PracticeUpdate Diabetes March 2019

EDITOR’S PICKS 9

Analysis of HbA1c as a Risk Factor for Coronary Artery Disease Diabetes Care

Take-home message • The authors sought to determine whether genet- ically elevated HbA1c is causally associated with coronary artery disease (CAD), using Mendelian randomization. Upon including 50 HbA1c-asso- ciated variants from a GWAS study of 159,940 participants, the authors found that CAD risk was increased among those with HbA1c variants resulting in increased HbA1c levels (OR, 1.61; P = 6.9 × 10 −12 ). This finding remained significant when looking at either glycemic or erythrocytic variants alone (OR, 2.23 and 1.30, respectively). • The authors conclude that these results suggest a causal relationship between elevated HbA1c levels and risk of CAD, which is driven by both glycemic and nonglycemic factors. Abstract OBJECTIVE Observational studies show that higher hemoglo- bin A1c (A1C) predicts coronary artery disease (CAD). It remains unclear whether this association is driven entirely by glycemia. We used Mendelian randomization (MR) to test whether A1C is causally associated with CAD through glycemic and/or nong- lycemic factors. RESEARCHDESIGNANDMETHODS To examine the association of A1C with CAD, we selected 50 A1C-associated variants (log10 Bayes factor ≥6) from an A1C genome-wide association study (GWAS; n = 159,940) and performed an inverse-variance weighted average of variant-specific causal estimates from CAD GWAS data (CAR- DIoGRAMplusC4D; 60,801 CAD case subjects/123,504 control subjects). We then replicated results in UK Biobank (18,915 CAD case subjects/455,971 control subjects) and meta-analyzed all results. Next, we conducted analyses using two subsets of var- iants, 16 variants associated with glycemic measures (fasting or 2-h glucose) and 20 variants associated with erythrocyte indices (e.g., hemoglobin [Hb]) but not glycemic measures. In additional MR analyses, we tested the association of Hb with A1C and CAD. RESULTS Genetically increased A1C was associated with higher CAD risk (odds ratio [OR] 1.61 [95% CI 1.40, 1.84] per %-unit, P = 6.9 × 10 −12 ). Higher A1C was associated with increased CAD risk when using only glycemic variants (OR 2.23 [1.73, 2.89], P = 1.6 × 10 −9 ) and when using only erythrocytic variants (OR 1.30 [1.08, 1.57], P = 0.004). Genetically decreased Hb, with concom- itantly decreased mean corpuscular volume, was associated with higher A1C (0.30 [0.27, 0.33] %-unit, P = 2.9 × 10 −6 ) per g/dL and higher CAD risk (1.18 [1.04, 1.33], P = 0.009). CONCLUSIONS Genetic evidence supports a causal link between higher A1C and higher CAD risk. This relationship is driven not only by glycemic but also by erythrocytic, glycemia-independ- ent factors. Mendelian Randomization Analysis of Hemoglobin A1c as a Risk Factor for Coronary Artery Disease. Diabetes Care 2019 Jan 18;[EPub Ahead of Print], A Leong, J Chen, E Wheeler, et al.

FINDINGS We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 par- ticipants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean albuminuria by the treat- ment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R 2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with base- line albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R 20·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the con- trol will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. INTERPRETATION Our results support a role for change in albuminuria as a sur- rogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Change in Albuminuria as a Surrogate Endpoint for Progression of Kidney Disease: A Meta-Analysis of Treatment Effects in Randomised Clinical Trials. Lancet Diabetes Endocrinol 2019 Jan 08;[EPub Ahead of Print], HJL Heerspink, results provide high confidence that lowering albuminuria is a prudent clinical approach to reducing the risk of progressive kidney disease. " " The results of these two large meta-analyses examining both observation and randomized study

T Greene, H Tighiouart, et al. www.practiceupdate.com/c/78482

www.practiceupdate.com/c/78749

VOL. 3 • NO. 1 • 2019