Background Previous studies reported that low levels of glycated hemoglobin A1c (HbA1c) were associated with increased mortality. We investigated rates and risks of all-cause and cardiovascular mortality in association with mean HbA1c levels with stratification of anemia and chronic kidney disease (CKD) stages, major causes of low HbA1c. Methods 47,145 patients with prescription of antidiabetic agents >6 months in the outpatient visits (2003–2018) were linked to Taiwan’s National Death Registry to identify all-cause and cardiovascular mortality. Poisson assumption was used to estimate the mortality rates, and the Cox proportional hazard regression model was used to evaluate the relative hazards of respective mortality in relation to mean HbA1c in different statuses of anemia and CKD stages. Results All-cause and cardiovascular mortality rates were the lowest in non-anemic stages 1–2 CKD patients, and the highest in anemic stages 3–5 CKD patients. In stages 1–2 CKD, excessive HRs observed in those with mean HbA1c <6.0% (Hazard Ratio [HR]) 1.58; 95% Confidence Interval [CI] 1.18–2.12) became inconsequential after adjustment of medications and laboratory results (HR: 1.26; 95% CI 0.89–1.79). The similar patterns were observed in anemic stages 1–2 CKD, anemic or non-anemic stages 3–5 CKD. Low HbA1c was not related to cardiovascular mortality in any anemia status or CKD staging. Conclusions Higher risks associated with low mean HbA1c and all-cause mortality were attenuated by adjustment of medications and comorbidities. It is imperative for the diabetologists to consider confounding effects of underlying illness before concluding low HbA1c associated higher mortality.

Background The optimal levels of low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes (T2D) are not currently clear. In this study, we determined the relationship between various mean LDL-C and all-cause or cardiovascular mortality risks in patients with T2D, stratifying by albumin level, age, sex, and antilipid medication use. We also evaluated the association of LDL-C standard deviation (LDL-C-SD) and all-cause and cardiovascular mortality by type of antilipid medication use. Methods A total of 46,675 T2D patients with a prescription for antidiabetic agents >6 months from outpatient visits (2003–2018) were linked to Taiwan’s National Death Registry to identify all-cause and cardiovascular mortality. The Poisson assumption was used to estimate mortality rates, and the Cox proportional hazard regression model was used to assess the relative hazards of respective mortality in relation to mean LDL-C in patient cohorts by albumin level, age, sex, and antilipid use adjusting for medications, comorbidities, and laboratory results. We also determined the overall, and anti-lipid-specific mortality rates and relative hazards of all-cause and cardiovascular mortality associated with LDL-C-SD using the Poisson assumption and Cox proportional hazard regression model, respectively. Results All-cause and cardiovascular mortality rates were the lowest in T2D patients with a mean LDL-C > 90-103.59 mg/dL in the normal albumin group (≥ 3.5 g/dL). Compared to T2D patients with a mean LDL-C > 90–103.59 mg/dL, those with a mean LDL-C ≤ 77 mg/dL had an elevated risk of all-cause mortality in both the normal and lower albumin groups. T2D patients with a mean LDL-C ≤ 90 and > 103.59–119 mg/dL had relatively higher risk of cardiovascular mortality in the normal albumin group, but in the lower albumin group (<3.5 g/dL), any level of mean LDL-C ≤ 119 mg/dL was not significantly associated with cardiovascular mortality. Increased risks of all-cause and cardiovascular mortality were observed in patients with a mean LDL-C ≤ 77 mg/dL in both sexes and in all age groups except in those aged <50 years, a lower mean LDL-C was not associated with cardiovascular mortality. Similarly, patients with an LDL-C-SD <10th and > 90th percentiles were associated with significant risks of all-cause and cardiovascular mortality. In statin users, but not fibrate users, lower and higher levels of mean LDL-C and LDL-C-SD were both associated with elevated risks of all-cause and cardiovascular mortality. Conclusions The optimal level of LDL-C was found to be >90–103.59 mg/dL in T2D patients. Lower and higher levels of mean LDL-C and LDL-C-SD were associated with all-cause and cardiovascular mortality, revealing U-shaped associations. Further studies are necessary to validate the relationship between optimal LDL-C levels and all-cause and cardiovascular mortality in patients with diabetes.

Background: Visit-to-visit variability (VVV) of glycated hemoglobin (HbA1c) levels have been found to be associated with prognosis of diabetes. However, little is known about whether or to what extent sex and age may modify the effects of VVV.Methods: To investigate age-and sex-specific rates of mortality from all causes and relative hazards of mortality in association with VVV of HbA1c levels, 47,145 patients with diabetes and prescription of any antidiabetic agents >6 months were identified from outpatient visits of a tertiary medical center in northern Taiwan during 2003-2018. VVV of HbA1c was measured by quartiles of standard deviation (SD), coefficient of variation (CV), and average real variability (ARV), respectively. The study subjects were linked to Taiwan's National Death Registry to identify all-cause mortality. The person-year approach with the Poisson assumption was used to assess the all-cause mortality rates, and Cox proportional hazard regression model was used to evaluate the relative hazards of all-cause mortality concerning various levels of VVV of HbA1c. Results:The lowest all-cause mortality rate was found in either the first or second quartile of various measures for VVV of HbA1c, but the highest mortality rate was consistently observed in the fourth quartile of VVV, regardless of SD, CV, or ARV across ages and sexes. Increased hazards of overall all-cause mortality were noticed from the second to fourth quartile of VVV of HbA1c. In detailed age-and sex-stratified analyses, elevated risk of mortality was seen in the fourth quartile of those aged <50 years while in those aged >69 years, increased risk of mortality was noticed in the third and fourth quartiles of any VVV of HbA1c irrespective of sex. In those aged 50-69 years, incremental increased hazards of mortality were consistently observed in the second to fourth quartiles of VVV of HbA1c.Conclusion: HbA1c variability whether it was SD, CV, or ARV could strongly predict the risks of all-cause mortality. The extent of the relationship between VVV of HbA1c and all-cause mortality in different age groups was comparable between both sexes. Given the importance of long-term glucose fluctuation, the inclusion of HbA1c variability calculated from the standardized method should be considered by clinical guideline policymakers as part of the biochemical panel in daily diabetes management.

Aim In patients with type 2 diabetes (T2D), levels of hypoglycemia and their risk of mortality are not well understood. The aim of this study was to ascertain the correlation among disparate levels of hypoglycemia and patients with T2D’s achieved mean glycated hemoglobin A1c (HbA1c) with all-cause and cardiovascular mortality. Methods 27,932 T2D patients taking hypoglycemic medications at outpatient visits for more than 6 months between 2008 and 2018 were linked to Taiwan’s National Death Registry. We determined the respective mortality rates with Poisson assumption, and explored the relative risks of all-cause and cardiovascular mortality according to dissimilar levels of hypoglycemia with their achieved mean HbA1c by Cox proportional hazard regression model with adjustment of potential confounders. Results T2D patients with level 3 hypoglycemia had the highest rates of all-cause and cardiovascular mortality. Compared with those who never encountered hypoglycemia, study subjects with level 1 and level 2 hypoglycemia did not show excessive risks of either all-cause or cardiovascular mortality. Only those with level 3 hypoglycemia revealed marginal risk of all-cause (Hazard ratio [HR]: 1.18; 95% Confidence Interval [CI] 1.04–1.33) but not cardiovascular mortality (HR: 1.16; 95% CI 0.88–1.53). In T2D patients with hypoglycemia, only those with mean HbA1c ≥9.0% increased all-cause mortality in level 3 hypoglycemia, and cardiovascular mortality in level 1 hypoglycemia. Conclusions Elevated risk of all-cause mortality was exclusively found in patients with level 3 hypoglycemia. In T2D patients with hypoglycemia, mean HbA1c ≥ 9% increased all-cause or cardiovascular mortality. Aggressive treatment of accompanying serious illness in severe hypoglycemia may help reduce mortality in patients with T2DM.