Table 1.
Cardiovascular outcome trials. CV: cardiovascular; MI: myocardial infarction; USA: unstable angina; ACS: acute coronary syndrome; T2D: type 2 diabetes; HR: hazard ratio; CI: confidence interval; RRR: relative risk reduction
| DRUG (YEAR) | TRIAL | STUDY DESIGN | RESULTS |
|---|---|---|---|
| Alogliptin (2013) | EXAMINE | N = 5380 Randomized, double-blind study in patients with T2D and either an acute MI/USA requiring hospitalization within the previous 15–90 days Groups: alogliptin vs placebo in addition to existing antihyperglycemic and CV drug therapy; primary end point of composite of death from CV causes, nonfatal MI, or nonfatal stroke; 40-mo follow-up | Primary end point: 11.3% with alogliptin vs 11.8% with placebo HR 0.96; [upper bound of the one-sided repeated CI, 1.16]; P < .001 for noninferiority |
| Saxagliptin (2013) | SAVOR-TIMI | N = 16492 Randomized double-blind study in patients with T2D with history of, or at risk for, CV events Groups: saxagliptin vs placebo; primary end point of composite of CV death, MI, or ischemic stroke; secondary end point of composite of CV death, MI, stroke, hospitalization for USA, coronary revascularization, or heart failure; median 2.1-yr follow-up | Primary end point: 7.3% with saxagliptin vs 7/2% with placebo HR 1.00; 95% CI 0.89–1.12; P = .99 for superiority; P < .001 for noninferiority Secondary end point: 12.8% with saxagliptin vs 12.4% with placebo HR 1.02; 95% CI 0.94–1.11; P = .66 Hospitalization for heart failure: 3.5% saxagliptin vs 2.8% placebo; HR: 1.27; 95% CI 1.07–1.51; P = .007 |
| Sitagliptin (2015) | TECOS | N = 14671 Randomized, double-blind study of patients with T2D and CV disease Groups: sitagliptin vs placebo plus existing therapy; primary outcome is composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for USA; median 3-yr follow-up | Primary outcome: 839 patients on sitagliptin (11.4%) vs 851 patients on placebo (11.6%) HR: 0.98; 95% CI: 0.88–1.09; P < .001 Hospitalization for heart failure: HR: 1.00; 95% CI 0.83–1.20; P = .98 |
| Lixisenatide (2015) | ELIXA | N = 6068 Randomized, double-blind study in patients with T2D with MI or USA within the previous 180 days Groups: lixisenatide vs placebo; primary composite end point of CV death, MI, stroke, or hospitalization for USA; median 25-mo follow-up | Primary end point: 13.4% with lixisenatide vs 13.2% with placebo HR: 1.02; 95% CI: 0.89–1.17 Inferiority: P < .001; superiority: P = .81 Rate of hospitalization for heart failure: HR: 0.96; 95% CI 0.75–1.23 Rate of death: HR: 0.94; 95% CI 0.78–1.13 |
| Empagliflozin (2015) | EMPA-REG | N = 7020 Randomized, double-blind study of patients with T2D at high CV risk Groups: 10 mg or 25 mg of empagliflozin vs placebo; primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke; secondary composite outcome of primary outcome plus hospitalization for USA; median 3.1-yr follow-up | Primary outcome: 10.5% with empagliflozin vs 12.1% with placebo HR: 0.86; 95.02% CI 0.74–0.99; P = .04 for superiority Rates of death from CV causes: 3.7% empagliflozin vs 5.9% placebo; 38% RRR Hospitalization for heart failure: 2.7% empagliflozin vs 4.1% placebo; 35% RRR Death from any cause: 5.7% empagliflozin vs 8.3% placebo; 32% RRR |
| Liraglutide (2016) | LEADER | N = 9340 Randomized, double-blind study of patients with T2D and high CV risk Groups: liraglutide 1.8 mg daily vs placebo; primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke; 3.8-yr follow-up | Primary outcome: 13.0% with liraglutide vs 14.9% with placebo HR: 0.87; 95% CI 0.78–0.97; P < .001 for noninferiority; P = .01 for superiority Deaths overall: HR 0.85; 95% CI 0.74–0.97 CV deaths: HR 0.78; 95% CI 0.66–0.93 |
| Semaglutide (2016) | SUSTAIN 6 | N = 3297 patients Randomized, double-blind study in patients with T2D on a standard-care regimen Groups: once-weekly semaglutide (0.5 mg or 1.0 mg) vs placebo; primary composite outcome of CV death, nonfatal MI, or nonfatal stroke; 104-wk follow-up | Primary outcome: 6.6% with semaglutide vs 8.9% with placebo HR: 0.74; 95% CI 0.58–0.95; P < .001 for noninferiority Nonfatal MI: 2.9% semaglutide vs 3.9% placebo; HR: 0.74; 95% CI 0.51–1.08; P = .12 Nonfatal stroke: 1.6% semaglutide vs 2.7% placebo; HR: 0.61; 95% CI 0.38–0.99; P = .04 Rates of death from CV causes were similar in the two groups |
| Canagliflozin (2017) | CANVAS | N = 10142 Randomized, double-blind study in patients with T2D and high CV risk Groups: canagliflozin vs placebo; primary outcome of composite of death from CV causes, nonfatal MI, or nonfatal stroke; mean 188.2-wk follow-up | Primary outcome: 26.9 canagliflozin vs 31.5 placebo per 1000 patient-years HR: 0.86; 95% CI 0.75–0.97; P < .001 for noninferiority; P = .02 for superiority Progression of albuminuria: HR: 0.73; 95% CI 0.67–0.79 Composite outcome of a sustained 40% reduction in estimated glomerular filtration rate, need for renal-replacement therapy, or death from renal causes: HR: 0.60; 95% CI 0.47–0.77 Risk of amputation: 6.3 canagliflozin vs 3.4 placebo participants per 1000 patient-years HR: 1.97; 95% CI 1.41–2.75 |
| Exenatide (2017) | EXSCEL | N = 14752 Randomized, double-blind study in patients with T2D, with or without previous CV disease Groups: extended-release exenatide at dose of 2 mg vs matching placebo once weekly; primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke; median 3.2-yr follow-up | Primary composite outcome: 11.4% with exenatide vs 12.2% with placebo HR: 0.91; 95% CI 0.83–1.00; P < .001 for noninferiority; P = .06 for superiority Rates of death from CV causes, fatal or nonfatal MI, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for ACS did not differ significantly between the two groups. |
| Dapagliflozin (2019) | DECLARE-TIMI 58 | PENDING | Estimated April 2019 |
| Ertugliflozin (2019) | VERTIS | PENDING | Estimated October 2019 |
Table 1.
Cardiovascular outcome trials. CV: cardiovascular; MI: myocardial infarction; USA: unstable angina; ACS: acute coronary syndrome; T2D: type 2 diabetes; HR: hazard ratio; CI: confidence interval; RRR: relative risk reduction
| DRUG (YEAR) | TRIAL | STUDY DESIGN | RESULTS |
|---|---|---|---|
| Alogliptin (2013) | EXAMINE | N = 5380 Randomized, double-blind study in patients with T2D and either an acute MI/USA requiring hospitalization within the previous 15–90 days Groups: alogliptin vs placebo in addition to existing antihyperglycemic and CV drug therapy; primary end point of composite of death from CV causes, nonfatal MI, or nonfatal stroke; 40-mo follow-up | Primary end point: 11.3% with alogliptin vs 11.8% with placebo HR 0.96; [upper bound of the one-sided repeated CI, 1.16]; P < .001 for noninferiority |
| Saxagliptin (2013) | SAVOR-TIMI | N = 16492 Randomized double-blind study in patients with T2D with history of, or at risk for, CV events Groups: saxagliptin vs placebo; primary end point of composite of CV death, MI, or ischemic stroke; secondary end point of composite of CV death, MI, stroke, hospitalization for USA, coronary revascularization, or heart failure; median 2.1-yr follow-up | Primary end point: 7.3% with saxagliptin vs 7/2% with placebo HR 1.00; 95% CI 0.89–1.12; P = .99 for superiority; P < .001 for noninferiority Secondary end point: 12.8% with saxagliptin vs 12.4% with placebo HR 1.02; 95% CI 0.94–1.11; P = .66 Hospitalization for heart failure: 3.5% saxagliptin vs 2.8% placebo; HR: 1.27; 95% CI 1.07–1.51; P = .007 |
| Sitagliptin (2015) | TECOS | N = 14671 Randomized, double-blind study of patients with T2D and CV disease Groups: sitagliptin vs placebo plus existing therapy; primary outcome is composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for USA; median 3-yr follow-up | Primary outcome: 839 patients on sitagliptin (11.4%) vs 851 patients on placebo (11.6%) HR: 0.98; 95% CI: 0.88–1.09; P < .001 Hospitalization for heart failure: HR: 1.00; 95% CI 0.83–1.20; P = .98 |
| Lixisenatide (2015) | ELIXA | N = 6068 Randomized, double-blind study in patients with T2D with MI or USA within the previous 180 days Groups: lixisenatide vs placebo; primary composite end point of CV death, MI, stroke, or hospitalization for USA; median 25-mo follow-up | Primary end point: 13.4% with lixisenatide vs 13.2% with placebo HR: 1.02; 95% CI: 0.89–1.17 Inferiority: P < .001; superiority: P = .81 Rate of hospitalization for heart failure: HR: 0.96; 95% CI 0.75–1.23 Rate of death: HR: 0.94; 95% CI 0.78–1.13 |
| Empagliflozin (2015) | EMPA-REG | N = 7020 Randomized, double-blind study of patients with T2D at high CV risk Groups: 10 mg or 25 mg of empagliflozin vs placebo; primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke; secondary composite outcome of primary outcome plus hospitalization for USA; median 3.1-yr follow-up | Primary outcome: 10.5% with empagliflozin vs 12.1% with placebo HR: 0.86; 95.02% CI 0.74–0.99; P = .04 for superiority Rates of death from CV causes: 3.7% empagliflozin vs 5.9% placebo; 38% RRR Hospitalization for heart failure: 2.7% empagliflozin vs 4.1% placebo; 35% RRR Death from any cause: 5.7% empagliflozin vs 8.3% placebo; 32% RRR |
| Liraglutide (2016) | LEADER | N = 9340 Randomized, double-blind study of patients with T2D and high CV risk Groups: liraglutide 1.8 mg daily vs placebo; primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke; 3.8-yr follow-up | Primary outcome: 13.0% with liraglutide vs 14.9% with placebo HR: 0.87; 95% CI 0.78–0.97; P < .001 for noninferiority; P = .01 for superiority Deaths overall: HR 0.85; 95% CI 0.74–0.97 CV deaths: HR 0.78; 95% CI 0.66–0.93 |
| Semaglutide (2016) | SUSTAIN 6 | N = 3297 patients Randomized, double-blind study in patients with T2D on a standard-care regimen Groups: once-weekly semaglutide (0.5 mg or 1.0 mg) vs placebo; primary composite outcome of CV death, nonfatal MI, or nonfatal stroke; 104-wk follow-up | Primary outcome: 6.6% with semaglutide vs 8.9% with placebo HR: 0.74; 95% CI 0.58–0.95; P < .001 for noninferiority Nonfatal MI: 2.9% semaglutide vs 3.9% placebo; HR: 0.74; 95% CI 0.51–1.08; P = .12 Nonfatal stroke: 1.6% semaglutide vs 2.7% placebo; HR: 0.61; 95% CI 0.38–0.99; P = .04 Rates of death from CV causes were similar in the two groups |
| Canagliflozin (2017) | CANVAS | N = 10142 Randomized, double-blind study in patients with T2D and high CV risk Groups: canagliflozin vs placebo; primary outcome of composite of death from CV causes, nonfatal MI, or nonfatal stroke; mean 188.2-wk follow-up | Primary outcome: 26.9 canagliflozin vs 31.5 placebo per 1000 patient-years HR: 0.86; 95% CI 0.75–0.97; P < .001 for noninferiority; P = .02 for superiority Progression of albuminuria: HR: 0.73; 95% CI 0.67–0.79 Composite outcome of a sustained 40% reduction in estimated glomerular filtration rate, need for renal-replacement therapy, or death from renal causes: HR: 0.60; 95% CI 0.47–0.77 Risk of amputation: 6.3 canagliflozin vs 3.4 placebo participants per 1000 patient-years HR: 1.97; 95% CI 1.41–2.75 |
| Exenatide (2017) | EXSCEL | N = 14752 Randomized, double-blind study in patients with T2D, with or without previous CV disease Groups: extended-release exenatide at dose of 2 mg vs matching placebo once weekly; primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke; median 3.2-yr follow-up | Primary composite outcome: 11.4% with exenatide vs 12.2% with placebo HR: 0.91; 95% CI 0.83–1.00; P < .001 for noninferiority; P = .06 for superiority Rates of death from CV causes, fatal or nonfatal MI, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for ACS did not differ significantly between the two groups. |
| Dapagliflozin (2019) | DECLARE-TIMI 58 | PENDING | Estimated April 2019 |
| Ertugliflozin (2019) | VERTIS | PENDING | Estimated October 2019 |
Table 2.
List of DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors approved by the U.S. Food and Drug Administration and related costs (grouped by drug class). DPP-4: dipeptidyl peptidase 4; GLP-1: glucagon-like peptide-1; SGLT-2: sodium glucose cotransporter 2
| BRAND | GENERIC | MANUFACTURER | ROUTE | FORM | DOSAGE^ | 30-DAY COST* |
|---|---|---|---|---|---|---|
| DPP-4 | ||||||
| Januvia | Sitagliptin phosphate | Merck | oral | tablet | 25 mg | $295 |
| oral | tablet | 50 mg | $295 | |||
| oral | tablet | 100 mg | $295 | |||
| Onglyza | Saxagliptin | Bristol-Myers Squibb | oral | tablet | 2.5 mg | $295 |
| oral | tablet | 5 mg | $295 | |||
| Tradjenta | Linagliptin | Eli Lilly | oral | tablet | 5 mg | $290 |
| Janumet | Sitagliptin phosphate + metformin hydrochloride | Merck Sharp & Dohme Corp. | oral | tablet | 50/500 mg | $295 |
| oral | tablet | 50/1000 mg | $295 | |||
| Nesina | Alogliptin | Takeda | oral | tablet | 6.25 mg | $374 |
| oral | tablet | 12.5 mg | $374 | |||
| oral | tablet | 25 mg | $374 | |||
| GLP-1 | ||||||
| Victoza | Liraglutide | Novo Nordisk | Subcutaneous | Injection | 3 pens of 18 mg/3 mL, 1 carton | $831 |
| Trulicity | Dulaglutide | Eli Lilly | Subcutaneous | Injection | 4 pens of 1.5 mg/0.5 mL, 1 carton | $733 |
| Bydureon | Exenatide | AstraZeneca | Subcutaneous | Injection | 4 pens of 2 mg/pen, 1 kit | $682 |
| Byetta | Exenatide | AstraZeneca | Subcutaneous | Injection | 10 mcg, 1 pen | $731 |
| Saxenda | Liraglutide | Novo Nordisk | Subcutaneous | Injection | Five 3-mL pens of 3 mg/0.5 mL, 1 carton | $1233 |
| Ozempic | Semaglutide | Novo Nordisk | Subcutaneous | Injection | 1 pen of 0.25 mg/0.5 mg, 1 carton | $698 |
| Adlyxin | Lixisenatide | Sanofi | Subcutaneous | Injection | Two 3-mL pens of 20 mcg, 1 carton | $610 |
| SGLT-2 | ||||||
| Invokana | Canagliflozin | Janssen | Oral | Tablet | 300 mg | $482 |
| Jardiance | Empagliflozin | Eli Lilly | Oral | Tablet | 25 mg | $449 |
| Farxiga | Dapagliflozin | AstraZeneca | Oral | Tablet | 10 mg | $482 |
| Steglatro | Ertugliflozin | Merck | Oral | Tablet | 5 mg | $282 |