Table 2.

Overview of key efficacy and safety outcomes in studies where patients achieved very low LDL‐C levels

Study name	Proportion of patients achieving very low LDL‐C	Key efficacy outcomes in patients achieving very low LDL‐C	Key safety outcomes in patients achieving very low LDL‐C
Statin monotherapy studies
TNT20	9769 of 10 001 patients enrolled in the study had LDL‐C measurements at 3 months These patients were stratified into quintiles according to achieved LDL‐C LDL‐C <1.7 mmol/L (<64 mg/dL): 19% of patients LDL‐C <1.0 mmol/L (<40 mg/dL): 1% of patients	The lowest rate of primary end‐pointa occurred in the <1.7 mmol/L quintile (P<.0001 for trend) For the total TNT cohort, each 1 mg/dL reduction in LDL‐C was associated with a 0.7% reduction in the relative risk of primary end‐point (P<.0001)	No difference in the treatment‐associated AE profile (including muscle‐related AEs) across LDL‐C levels No significant trend in the incidence of mortality, suicide, haemorrhagic stroke or cancer deaths across LDL‐C levels Haemorrhagic stroke: 0.3% in <1.7 mmol/L quintile vs. 0.3–0.4% in other quintiles
PROVE IT‐TIMI 2221	1949 of 4162 patients enrolled in the study had LDL‐C measurements at 4 months These patients were stratified into groups according to achieved LDL‐C LDL‐C ≤1.0 mmol/L (<40 mg/dL): 10% of patients	Patients in the LDL‐C ≤1.0 mmol/L and >1.0–1.6 mmol/L groups had the lowest rate of primary end‐pointb (P=.1 for trend) Risk of primary end‐point compared with the >2.1–2.6 mmol/L group: ○ ≤1.0 mmol/L group: HR=0.61 (95% CI, 0.40–0.91) ○ 1.0–1.6 mmol/L group: HR=0.67 (95% CI, 0.50–0.92)	No differences in safety parameters (including muscle and liver side effects, haemorrhagic stroke, retinal AEs and mortality) across LDL‐C levels Haemorrhagic stroke: one case recorded in each of the 1.6–2.1 and 2.1–2.5 mmol/L groups
JUPITER22, 63	8154 patients who received rosuvastatin were stratified into groups according to achieved LDL‐C LDL‐C <1.3 mmol/L (<50 mg/dL): 51% of patients LDL‐C <0.8 mmol/L (<30 mg/dL): 5% of patients	Risk of primary end‐pointc compared with the placebo group: ○ LDL‐C ≥1.3 mmol/L: HR=0.76 (95% CI, 0.57–1.00) ○ LDL‐C <1.3 mmol/L: HR=0.35 (95% CI, 0.25–0.49) ○ P<.0001 for trend	Increases in the risk of type 2 diabetes, haematuria and certain musculoskeletal, hepatobiliary and psychiatric AEs in patients with LDL‐C <0.8 mmol/L No differences in the incidence of renal failure, cancer, memory impairment or haemorrhagic stroke across LDL‐C levels Haemorrhagic stroke: eight cases recorded in the placebo group vs. five in the rosuvastatin group; only one case recorded in the <1.3 mmol/L group
Statin + ezetimibe combination study
IMPROVE‐IT23	15 191 of 18 144 patients enrolled in the study had LDL‐C measurements at 1 month These patients were stratified into groups according to achieved LDL‐C LDL‐C 0.8 to <1.3 mmol/L (30–<50 mg/dL): 30% of patients LDL‐C <0.8 mmol/L (<30 mg/dL): 6% of patients	The risk of primary end‐pointd was significantly reduced in patients with LDL‐C <1.3 mmol/L vs. ≥1.3 mmol/L (HR=0.90; 95% CI, 0.85–0.96; P=.002)	No increase in AEs (including muscle, liver, gall bladder and neurocognitive AEs), cancer, haemorrhagic stroke or non‐CV death across LDL‐C levels
Statin + PCSK9 inhibitor combination studies
ODYSSEY LONG TERM24	1553 patients received alirocumab LDL‐C <0.6 mmol/L (<25 mg/dL): 37% of patients	N/A	Rates of AEs were similar in patients with LDL‐C <0.6 mmol/L compared with the overall alirocumab group Fatal or non‐fatal ischaemic stroke: 0.6% in alirocumab group vs. 0.3% in placebo group Incidence of haemorrhagic stroke not reported
OSLER‐1 and OSLER‐225	2976 patients received evolocumab LDL‐C <0.6 mmol/L (<25 mg/dL): 26% of patients	N/A	Rates of AEs (including muscle and neurocognitive AEs) and elevations in aminotransferase and creatine kinase levels were similar across LDL‐C levels Stroke: 0.1% in either group Transient ischaemic attack: 0% in evolocumab group vs. 0.3% in control group Incidence of haemorrhagic stroke not reported

AE, adverse event; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; LDL‐C, low‐density lipoprotein cholesterol; MI, myocardial infarction; N/A, not applicable; PCSK9, proprotein convertin subtilisin/kexin type 9; UA, unstable angina.^aIn the TNT study, the primary end‐point was defined as death from coronary heart disease, non‐fatal, non‐procedure‐related MI, resuscitation after cardiac arrest or fatal or non‐fatal stroke.^bIn the PROVE IT‐TIMI 22 study, the primary end‐point was defined as a composite of death, MI, stroke, revascularisation and UA requiring hospitalisation. ^cIn the JUPITER study, the primary end‐point was defined as a composite of MI, stroke arterial revascularisation, UA or death from CV causes.^dIn the IMPROVE‐IT study, the primary end‐point was defined as a composite of CV death, MI, UA, coronary revascularisation ≥30 days after randomisation or stroke.