Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
New England Journal of Medicine, 2016 · paper · Clinical trials
A randomized trial of empagliflozin versus placebo in 7,020 type 2 diabetes patients at high cardiovascular risk. Empagliflozin lowered the composite of cardiovascular death, heart attack or stroke, and lowered death from any cause, with more genital infections.
4 findings
Substance The Discussion gives "an adjusted mean glycated hemoglobin level at week 206 of 7.81% in the pooled empagliflozin group and 8.16% in the placebo group", but the per-dose differences of −0.24 and −0.36 points and Figure 3 put the 10-mg group at about 7.92% and the 25-mg group at about 7.81%.
- p. 9 Discussion
hemoglobin level at week 206 of 7.81% in the pooled empagliflozin group and 8.16% in the
- p. 7 Results, Glycemic Control
206, the differences were −0.24 percentage points
- p. 9 Figure 3, week 206
Empagliflozin 25 mg
- p. 7 Results, Glycemic Control
−0.24 percentage points (95% CI, −0.40 to −0.08) and −0.36 per-centage points
Only the authors can say what is right here.
Judge's note: On p9, Figure 3 at week 206 shows placebo at about 8.16, 10 mg at about 7.93 and 25 mg at about 7.81. The p7 Results give week-206 differences of −0.24 and −0.36. A pooled mean should fall between the two dose groups (about 7.86), but the printed pooled value equals the 25-mg value. The pooled figure may come from a separate model, so only the authors can confirm it.
Second check: another model agreed
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Wording Author Theresa Devins, whose affiliation is "Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (T.D.)", is not among the authors listed as "being employees of Boehringer Ingelheim", and the statement ends "No other potential conflict of interest relevant to this article was reported."
- p. 11 Disclosures
Drs. Bluhmki, Hantel, Johansen, Woerle, and Broedel and Ms. Mattheus, be-ing employees of Boehringer Ingelheim
- p. 1 Affiliations
Boehringer Ingelheim Pharmaceuticals, Ridge-field, CT (T.D.)
Only the authors can say what is right here.
Judge's note: Checked the p1 affiliations and the p11 disclosure paragraph. A text search finds no 'Devins' in the disclosures. Every other author with a Boehringer Ingelheim affiliation is listed as an employee. Only the authors can confirm whether this is an omission.
Second check: another model agreed
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Wording The confirmed hypoglycemic adverse event is defined as "plasma glucose level, ≤70 mg per deciliter [3.9 mmol per liter]" in Methods (p3) but as "a plasma glucose level of less than 70 mg per deciliter (3.9 mmol per liter)" in the Table 2 ¶ footnote (p10).
- p. 3 Study Outcomes
plasma glucose level, ≤70 mg per deciliter [3.9 mmol per liter]
- p. 10 Table 2 footnote ¶
a plasma glucose level of less than 70 mg per deciliter (3.9 mmol per liter)
- p. 3 Study Outcomes
plasma glucose level, ≤70 mg
- p. 10 Table 2 footnote ¶
a plasma glucose level of less than 70 mg per deciliter
Only the authors can say what is right here.
Judge's note: Both images were checked. The Methods text clearly shows the ≤ symbol, and the Table 2 footnote says 'less than'. The two definitions differ exactly at 70 mg/dl. Only the authors can say which threshold was used.
Second check: another model agreed
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Wording Results list "acute renal failure" among events whose proportions "were similar in the two study groups", but Table 2 gives 155 (6.6%) vs 246 (5.2%)§ (P<0.01), and the Discussion says acute renal failure "was lower in the empagliflozin groups than in the placebo group".
- p. 7 Results, Safety and Adverse Events
adverse events, acute renal failure, diabetic keto-
- p. 10 Table 2, Acute renal failure row
246 (5.2)§
- p. 11 Discussion
acute renal failure (including acute kidney injury) was lower in the empagliflozin groups than in the placebo group
- p. 7 Results, Safety and Adverse Events
adverse events, acute renal failure, diabetic keto-acidosis, thromboembolic events, bone fracture, and events consistent with volume depletion were similar in the two study groups
Judge's note: Checked the p7 Results text, the p10 Table 2 row 'Acute renal failure' (placebo 155 (6.6); pooled 246 (5.2)§, where the § footnote means P<0.01 vs placebo), and the p11 Discussion. The Results sentence contradicts both the table flag and the Discussion. The evident fix is to drop acute renal failure from the 'similar' list.
Second check: another model agreed
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5 minor (typos and the like; most checked by the judge only)
Wording The key secondary outcome is reported with "hazard ratio, 0.89; 95% CI, 0.78 to 1.01", while the final hierarchical tests use a two-sided 0.0498 level and the primary outcome is reported with a 95.02% CI.
- p. 4 Results, Cardiovascular Outcomes
(hazard ratio, 0.89; 95% CI, 0.78 to 1.01;
- p. 4 Statistical Analysis
two-sided 95.02% confi-
Judge's note: On p3 and p4 the Methods give the Haybittle–Peto two-sided level of 0.0498 for the final analyses, which covers the four hierarchical tests including the key secondary outcome. The 95.02% CI is mentioned explicitly only for primary-outcome noninferiority. Results report the key secondary interval as 95% CI, so the reader cannot tell which confidence level was used. The practical difference would be negligible.
Second check: another model agreed
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Wording Results say proportions with adverse events, serious adverse events and adverse events leading to discontinuation "were similar in the empagliflozin group and the placebo group (Table 2)", while Table 2 flags 4230 (90.2)†, 1789 (38.2)† and 813 (17.3)§ as significantly different from placebo.
- p. 7 Results, Safety and Adverse Events
leading to the discontinuation of a study drug were similar in the empagliflozin group and the placebo group (Table 2)
- p. 10 Table 2
4230 (90.2)†
- p. 10 Table 2
1789 (38.2)†
- p. 10 Table 2
813 (17.3)§
Judge's note: In Table 2 (p10), † means P<0.001 and § means P<0.01. Placebo values are 91.7%, 42.3% and 19.4%. The absolute differences are small and favour empagliflozin, so 'similar' may be meant clinically. Still, the text cites the table, and the table marks each difference as significant.
Second check: another model agreed
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Typo Author name misspelled in the disclosures: "Hantel, Johansen, Woerle, and Broedel and Ms. Mattheus". The byline and references 18 and 22 spell it "Broedl".
- p. 11 Disclosures
Hantel, Johansen, Woerle, and Broedel and Ms. Mattheus
- p. 1 Author byline
Uli C. Broedl, M.D.
- p. 11 Disclosures
Hantel, Johansen, Woerle, and Broedel
- p. 11 Disclosures
Woerle, and Broedel and Ms. Mattheus
Judge's note: The p11 image shows 'Broedel'. The byline on p1 has 'Uli C. Broedl', and references 18 and 22 use 'Broedl UC'.
Second check: none (judge only)
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Typo Duplicated word in Study Oversight: "the Declaration of Helsinki and the the International Conference on Harmonisation".
- p. 2 Methods, Study Oversight
the the International Conference on Harmonisa-
- p. 2 Methods, Study Oversight
the the International Conference on Harmonisa-tion
Judge's note: The p2 page image shows "and" at the end of one line and "the the International Conference" on the next line, so both 'the's sit on the same printed line. This is not an extraction artefact.
Second check: none (judge only)
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Typo Stray article: "Sensitivity analyses are described in the Section F in the Supplementary Appendix."
- p. 4 Statistical Analysis
scribed in the Section F in the Supplementary
Judge's note: The p4 image shows 'in the Section F'. Every other supplement pointer in the paper reads 'in Section X'.
Second check: none (judge only)