Differential cardiovascular profiles of sodium-glucose cotransporter 2 inhibitors: critical evaluation of empagliflozin

Figures & data

Table 1 Relevant major CV outcome studies with oral hypoglycemics

Trial	Details	Results	Comments
UKPDS^Citation6	• N=4,075 patients with DM • Primary end point  ○ Death  ○ All-cause mortality  ○ DM-related end point • Secondary end point  ○ MI, CVA, PVD, microvascular events • Nonoverweight patients randomized to either intensive therapy with sulfonylurea, insulin, or diet • Subset of 342 overweight patients randomized to metformin, intensive therapy with a sulfonylurea, or insulin.	• Improvement in microvascular events but no improvement in macrovascular events in nonoverweight patients • In the overweight subgroup, metformin  ○ Reduced all-cause mortality 36% (9–55, P=0.011)  ○ Reduced diabetes-related death 42% (9–63, P=0.017)   Risk reductions of 32% (95% CI: 13–47, P=0.002) for any diabetes-related end point.	• Increased mortality in a subgroup of patients given metformin and sulfonylurea.
PROACTIVE^Citation5	• N=5,238 patients with type 2 DM and macrovascular disease (MI or CVA within 6 mo, PCI or CABG within 6 mo or objective evidence of CAD or PVD). • Randomized to pioglitazone or placebo • Primary end point  ○ All-cause mortality, nonfatal MI, CVA, ACS, vascular intervention, or amputation • Secondary end points  ○ Death from any cause, MI (excluding silent MI), and CVA.	• Significant decrease in the secondary outcome in pioglitazone vs placebo 301 vs 358; HR 0.84; CI: 0.72–0.98; P=0.027.	• Statistically significant increase in heart failure events (417 vs 302; P<0.0001) in the treatment group.
EMPA-REG OUTCOME^Citation18	• N=7,020 patients with cardiovascular disease to either empagliflozin or placebo • Primary outcome  ○ Death from cardiovascular causes, nonfatal MI, (excluding silent MI), or nonfatal stroke. • Secondary outcome  ○ Composite of the primary outcome plus hospitalization for unstable angina.	• Reduction in primary composite outcome at 10.5% vs 12.1%, HR 0.86, CI: 0.74–0.99, P=0.04 • Reduction in CV death 3.7% vs 5.9%, HR 0.62, CI: 0.49–0.77, P<0.001 • Reduced all-cause mortality 5.7% vs 8.3%, HR 0.68, CI: 0.57–0.82, P<0.001 • Reduced hospitalizations for heart failure 2.7% vs 4.1%, HR 0.65, CI: 0.50–0.85 • Reduction in weight, waist circumference, and systolic blood pressure.	• Increased genital infections (6.4% vs 1.8%; P<0.001).

Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; DM, diabetes mellitus; MI, myocardial infarction; CVA, cardiovascular accident; mo, months; CAD, coronary artery disease; HR, hazard ratio; CI, confidence interval; PVD, peripheral vascular disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graph.

Figure 1 The recent hypoglycemia trials for diabetes with cardiovascular event rates per year.

Note: Note the marked reduction in CV death, hospitalizations for heart failure, and all-cause mortality with empagliflozin.
Abbreviations: CV, cardiovascular; SGLT2, sodium-glucose cotransporter 2; NS, nonsignificant; SAVOR, saxagliptin reduce the risk of cardiovascular events; EXAMINE, examination of cardiovascular outcomes with alogliptin versus standard of care; TECOS, trial evaluating cardiovascular outcomes with sitagliptin; EMPA-REG, empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.

Figure 2 The macula densa and SGLT2 inhibitors.

Notes: The effect of marked diuresis and flow changes could have major impact on activation of macular densa cells. Recent reports have noted significant changes in aldosterone levels. Clinical importance remains to be determined.
Abbreviation: SGLT2, sodium-glucose cotransporter 2.

Figure 3 Three large CV outcome trials have increasing cardiovascular event rates as diabetes is added to high-risk patients.

Notes: There is increase in the percentage of patients with hypertension in the more recent diabetes trials. 4S trial simvastatin: 182/2,221 (8.2%), placebo: 256/2,223 (11.5%) HR =0.71 (0.59–0.85), HOPE trial ramipril: 482/4,645 (10.4%), placebo: 569/4,652 (12.2%) HR =0.85 (0.76–0.95), EMPA-REG empa: 269 (5.7%)/2,333, placebo: 194 (8.3%)/4,687 HR =0.68 (0.57–0.82). The number needed to treat calculations find that empagliflozin in only 3 years has a NNT that is very close to 4S that needed 5.4 years to have NNT of 30.
Abbreviations: CV, cardiovascular; HR, hazard ratio; NNT, number needed to treat; HT, hypertension.

Figure 4 Potential mechanism reducing cardiovascular events.

Figure 5 The vascular wall in patients with diabetes is well known to have advanced atherosclerosis.

Notes: The wall stress increases stress on the diseased diabetes vascular wall leading to plaque fracture. The thin cap is not as elastic, and the stiffness of this plaque cap increases the risk for plaque rupture. In addition, the cap frequently is much thinner with a necrotic core as seen in the PROSPECT trial.^23,49
Abbreviations: BP, blood pressure; NIRS, near infrared spectroscopy; ROS, reactive oxygen species; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; OCT, optical coherence tomography; NO, nitric oxide.

Figure 6 Reductions in systolic blood pressure are well known to reduce CV risk from multiple studies.

Notes: These three large trials found similar benefits with the caveat that EMPA-REG has an impressive reduction in CV death. This suggests that SGLT2 inhibitors may have multiple mechanisms related to reducing CV events in diabetic patients.
Abbreviations: CV, cardiovascular; SGLT2, sodium-glucose cotransporter 2; SBP, systolic blood pressure.

Figure 7 The significant reduction in both CV deaths and hospitalization for heart failure.

Abbreviations: CV, cardiovascular; MI, myocardial infarction; CVA, cardiovascular accident; hosp, hospitalization; HF, heart failure.

Table 2 Keypoints and clinical impact of empagliflozin

Outcomes vs placebo:

Reduction in CV death (3.7% vs 5.9%, HR 0.62)

Reduction in all-cause mortality (5.7% vs 8.3%, HR 0.68)

Reduction in hospitalization for heart failure (2.7% vs 4.1%, HR 0.65)

Surrogate effects:

Osmotic diuresis

Lowers blood sugar: HbA1c reduction of −0.66%^Citation21

Lowers blood pressure: WMD reduction of −4.19 mmHg/−1.88 mmHg^Citation21

Lowers weight: 1.84 kg reduction^Citation21

Lowers waist circumference: ~2 cm reduction^Citation18

Decrease in pulse pressure: 2.3 mmHg reduction^Citation27

Increases HDL: increases ~2 mg/dL^Citation18

Decreases uric acid: decreases 0.4 mg/dL^Citation18

Abbreviations: CV, cardiovascular; HR, hazard ratio; HbA1c, hemoglobin A1C; WMD, weighted mean difference; HDL, high-density lipoprotein.

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)Lancet199835291318548659742977

 PubMed Web of Science ®Google Scholar

DormandyJACharbonnelBEcklandDJSecondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone clinical trial in macroVascular events): a randomised controlled trialLancet200536694931279128916214598

 PubMed Web of Science ®Google Scholar

ZinmanBWannerCLachinJMEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetesN Engl J Med2015373222117212826378978

 PubMed Web of Science ®Google Scholar

OjimaAMatsuiTNishinoYNakamuraNYamagishiSEmpagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axisHorm Metab Res201547968669225611208

 PubMed Web of Science ®Google Scholar

OkadaMMatsumoriAOnoKCyclic stretch upregulates production of interleukin-8 and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in human endothelial cellsArterioscler Thromb Vasc Biol19981868949019633928

 PubMed Web of Science ®Google Scholar

LiakosAKaragiannisTAthanasiadouEEfficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysisDiabetes Obes Metab2014161098499324766495

 PubMed Web of Science ®Google Scholar

ChiltonRTikkanenICannonCPEffects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetesDiabetes Obes Metab201517121180119326343814

 PubMed Web of Science ®Google Scholar