the sub‐groups and allocated treatment was used. ANCOVA was conducted for 6 month change in LV end systolic volume (LVESV) indexed to body surface area (LVESVi), LV end diastolic volume (LVEDV) indexed to body surface area (LVEDVi) and LV ejection fraction (LVEF) adjusting for baseline values in each of the sub‐groups. The results of the regression models were summarized as adjusted differences with two‐sided 95% confidence intervals. 6 month change in LVMi was predicted from estimation of a fractional polynomial of diabetes duration and its 95% CIs. Patients were excluded where there was missing outcome or covariate data. All statistical analyses were performed using the STATA statistical software version 17 (StataCorp LP, College Station, TX, USA) and a P‐value <0.05 was considered statistically significant.
Results
The mean duration of T2DM in the overall trial was 11 years (SD: 8.2 years). Forty patients had lived with T2DM for <10 years at the baseline visit. The median duration of T2DM in this subgroup at baseline was 4 years (IQR: 2.0 years to 7.0 years); that for the subgroup with baseline T2DM duration ≥10 years subgroup was 15 years (IQR: 12 years to 20 years) (Table 1 ). While a higher percentage of those in the T2DM duration <10 years group were on metformin (<10 years group, 40 patients [100.0%] using metformin; ≥10 years group, 51 patients [89.5%] using metformin; P‐value = 0.041), proportionally more of those who had lived with T2DM for ≥10 years were using insulin (<10 years group, 3 patients [7.5%] using insulin; ≥10 years group, 21 patients [36.8%] using insulin; P‐value <0.001). All other baseline characteristics were similar between both cohorts (Table 1 ).
Table 1.
Baseline characteristics of individuals enrolled in the EMPA‐HEART CardioLink‐6 trial stratified by diabetes duration <10 years or ≥10 years
| T2DM duration <10 years (n = 40) | T2DM duration ≥10 years (n = 57) | P‐value | |
|---|---|---|---|
| Age, years | 63 (55–70) | 65 (57–71) | 0.51 |
| Male sex | 38 (95.0) | 52 (91.2) | 0.48 |
| BMI, kg/m2 | 27.6 (24.6–30.0) | 26.2 (24.2–29.9) | 0.49 |
| Duration of T2DM, years | 4.0 (2.0–7.0) | 15.0 (12.0–20.0) | <0.001 |
| HbA1c, % | 7.9 (7.3–8.6) | 7.9 (7.3–8.5) | 0.84 |
| Glucose (random), mmol/L | 9.2 (6.8–12.9) | 7.8 (6.6–11.9) | 0.38 |
| SBP, mmHg | 131 (120–152) | 131 (121–143) | 0.69 |
| DBP, mmHg | 76 (68–83) | 74 (71–80) | 0.62 |
| Cholesterol (random), mg/dL | 121.6 (106.5–140.0) | 122.6 (108.7–138.1) | 0.92 |
| LDL‐C, mg/dL | 48.1 (39.6–68.8) | 52.4 (39.1–67.3) | 0.93 |
| HDL‐C, mg/dL | 37.5 (31.7–43.5) | 38.7 (34.8–44.5) | 0.55 |
| TG, mg/dL | 157.2 (111.6–232.9) | 164.7 (119.6–192.2) | 0.68 |
| eGFR, mL/min/1.73 m2 | 88.6 (80.4–98.1) | 86.5 (71.8–97.9) | 0.46 |
| Creatinine, mg/dL | 0.9 (0.8–1.0) | 0.9 (0.8–1.1) | 0.63 |
| Haemoglobin, g/dL | 14.1 (13.1–15.0) | 14.0 (12.9–15.0) | 0.72 |
| Haematocrit, % | 0.42 (0.40–0.44) | 0.42 (0.40–0.44) | 0.77 |
| NT‐proBNP, pg/mL | 114 (51–224) | 103 (58–198) | 0.68 |
| Previous PCI | 19 (47.5) | 26 (45.6) | 0.85 |
| Previous CABG | 22 (55.0) | 33 (57.9) | 0.78 |
| Heart failure | 1 (2.5) | 5 (8.8) | 0.40 |
| Hypertension | 36 (90.0) | 52 (91.2) | 1.00 |
| Diabetic nephropathy | 0 (0.0) | 2 (3.5) | 0.51 |
| Stroke or TIA | 6 (15.0) | 8 (14.0) | 1.00 |
| Peripheral artery disease | 1 (2.5) | 4 (7.0) | 0.65 |
| Smoking history | 17 (42.5) | 25 (43.9) | 0.89 |
| Medications | |||
| Metformin | 40 (100.0) | 51 (89.5) | 0.041 |
| Insulin | 3 (7.5) | 21 (36.8) | <0.001 |
| Statin | 37 (92.5) | 56 (98.2) | 0.30 |
| ACEi/ARB | 33 (82.5) | 48 (84.2) | 1.00 |
| Furosemide/thiazide | 7 (17.5) | 8 (14.0) | 0.78 |
| Beta‐blocker | 33 (82.5) | 44 (77.2) | 0.62 |
| Calcium channel blocker | 7 (17.5) | 14 (24.6) | 0.46 |
| ASA/P2Y12 inhibitor | 32 (80.0) | 49 (86.0) | 0.58 |
All data are presented as either n (%) or median (interquartile range).
ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin‐receptor blocker; ASA, acetylsalicylic acid; BMI, body mass index; CABG, coronary artery bypass graft; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; NT‐proBNP, N‐terminal pro‐b‐type natriuretic peptide; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus; TG, triglycerides; TIA, transient ischemic attack.
There was no significant difference in baseline LVMi between the two groups (<10 years group, median baseline LVMi 62.0 g/m2 [IQR: 53.1 g/m2 to 70 g/m2]; ≥10 years group, median baseline LVMi 57.5 g/m2 [IQR: 52.1 g/m2 to 66.2 g/m2]; P‐value = 0.11) (Table 2 ).
Table 2.
Baseline, 6 month and 6 month difference in echocardiographic parameters stratified by diabetes duration <10 years or ≥10 years
| T2DM duration <10 years (n = 40) | T2DM duration ≥10 years (n = 57) | P‐value | |
|---|---|---|---|
| LVMi, g/m2 | |||
| Baseline | 62.0 (53.1–70.0) | 57.5 (52.1–66.2) | 0.11 |
| 6 months | 59.3 (53.5–66.7) | 56.0 (50.7–63.5) | 0.10 |
| Difference | −2.1 (−6.2–3.2) | 0.5 (−5.6–3.2) | 0.68 |
| LVM, g | |||
| Baseline | 118.5 (102.3–139.1) | 108.2 (95.7–135.4) | 0.16 |
| 6 months | 116.8 (95.5–145.8) | 102.8 (93.6–131.1) | 0.16 |
| Difference | −4.2 (−11.3–7.1) | 0.9 (−10.6–6.4) | 0.77 |
| LVEDV, mL | |||
| Baseline | 132.6 (106.8–158.1) | 120.2 (102.3–150.1) | 0.16 |
| 6 months | 132.9 (104.8–159.4) | 116.1 (97.3–140.0) | 0.086 |
| Difference | 1.8 (−7.6–5.7) | −5.1 (−20.7–7.8) | 0.16 |
| LVESV, mL | |||
| Baseline | 52.8 (39.3–78.7) | 51.8 (43.1–60.3) | 0.33 |
| 6 months | 55.3 (41.7–81.1) | 48.7 (36.0–59.7) | 0.044 |
| Difference | 2.7 (−6.3–7.5) | −2.1 (−10.0–4.6) | 0.12 |
| LVEDVi, mL/m2 | |||
| Baseline | 68.2 (60.7–80.1) | 64.4 (56.5–73.6) | 0.14 |
| 6 months | 66.4 (58.0–78.8) | 60.0 (56.0–70.9) | 0.067 |
| Difference | 1.1 (−3.6–2.7) | −2.8 (−10.5–4.4) | 0.23 |
| LVESVi, mL/m2 | |||
| Baseline | 25.8 (21.6–40.3) | 28.0 (22.4–30.4) | 0.43 |
| 6 months | 28.8 (22.6–41.3) | 24.9 (18.9–30.5) | 0.045 |
| Difference | 1.4 (−3.8–4.1) | −1.2 (−5.4–2.3) | 0.14 |
| LVEF, % | |||
| Baseline | 58.3 (48.3–63.9) | 58.2 (52.6–63.6) | 0.58 |
| 6 months | 54.9 (47.5–62.6) | 59.8 (52.5–65.1) | 0.047 |
| Difference | −2.0 (−5.2–1.5) | 0.7 (−2.8–3.7) | 0.064 |
All data are presented as median (interquartile range).
LVEDV, left ventricular end diastolic volume; LVEDVi, LVEDV indexed to body surface area; LVEF, left ventricular ejection fraction; LVESV, left ventricular end systolic volume; LVESVi, LVESV indexed to body surface area; LVM, left ventricular mass; LVMi, LVM indexed to body surface area; T2DM, type 2 diabetes mellitus.
Comparing treatment regimens, empagliflozin vs placebo, within each group showed an adjusted difference in LVMi of −2.90 g/m2 (95% CI: −6.64 g/m2 to 0.84 g/m2; P‐value = 0.12) in the <10 years duration group and an adjusted difference of −3.69 g/m2 (95% CI: −0.14 g/m2 to −7.24 g/m2; P‐value = 0.042) in the ≥10 years duration group. The P interaction between the two groups was 0.07 (Figure 1 ). When disease duration and 6 month change in LVMi was analysed in a continuous analysis the result is not significant (Figure 2 ).
Figure 1.
Treatment and 6 month change in LVMi stratified by baseline duration of type 2 diabetes mellitus <10 years or ≥10 years. Data are presented as mean (95% confidence intervals). LVMi, left ventricular mass indexed to body surface area; T2DM, type 2 diabetes mellitus.
Figure 2.
Treatment and 6 month change in LVMi estimated over type 2 diabetes duration, fitted to a fractional‐polynomial prediction and its 95% confidence intervals. LVMi, left ventricular mass indexed to body surface area; T2DM, type 2 diabetes mellitus.
Our results suggest a trend toward a greater decrease in LVESVi in patients treated with empagliflozin and who have a T2DM duration ≥10 years (<10 years group, adjusted difference −0.66 mL/m2 [95% CI: −4.66 mL/m2 to 3.35 mL/m2]; ≥10 years group, adjusted difference −1.82 mL/m2 [95% CI: −5.24 mL/m2 to 1.61 mL/m2]; P interaction = 0.06) (Figure 3 ). The results for all other secondary outcome measures are shown in Table 2 .
Figure 3.
Treatment and 6 month change in LVESVi, LVEDVi and LVEF stratified by diabetes duration adjusted with baseline values of LVESVi, LVEDVi and LVEF. All values are shown as mean (95% confidence intervals). LVEDVi, left ventricular end diastolic volume indexed to body surface area; LVESVi, left ventricular end systolic volume indexed to body surface area; LVEF, left ventricular ejection fraction.
Conclusions
This sub‐analysis investigating the effects of T2DM duration on LV mass regression with empagliflozin is, to the best of our knowledge, the first of its kind.
The results of this sub‐analysis indicate that while empagliflozin offers LVMi regression benefits in individuals with CAD regardless of whether they have lived with T2DM for less or more than 10 years, SGLT2i may be associated with greater LVMi regression in those with T2DM ≥ 10 years. Other post hoc analyses of cardiovascular outcome trials with SGLT2i comparing diabetes duration, as well as other surrogate markers for diabetes severity, have shown consistent benefit for all patients with type 2 diabetes, 18 , 20 , 21 with one analysis suggesting greater benefits may be observed among those with long‐standing diabetes. 19 This may be of clinical significance as it has been shown that the duration of T2DM is independently associated with an increase in both micro‐ and macrovascular complications, heart failure risk and death. 11 , 12 , 13 , 14 For example, a large, multi‐site, prospective, cohort study containing 9,734 participants with over 22.5 years of follow‐up reported a 17% (95% CI: 11% to 22%) relative increase in heart failure risk for each 5 year increase in diabetes duration. 14 Whether or not SGLT2i provide varying degrees of benefit to patients with different T2DM durations remains unclear, and further investigations are clearly warranted.
There was a similar trend toward a greater decrease in LVESV in patients with T2DM ≥ 10 years after empagliflozin treatment. A recent meta‐analysis of five cMRI trials involving SGLT2i therapy reported a trend toward reductions in LVESV post‐treatment. 22 Our results suggest the degree of reduction in LVESV may differ between patients when stratified by T2DM duration.
Patients with a longer T2DM duration were shown to have significantly higher insulin use. Empagliflozin has been shown to reduce insulin requirement after 12‐week treatment 23 ; therefore, individuals with longer disease duration and markedly high insulin use stand to receive significant benefit from SGLT2i therapy.
Our results should be interpreted with consideration of the study limitations that include the post hoc exploratory design, large proportion of male participants, small sample size, and the inability to investigate longer T2DM durations.
In conclusion, this study suggests that regression in LVMi after 6 month treatment with empagliflozin is consistent across all T2DM durations. The results of this sub‐analysis support future investigations into the effect of diabetes duration on the benefit derived from SGLT2i therapy.
Conflict of interest
C.D.M. reports advisory board honoraria/consulting fees from Amgen, AstraZeneca, BioAge, Boehringer Ingelheim and PhaseBio and DSMB stipends from Beth Israel Deaconess Medical Center, Cerus and Takeda. K.A.C. has received research grants to his institution from Astra Zeneca and Boehringer Ingelheim, received support for travel to scientific meeting from Boehringer Ingelheim and honoraria for speaking engagements and ad hoc participation in advisory boards from Astra Zeneca, Boehringer Ingelheim and Janssen. H.T. reports personal fees from the Canadian Medical and Surgical Knowledge Translation Research Group. S.V. reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, S&L Solutions, and the Toronto Knowledge Translation Working Group. S.V. is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not‐for‐profit physician organization. All other authors have no conflicts of interest to declare.
Funding
The conduct of the EMPA‐HEART CardioLink‐6 trial was supported by an unrestricted investigator‐initiated study grant from Boehringer Ingelheim.
Acknowledgements
C.D.M. is supported by a Merit Award from the University of Toronto Department of Anesthesiology and Pain Medicine. K.A.C. holds the Keenan Chair in Research Leadership at Unity Health Toronto, University of Toronto. S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery.
Moroney, M. , Verma, R. , Hibino, M. , Mazer, C. D. , Connelly, K. A. , Yan, A. T. , Quan, A. , Teoh, H. , Verma, S. , and Puar, P. (2023) Impact of diabetes duration on left ventricular mass regression with empagliflozin. ESC Heart Failure, 10: 2134–2140. 10.1002/ehf2.14357.
Michael Moroney and Raj Verma have equal contribution.
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