Hypoglycemic Drugs in Patients with Diabetes Mellitus and Heart Failure: A Narrative Review
Abstract
:1. Introduction
2. Metformin
2.1. Clinical Cardiac Impact
2.2. Clinical Decision-Making
3. SUs
3.1. Clinical Cardiac Impact
3.2. Clinical Decision-Making
4. Insulin
4.1. Clinical Cardiac Impact
4.2. Clinical Decision-Making
5. Thiazolidinediones (TZDs)
5.1. Clinical Cardiac Impact
5.2. Clinical Decision-Making
6. DPP-4 Inhibitors
6.1. Clinical Cardiac Impact
Study | Year | Drug | N | Baseline HF (%) | Baseline CVD (%) | Median Follow-Up (Years) | HF Hospitalization Risk [HR (95%CI), p Value] | CV Death Risk [HR (95%CI), p Value] |
---|---|---|---|---|---|---|---|---|
SAVOR-TIMI 53 [59] | 2013 | Saxagliptin | 16,492 | 12.8 | 78 | 2.1 | 1.27 (1.07–1.51) 0.007 | 1.03 (0.87–1.22) 0.72 |
EXAMINE [63] | 2013 | Alogliptin | 5,380 | 28 | 100 | 1.5 | 1.07 (0.79–1.46) | 0.79 (0.60–1.04) 0.10 |
TECOS [62] | 2015 | Sitagliptin | 14,671 | 18 | 100 | 3 | 1.00 (0.83–1.20) 0.98 | 1.03 (0.89–1.19) 0.71 |
CARMELINA [33] | 2019 | Linagliptin | 6991 | 27 | 58 | 2.2 | 0.90 (0.74–1.08) 0.26 | 0.96 (0.81–1.14) 0.63 |
CAROLINA * [34] | 2019 | Linagliptin | 6033 | 4.5 | 42 | 6.3 | 1.21 (0.92–1.59) | 1.00 (0.81–1.24) |
6.2. Clinical Decision-Making
7. GLP-1 RAs
7.1. Clinical Cardiac Impact
7.2. Clinical Decision-Making
8. SGLT2i
8.1. Clinical Cardiac Impact
8.2. Major CVOTs
Study | Year | Drug | N | Baseline HF (%) | Baseline CVD (%) | Median Follow-Up (Years) | HF Hospitalization Risk [HR (95%CI), p Value] | CV Death Risk [HR (95%CI), p Value] |
---|---|---|---|---|---|---|---|---|
EMPA-REG [99] | 2015 | Empagliflozin | 7020 | 10 | 99 | 3.1 | 0.65 (0.50–0.85) 0.002 | 0.62 (0.49–0.77) <0.001 |
CANVAS [100] | 2017 | Canagliflozin | 10,142 | 14.4 | 65.6 | 2.4 | 0.67 (0.52–0.87) | 0.87 (0.72–1.06) |
DECLARE-TIMI 58 [101] | 2018 | Dapagliflozin | 17,160 | 10 | 41 | 4.2 | 0.73 (0.61−0.88) | 0.98 (0.82−1.17) |
VERTIS-CV [103] | 2020 | Ertugliflozin | 8246 | 23.7 | 75.9 | 3 | 0.70 (0.54–0.90) | 0.92 (0.77–1.11) |
DAPA-HF * [105] | 2019 | Dapagliflozin | 4744 | 100 | 56 | 1.5 | 0.7 (0.59–0.83) | 0.82 (0.69–0.98) |
EMPEROR-reduced * [106] | 2020 | Empagliflozin | 3730 | 100 | 52 | 1.3 | 0.69 (0.59–0.81) | 0.92 (0.75–1.12) |
SOLOIST-WHF [107] | 2020 | Sotagliflozin | 1222 | 100 | ΝA | 0.75 | 0.64 (0.49 to 0.83) <0.001 | 0.84 (0.58 to 1.22) 0.36 |
EMPEROR-preserved * [108] | 2021 | Empagliflozin | 5988 | 100 | 35.5 | 2.2 | 0.71 (0.60–0.83) | 0.91 (0.76–1.09) |
DELIVER [109] | 2022 | Dapagliflozin | 6263 | 100 | NA | 2.3 | 0.79 (0.69–0.91) | 0.88 (0.74–1.05) |
CREDENCE [110] | 2019 | Canagliflozin | 4401 | 14.8 | 50.4 | 2.62 | 0.61 (0.47–0.8) <0.001 | 0.78 (0.61–1.00) 0.05 |
SCORED [111] | 2020 | Sotagliflozin | 10,584 | 31 | 22 | 1.3 | 0.67 (0.55–0.82) <0.001 | 0.90 (0.73–1.12) 0.35 |
DAPA-CKD * [112] | 2020 | Dapagliflozin | 4304 | 11 | 37.5 | 2.4 | 0.71 (0.55–0.92) ** | 0.81 (0.58–1.12) |
8.3. HF Outcome Trials
8.4. Cardiac Function Impact
9. SGLT2i and GLP-RA Combination
9.1. Established Knowledge
9.2. Future Directions
10. Indication of Antidiabetic Drugs in HF According to Guidelines
- Metformin remains the first-line treatment in combination with lifestyle interventions in patients with T2DM without cardio-renal comorbidities. In terms of CV and renal outcomes, novel antidiabetic agents (SGLT2is and GLP-1 RAs) have proven their beneficial effects on 3P-MACE, HF hospitalization, and mortality independent of metformin use. Hence, these drugs should be firstly considered in patients with established or a high risk of CVD, HF, and CKD, irrespectively of metformin use. In patients with T2DM and stable HF, metformin may be continued for glucose lowering if the eGFR remains > 30 mL/min/1.73 m2 but should be avoided in unstable or hospitalized individuals with HF.
- SUs have met controversial results concerning CV safety and the risk of HF hospitalization. Hence, in patients with T2DM and HF, SUs should only be considered in the case of poor glycemic control with alternative options and be used with caution.
- Insulin should be considered in patients with DM and acute decompensated HF.
- TZDs: Pioglitazone could be considered as second-line therapy in patients at very high risk or with established CVD, if the glycemic target is not achieved or novel agents are contraindicated. However, TZDs (pioglitazone and rosiglitazone) are generally contraindicated in patients with T2DM at risk or with established HF due to the increase in HF incidence.
- DPP-4 inhibitors (sitagliptin and linagliptin) showed a neutral effect on the risk of HF hospitalization or 3P-MACE and may be considered for DM management in patients with HF. Only saxagliptin was related to an increased risk of HF hospitalization, and it is not recommended in patients with T2DM at risk or with manifest HF. However, the AHA/ACCF/HFSA consensus recommends avoiding DPP-4 inhibitors over stage-B HF.
- GLP-1 RAs are highly recommended in patients with T2DM, with or without established CVD and irrespectively of other hypoglycemic therapies or glycose-lowering targets. Specifically, a GLP-1 RA with proven benefits could be used in patients with very high risk for CVD (>55 years, hypertension, smoking, dyslipidemia, obesity, or albuminuria) and should be used in patients with established CVD, to reduce 3P-MACE. GLP-1 RAs (lixisenatide, liraglutide, exenatide, semaglutide, and dulaglutide) had a neutral effect on HF hospitalization and could be considered as an alternative treatment of DM in patients with HF. However, it would be preferable to avoid GLP-1 RAs in HFrEF and recently decompensated acute HF.
- SGLT2is are recommended in patients with T2DM with or without established CVD, HF, or CKD (eGFR > 20 mL/min per 1.73 m²), to reduce 3P-MACE and improve kidney outcomes, irrespectively of other antidiabetic drugs or glucose-lowering goals. Specifically, dapagliflozin, empagliflozin, and sotagliflozin are strongly recommended in patients with T2DM and CVD or HF, irrespectively of LVEF, to reduce HF hospitalization and CV death.
11. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Study | Year | Drug | N | Baseline HF (%) | Baseline CVD (%) | Median Follow-up (Years) | HF Hospitalization Risk [HR (95%CI), p Value] | CV Death Risk [HR (95%CI), p Value] |
---|---|---|---|---|---|---|---|---|
ELIXA [73] | 2015 | Lixisenatide | 6068 | 22 | 100 | 2.1 | 0.96 (0.75–1.23) | 0.98 (0.78 −1.22) |
LEADER [79] | 2016 | Liraglutide | 9340 | 17.8 | 81 | 3.8 | 0.87 (0.73–1.05) | 0.78 (0.66–0.93) |
SUSTAIN-6 [80] | 2016 | Semaglutide | 3297 | 23.6 | 83 | 2.1 | 1.11 (0.77–1.61) | 0.98 (0.65–1.48) |
REWIND [81] | 2019 | Dulaglutide | 9901 | 8.6 | 31.5 | 5.4 | 0.93 (0.77-1.12) | 0.91(0.78-1.06) |
AMPLITUDE-O [82] | 2021 | Efpeglenatide | 4076 | 18.1 | 89.6 | 1.81 | 0.61 (0.38–0.98) | 0.72 (0.50–1.03) |
EXSCEL [83] | 2017 | Exenatide | 14,752 | 16 | 73.1 | 3.2 | 0.94 (0.78−1.13) | 0.88 (0.76−1.02) |
HARMONY [84] | 2018 | Albiglutide | 9463 | 20 | 100 | 1.6 | 0.71 (0.53–0.94) | 0.93 (0.73–1.19) |
PIONEER-6 [85] | 2019 | Semaglutide | 3183 | NA | 85 | 1.3 | 0.86 (0.48–1.55) | 0.49 (0.27–0.92) |
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Nikolaidou, A.; Ventoulis, I.; Karakoulidis, G.; Anastasiou, V.; Daios, S.; Papadopoulos, S.-F.; Didagelos, M.; Parissis, J.; Karamitsos, T.; Kotsa, K.; et al. Hypoglycemic Drugs in Patients with Diabetes Mellitus and Heart Failure: A Narrative Review. Medicina 2024, 60, 912. https://doi.org/10.3390/medicina60060912
Nikolaidou A, Ventoulis I, Karakoulidis G, Anastasiou V, Daios S, Papadopoulos S-F, Didagelos M, Parissis J, Karamitsos T, Kotsa K, et al. Hypoglycemic Drugs in Patients with Diabetes Mellitus and Heart Failure: A Narrative Review. Medicina. 2024; 60(6):912. https://doi.org/10.3390/medicina60060912
Chicago/Turabian StyleNikolaidou, Anastasia, Ioannis Ventoulis, Georgios Karakoulidis, Vasileios Anastasiou, Stylianos Daios, Spyridon-Filippos Papadopoulos, Matthaios Didagelos, John Parissis, Theodoros Karamitsos, Kalliopi Kotsa, and et al. 2024. "Hypoglycemic Drugs in Patients with Diabetes Mellitus and Heart Failure: A Narrative Review" Medicina 60, no. 6: 912. https://doi.org/10.3390/medicina60060912
APA StyleNikolaidou, A., Ventoulis, I., Karakoulidis, G., Anastasiou, V., Daios, S., Papadopoulos, S.-F., Didagelos, M., Parissis, J., Karamitsos, T., Kotsa, K., Ziakas, A., & Kamperidis, V. (2024). Hypoglycemic Drugs in Patients with Diabetes Mellitus and Heart Failure: A Narrative Review. Medicina, 60(6), 912. https://doi.org/10.3390/medicina60060912