TABLE 1.
List of clinical trials associated with treatment of DMCM.
| Name of the trial (number of subjects) | Molecule studied (dose and route of administration) | MACE HR (CI/p value) | CV death | Heart failure HR (95% CI) | Outcomes | Limitations of study | References |
| PARADIGM-HF (8442) | LCZ696 (200 mg twice daily) and enalapril (10 mg daily) | 0.80 (0.73–0.87) p < 0.001 | 0.80 (0.71–0.89) p < 0.001 | 0.79 (0.71–0.89) p < 0.001 | LCZ696 performed better in comparison of enalapril to reduce risk of death and hospitalization in heart failure | LCZ696 showed the hypotension in patients | McMurray et al. (2014) |
| PARAGON-HF (4822) | Sacubitril–valsartan (97 mg sacubitril and 103 mg valsartan twice daily) and valsartan (160 mg twice daily) | 0.87 (0.75–1.01) | 0.95 (0.79–1.16) | 0.85 (0.72–1.00) | Sacubitril–valsartan did not significantly lowered the risk of death due to HF and hospitalization in heart failure | Did not shown any cardiovascular benefits in patients of heart failure with preserved ejection fraction | Solomon et al. (2019) |
| PROACTIVE STUDY (5238) | Pioglitazone (15–45 mg orally OD) | 0.96 (0.78–1.18) | NA | NA | Reduced the all kind of mortality including non-fatal MI and stroke in T2DM patients | NA | Dormandy et al. (2005) |
| LEADER (9340) | Liraglutide (1.8 mg s/c OD) | 0.87 (0.78–0.97) p < 0.015 | 0.78 (0.66–0.93) p < 0.007 | 0.87 (0.73–1.05) p < 0.14 | Liraglutide reduces the event of death due to cardiovascular causes and non-fatal stroke T2DM patients with the comparison of placebo group | Safety and efficacy data need further validation due to short time period of study on patients (3.5–5 years study) | Marso et al. (2016b) |
| SUSTAIN-6 (3297) | Semaglutide (0⋅5 or 1 mg s/c per week) | 0.74 (0.58–0.95) p < 0.016 | 0.98 (0.65–1.48) p < 0.92 | 1.11 (0.77–1.61) p < 0.57 | Semaglutide significantly reduces the event of cardiovascular death and non-fatal MI in patients of T2DM with the placebo group | Patients were studied for shorter time period (2.1 years) and events of gastrointestinal abnormality reported | Marso et al. (2016a) |
| EXSCEL (14752) | Exenatide (2 mg s/c weekly) | 0.91 (0.83–1.00) p < 0.061 | 0.88 (0.76–1.02) p < 0.096 | 0.94 (0.78-1.13) | No significant difference in key adverse cardiovascular occurrence in both groups (exenatide vs. placebo) | Loss to follow up rate was high. First generation injection device was complex. There was no run-in period determined by researcher. Not a standardized method of care | Holman et al. (2017a) |
| Harmony outcomes (9463) | Albiglutide (30 or 50 mg s/c weekly) | 0.78 (0.68–0.90) p < 0.0001 | 0.93 (0.73–1.19) p < 0.58 | 0.85 (0.70–1.04) p < 0.113 | Reduced the potential of CV complications. Improved cardiovascular outcomes for T2DM patients. | Short follow up. 25% of participants discontinued the study prior to completion. Microvascular complications were not noted. Urinary albumin excretion and lipids were no measured. | Hernandez et al. (2018) |
| REWIND (9901) | Dulaglutide (1.5 mg per week s/c) | 0.88 (0.79–0.99) p < 0.026 | 0.91 (0.78–1.06) p < 0.21 | 0.93 (0.77–1.12) p < 0.46 | Lowers CV outcomes within 5 years. Lowers blood pressure. Increases weight loss. Lowers glucose levels while preventing risk of hypoglycemia | Over 25% of participants stopped using dulaglutide before study was completed. | Gerstein et al. (2019) |
| EMPA-REG (7020) | Empagliflozin (10–25 mg once daily) | 0.86 (0.74–0.99) | 0.62 (0.49–0.77) p < 0.001 | 0.65 (0.5–0.85) p < 0.002 | Lowered the rate of primary composite CV outcome and death from any cause when studying the drug added to standard care | The discontinuation rate of both groups very similar | Zinman et al. (2015) |
| DAPA-HF (4744) | Dapagliflozin (10 mg once daily) | 0.74 (0.65–0.85) p < 0.001 | 0.82 (0.69–0.98) | 0.70 (0.59–0.83) | Reduces the risk of worsening CV conditions compared to the placebo. The adverse event rate did not differ | Inclusion and exclusion criteria were very particular which could have decreased the generalizability of the study. The study also had limited diversity, also lowering generalizability | McMurray et al. (2019) |
| CANVAS PROGRAM (10142) | Canagliflozin (100 mg and 300 mg orally daily) | 0.86 (0.75–0.97) p < 0.60 | 0.9 (0.7–1.15) | 0.67 (0.52–0.87) | Decreases risk of mortality from CV complication, non-fatal MI and non-fatal stroke. Increased risk of amputation | Low levels of end-stage renal disease. Increase use of glucose-lowering solutions in the placebo group may have resulted in risks or benefits of Canagliflozin | Neal et al. (2017) |
| EMPEROR-reduced (3730) | Empagliflozin (10 mg daily) | 0.75 (0.65–0.86) p < 0.001 | 0.92 (0.75–1.12) | 0.69 (0.59–0.81) | Reduction in the risk of CV death or hospitalization for HF compared to the placebo. Slower progression of renal failure with chronic HF and reduced ejection fraction. | Uncomplicated genital tract infection was found higher in empagliflozin treated group | Packer et al. (2020) |
| DECLARE-TIMI 58 (17,160) | Dapagliflozin (10 mg daily) | 0.93 (0.84–1.03) p < 0.17 | 0.98 (0.82–1.17) | 0.73 (0.61–0.88) | Reduction in the hospitalization of the patients with heart failure | Genital tract infection were higher in treated groups that leads to discontinuation of study | Wiviott et al. (2019) |
MACE, major adverse cardiovascular events; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; mg, milligram; s/c, sub-cutaneous; OD, once daily; T2DM, type 2 diabetes mellitus; MI, myocardial infarction; HF, heart failure; NA, not applicable.