Associations between Prediabetes and Vascular Complications

Do patients with prediabetes share the same risk of vascular complications seen in patients with T2D? 

It is estimated that 33.9% of US adults have prediabetes. Though glucose metabolism is not impaired to the extent of type 2 diabetes, 30-50% of individuals with prediabetes develop T2D within five years of impaired metabolism onset. Lifestyle management is recommended to prevent the progression of prediabetes by reducing risk factors of T2D, such as promoting smoking cessation, dietary modification, and weight loss. Patients at higher risk of developing T2D (women with a history of GDM and individuals with a BMI ≥ 35 kg/m2 or >60 yrs old) can also be prescribed metformin for diabetes prevention. Prediabetes has been associated with higher cardiovascular risk, but associations between micro- and macrovascular complications commonly seen in patients with T2D are unclear.  

This study was designed to analyze the relationship between prediabetes and the risk of micro- and macrovascular complications, including CKD, CAD, and stroke. It consisted of a meta-analysis, including 37 observation studies that pooled data from 1,326,915 participants. Mendelian randomization (MR) was also conducted to confirm the causal inference of the analysis. For the articles to be included in the meta-analysis, baseline glycemia measurements had to be available. The outcomes assessed had to include CKD, CAD, or stroke, comparison to normoglycemic participants was required, and the participants of the studies had to pull from the general population. Studies were excluded from any participants’ analysis if they had confirmed diabetes diagnoses or hyperglycemic laboratory measurements at baseline or follow-up. The median follow-up for the studies was 9.6 years. 

The MR was designed to test whether A1c and nondiabetic IFG had a causal relationship with CKD development, CAD, and stroke by utilizing SNPs with nondiabetic glycemic traits that show no risk of type 2 diabetes. The analysis only included participants of European descent to reduce population stratification bias. All data for the MR was drawn from the GWAS database.  

The meta-analysis demonstrated a 16% increased risk of developing CAD associated with prediabetes participants than normoglycemic patients (RR 1.16; 95% CI 1.09 – 1.23). Patients with prediabetes were also associated with an 11% increased risk for stroke (RR 1.11; 95% CI 1.03 – 1.18). No significant difference was seen in the associated risk of CKD between participants with prediabetes and patients who were normoglycemic (95% CI 0.98 – 1.12). Though the MR did find a causal relationship between variations in nondiabetic FBG and CAD, a causal relationship was not found between patients with prediabetes in the associated risk of CKD or stroke (CKD: 95% CI 0.87 – 1.25; any stroke: 955 CI 0.64 – 1.07). Patients had 29% higher odds of developing CAD (OR 1.29; 95% CI 1.13 – 1.47) and 26% higher odds per 1 mmol/L increase in FBG (OR 1.26; 95% CI 1.16 – 1.38). 

Sensitivity analyses performed showed no significant association between type 2 diabetes and SNPs with solely prediabetes traits (95% CI 0.82 – 1.14) but found a strong causal relationship between type 2 diabetes and all significant SNPs relating to FBG (p < 0.01). 

Whereas a meta-analysis of observational studies found that prediabetes is associated with a slightly increased risk of CAD and stroke, MR found that prediabetic FBG without traits of type 2 diabetes was only associated with higher odds of developing CAD. Further study could be conducted to determine if patients could benefit from interventions that prevent diabetes-related CAD before the onset of diabetes. 

Practice Pearls: 

• Though meta-analysis found that prediabetes is associated with a slightly increased risk of CAD and stroke, MR only identified a causal relationship between prediabetes and CAD development risk.
• No causal relationship was found between prediabetes and CKD in either analysis.
• Further studies could be conducted to determine if patients could benefit from interventions that prevent diabetes-related CAD before the onset of diabetes.

References for “Associations between Prediabetes and Vascular Complications”:

“Standards Of Medical Care In Diabetes—2020 Abridged For Primary Care Providers”. Vol 38, no. 1, 2019, pp. 10-38. American Diabetes Association, https://doi.org/10.2337/cd20-as01. Accessed October 10, 2020. 

Mutie, Pascal M. et al. “An Investigation Of Causal Relationships Between Prediabetes And Vascular Complications.” Nature Communications, vol 11, no. 1, 2020. Springer Science And Business Media LLC, https://doi.org/10.1038/s41467-020-18386-9. Accessed October 8, 2020. 

Destiny Reed, PharmD. Candidate, Florida A&M College of Pharmacy and Pharmaceutical Sciences