Prediabetes and risk of mortality, diabetes-related complications and comorbidities: umbrella review of meta-analyses of prospective studies

Abstract

Aims/hypothesis: The term prediabetes is used for individuals who have impaired glucose metabolism whose glucose or HbA_1c levels are not yet high enough to be diagnosed as diabetes. Prediabetes may already be associated with an increased risk of chronic 'diabetes-related' complications. This umbrella review aimed to provide a systematic overview of the available evidence from meta-analyses of prospective observational studies on the associations between prediabetes and incident diabetes-related complications in adults and to evaluate their strength and certainty.

Methods: For this umbrella review, systematic reviews with meta-analyses reporting summary risk estimates for the associations between prediabetes (based on fasting or 2 h postload glucose or on HbA_1c) and incidence of diabetes-related complications, comorbidities and mortality risk were included. PubMed, Web of Science, the Cochrane Library and Epistemonikos were searched up to 17 June 2021. Summary risk estimates were recalculated using a random effects model. The certainty of evidence was evaluated by applying the GRADE tool. This study is registered with PROSPERO, CRD42020153227.

Results: Ninety-five meta-analyses from 16 publications were identified. In the general population, prediabetes was associated with a 6-101% increased risk for all-cause mortality and the incidence of cardiovascular outcomes, CHD, stroke, heart failure, atrial fibrillation and chronic kidney disease, as well as total cancer, total liver cancer, hepatocellular carcinoma, breast cancer and all-cause dementia with moderate certainty of evidence. No associations between prediabetes and incident depressive symptoms and cognitive impairment were observed (with low or very low certainty of evidence). The association with all-cause mortality was stronger for prediabetes defined by impaired glucose tolerance than for prediabetes defined by HbA_1c.

Conclusions/interpretation: Prediabetes was positively associated with risk of all-cause mortality and the incidence of cardiovascular outcomes, CHD, stroke, chronic kidney disease, cancer and dementia. Further high-quality studies, particularly on HbA_1c-defined prediabetes and other relevant health outcomes (e. g. neuropathy) are required to support the evidence.

Keywords: Complications; Meta-analysis; Mortality; Prediabetes; Systematic review; Umbrella review.

Fig. 1

Flow chart of the study selection process

Fig. 2

Associations between prediabetes and risk of diabetes-related complications, comorbidities and mortality among the general population. ^aInterpretation of the certainty of evidence is denoted by crossed circles: four symbols, high; three symbols, moderate; two symbols, low; and one symbol, very low. ^bCould not be recalculated because of missing information. ^cIndividuals with diabetes at follow-up were excluded. Boldface indicates that the 95% CI does not include the null value and findings are precisely estimated. CoE, certainty of evidence; CV, cardiovascular; N, number of primary studies; na, not available; RoB, risk of bias

Fig. 3

Associations between prediabetes and risk of CVD, cardiovascular mortality and overall mortality among patients with pre-existing diseases. ^aInterpretation of the certainty of evidence is denoted by crossed circles: four symbols, high; three symbols, moderate; two symbols, low; and one symbol, very low. ^bPatients with atherosclerotic CVD. ^cPatients after percutaneous coronary intervention. ^dPatients with history of stroke/transient ischaemic attack. ^ePoor outcome of stroke defined as degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. Boldface indicates that the 95% CI does not include the null value and findings are precisely estimated. CoE, certainty of evidence; CV, cardiovascular; N, number of primary studies; MACE, major adverse cardiac events; RoB: Risk of bias