We found that over 6 years of follow-up an increase in glycaemia was positively associated with change in TC, LDL-c, TG and non-HDL-c in adults with type 1 diabetes who were not on dyslipidaemia medications. This strong association was not observed in patients who were on dyslipidaemia medications. Although glycaemic control is important for reduction of vascular complications, we believe these data suggest that the effect of dyslipidaemia treatment on lipids is stronger than the effect of glycaemia on lipids and, therefore, may obscure the effect of glucose control on lipids. Therefore, this suggests that both glucose control and treatment with dyslipidaemia medications (if lipids exceed treatment goals) in adults with type 1 diabetes should be emphasised to achieve lipid and cardiovascular health. Furthermore, given the magnitude of the association of change in HbA1c with change in lipids, for some patients with significantly elevated lipids it is likely that intensification of glycaemic control may be insufficient to achieve lipid treatment goals [7, 17].
In post hoc analyses, we found that the association of HbA1c with TC, LDL-c and non-HDL-c was of reduced magnitude in women as compared with men. HbA1c was not associated with HDL-c in either men or women, and the association of HbA1c with TG was significant only in women not on dyslipidaemia medications, whereas men had a more variable pattern. Sex-based differences in CVD risk in type 1 diabetes have been previously reported [18–20] and we have reported that insulin resistance was associated with a proatherogenic lipoprotein subfraction cholesterol distribution in women . Further investigation of sex-based differences in CVD risk in type 1 diabetes is needed.
CACTI is an observational cohort, and use of dyslipidaemia medications increased from 17% to 46% over the mean 6 years of follow-up, demonstrating increased use of dyslipidaemia medications for lipid and cardiovascular health in type 1 diabetes. Not surprisingly, the fasting lipid profile improved over the study period despite increases in adiposity measures. In contrast, there was minimal average improvement in HbA1c over the study period. In the DCCT trial, TC, LDL-c and TG were significantly lower in the intensively treated arm than in the conventionally treated arm . In addition, no participants were on statins at the end of the DCCT in 1993, while in 2004 in EDIC 33% and 34% in the intensive and conventional arms, respectively, were on statins . The improved lipid profile in CACTI over time is likely due to increased use of dyslipidaemia medications, not improved glycaemic control.
Data clearly suggest that care for type 1 diabetes has improved in the past two decades, as evidenced by reduced rates of microvascular disease [23–25]; however, substantially less progress has been made in reduction of macrovascular disease rates [25–27], despite the DCCT/EDIC study showing that intensive glycaemic control over a mean of 6.5 years reduced CVD complications by 57% after a mean of 17 years of follow-up . People with type 1 diabetes continue to have excess morbidity and mortality, with a dramatic increase in CVD mortality risk compared with people without diabetes .
To describe the clinical course of type 1 diabetes in the post-DCCT age of intensive insulin therapy, data from 161 participants of the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study (n = 88 at the 2006 follow-up) were compared with those from the DCCT/EDIC Study . The EDC reported a mean HbA1c similar to that of the conventional arm of the DCCT (9%) until EDC year 8 (1994–1996), when HbA1c fell by 0.5%, subsequent to publication of initial data from the DCCT demonstrating reduced microvascular complications with intensive control . Subjects in the observational EDC reported a decrease in HbA1c from 9.0% to 8.3%, an increase in BMI from 24 to 28 kg/m2, and an increase in statin use from 1% to 38% from 1986–1988 to 2006, similar to the CACTI data. The authors emphasise that, based on these findings, current outcomes for people with type 1 diabetes should be much improved in comparison to cohorts who had onset of type 1 diabetes in the 1950s to 1970s.
In addition to glycaemic control, dyslipidaemia is another important CVD risk factor with extensive data to support its role as a target to improve cardiovascular health in people with type 1 diabetes . Despite abundant data on the importance of controlling dyslipidaemia, adequate control of this CVD risk factor is frequently not achieved . Our results add to those of the DCCT/EDIC and EDC studies by providing data on glycaemic and lipid control in a large observational cohort in the early 21st century. Moreover, we investigate the interplay of glycaemic control and dyslipidaemia medication use on the fasting lipid profile over a 6 year period in a large cohort of adults with type 1 diabetes. As the DCCT/EDIC study has shown that hyperglycaemia is a risk factor for hypertension , our data support a similar role for hyperglycaemia as a risk factor for a more atherogenic lipid profile; however, the association of glycaemia with lipids is attenuated by dyslipidaemia medication use in CACTI, whereas in the DCCT/EDIC study the association of intensive therapy with reduced incidence of hypertension remained significant in sensitivity analyses when accounting for use of antihypertensive medications .
While intensive treatment of glycaemia has been shown to reduce vascular complications in type 1 diabetes , there is also concern that intensive control is associated with weight gain, leading to adverse effects on blood pressure and lipids . In the CACTI cohort, HbA1c was relatively stable, adiposity measures increased and lipids improved over time. How this improved lipid profile translates into changes in health outcomes remains an important future research objective. Limited clinical trial data exist on the effect of dyslipidaemia medications on lipids and outcomes in type 1 diabetes, but the Heart Protection Study included 615 participants with type 1 diabetes. Though the study was underpowered to detect an effect in subgroup analysis, the magnitude of the risk reduction was similar to that in type 2 diabetes , consistent with a subsequent meta-analysis .
As noted, CACTI is an observational cohort study and not the result of a randomised clinical trial; therefore our data have limitations to consider when applying these findings to clinical scenarios. While 8% of participants did not have at least one follow-up visit, minimal differences exist between those who did and did not follow up. We also did not measure the effect of change in diet and exercise on change in lipid levels in these analyses, although these effects would likely be captured in the adiposity measures, which were adjusted for in the analyses. Nonetheless, CACTI participants represent one of the largest cohorts of persons with type 1 diabetes followed over 6 years who have had detailed and repeated measures of glycaemia, lipids, dyslipidaemia medications and adiposity. Our analyses stratified by sex were post hoc and should be further investigated. Finally, sensitivity analyses were performed in which participants with serum creatinine >2.0 mg/dl or microalbuminuria were removed from the analysis, and the associations of change in HbA1c with change in lipids were similar.
In conclusion, over a 6 year period in the CACTI cohort, change in glycaemia was associated with a concomitant change in TC, LDL-c, TG and non-HDL-c, which was not observed in the participants who were on dyslipidaemia medications. These data suggest that there is a statistically strong association between change in glycaemia and change in lipid levels; however, this association may not be as clinically relevant compared with the stronger effect of treatment with dyslipidaemia medications on lipid levels. Therefore, both glycaemic control and treatment with dyslipidaemia medications, when indicated, in adults with type 1 diabetes may be required to optimise lipid and cardiovascular health and improve patient outcomes. Further data are needed to inform clinical decisions on lipid lowering in type 1 diabetes.