Higher HbA1c variability is associated with increased arterial stiffness in individuals with type 1 diabetes.

BACKGROUND: Both long-term glycaemic variability and arterial stiffness have been recognized as cardiovascular risk factors. This study aims to investigate whether an association between these phenomena exists in individuals with type 1 diabetes. METHODS: This cross-sectional study included 673 adults (305 men, 368 women) with type 1 diabetes and combined available retrospective laboratory data on HbA1c from the preceding 10 years with outcome data on arterial stiffness and clinical variables from a comprehensive study visit. HbA1c variability was calculated as adjusted standard deviation (adj-HbA1c-SD), coefficient of variation (HbA1c-CV) and average real variability (HbA1c-ARV). As measures of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV; n = 335) and augmentation index (AIx; n = 653) were assessed using applanation tonometry. RESULTS: The study population had a mean age of 47.1 (± 12.0) years and a median duration of diabetes of 31.2 (21.2-41.3) years. The median number of HbA1c assessments per individual was 17 (12-26). All three indices of HbA1c variability were significantly correlated with both cfPWV and AIx after adjustment for sex and age (p < 0.001). In separate multivariable linear regression models, adj-HbA1c-SD and HbA1c-CV were significantly associated with cfPWV (p = 0.032 and p = 0.046, respectively) and AIx (p = 0.028 and p = 0.049, respectively), even after adjustment for HbA1c-mean. HbA1c-ARV was not associated with cfPWV or AIx in the fully adjusted models. CONCLUSIONS: An association independent of HbA1c-mean was found between HbA1c variability and arterial stiffness, suggesting a need to consider multiple HbA1c metrics in studies assessing cardiovascular risk in type 1 diabetes. Longitudinal and interventional studies are needed to confirm any causal relationship and to find strategies for reducing long-term glycaemic variability.

Prognosis After First-Ever Myocardial Infarction in Type 1 Diabetes Is Strongly Affected by Chronic Kidney Disease.

OBJECTIVE: To study prognosis after a first-ever myocardial infarction (MI) in type 1 diabetes, as well as how different MI- and diabetes-related factors affect the prognosis and risk of secondary cardiovascular events. RESEARCH DESIGN AND METHODS: In this observational follow-up study of 4,217 individuals from the Finnish Diabetic Nephropathy (FinnDiane) Study with no prior MI or coronary revascularization, we verified 253 (6.0%) MIs from medical records or death certificates. Mortality from cardiovascular or diabetes-related cause was our main end point, whereas hospitalization due to heart failure, coronary revascularization, and recurrent MI were secondary end points, while accounting for death as a competing risk. RESULTS: Of the individuals studied, 187 (73.9%) died during the median post-MI follow-up of 3.07 (interquartile range 0.02-8.45) years. Independent risk factors for cardiovascular and diabetes-related mortality were estimated glomerular filtration rate categories grade 3 (G3) (hazard ratio [HR] 3.27 [95% CI 1.76-6.08]), G4 (3.62 [1.69-7.73]), and G5 (4.03 [2.24-7.26]); prior coronary heart disease diagnosis (1.50 [1.03-2.20]); and older age at MI (1.03 [1.00-1.05]). Factors associated with lower mortality were acute revascularization (HR 0.35 [95% CI 0.18-0.72]) and subacute revascularization (0.39 [0.26-0.59]). In Fine and Gray competing risk analyses, kidney failure was associated with a higher risk of recurrent MI (subdistribution HR 3.27 [95% CI 2.01-5.34]), heart failure (3.76 [2.46-5.76]), and coronary revascularization (3.04 [1.89-4.90]). CONCLUSIONS: Individuals with type 1 diabetes have a high cardiovascular and diabetes-related mortality after their first-ever MI. In particular, poor kidney function is associated with high mortality and excessive risk of secondary cardiovascular events.

Progression and regression of kidney disease in type 1 diabetes.

Diabetic kidney disease is distinguished by the presence of albuminuria, hypertension, declining kidney function, and a markedly elevated cardiovascular disease risk. This constellation of clinical features drives the premature mortality associated with type 1 diabetes. The first epidemiological investigations concerning type 1 diabetes-related albuminuria date back to the 1980s. The early studies found that proteinuria - largely equivalent to severe albuminuria - developed in 35 to 45% of individuals with type 1 diabetes, with the diabetes duration-specific incidence rate pattern portraying one or two peaks. Furthermore, moderate albuminuria, the first detectable sign of diabetic kidney disease, was found to nearly inexorably progress to overt kidney disease within a short span of time. Since the early reports, studies presenting more updated incidence rates have appeared, although significant limitations such as study populations that lack broad generalizability, study designs vulnerable to substantive selection bias, and constrained follow-up times have been encountered by many. Nevertheless, the most recent reports estimate that in modern times, moderate - instead of severe - albuminuria develops in one-third of individuals with type 1 diabetes; yet, a considerable part (up to 40% during the first ten years after the initial albuminuria diagnosis) progresses to more advanced stages of the disease over time. An alternative pathway to albuminuria progression is its regression, which affects up to 60% of the individuals, but notably, the relapse rate to a more advanced disease stage is high. Whether albuminuria regression translates into a decline in cardiovascular disease and premature mortality risk is an area of debate, warranting more detailed research in the future. Another unclear but alarming feature is that although the incidence of severe albuminuria has fallen since the 1930s, the decline seems to have reached a plateau after the 1980s. This stagnation may be due to the lack of kidney-protective medicines since the early 1980s, as the recent breakthroughs in type 2 diabetes have not been applicable to type 1 diabetes. Therefore, novel treatment strategies are at high priority within this patient population.

Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations.

BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits. METHODS: We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy. RESULTS: The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10-8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p<2.9×10-6). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10-4), apolipoprotein B (p=5.6×10-4), and LDL cholesterol (p=9.5×10-4) concentrations. CONCLUSIONS: We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.

Incidence rate patterns, cumulative incidence, and time trends for moderate and severe albuminuria in individuals diagnosed with type 1 diabetes aged 0-14 years: a population-based retrospective cohort study.

BACKGROUND: The incidence and temporal trends of moderate and severe albuminuria during recent decades are poorly described in type 1 diabetes. We aimed to assess diabetes duration-specific incidence rates, cumulative incidence, and secular trends of albuminuria in type 1 diabetes in Finland. METHODS: We conducted a population-based, retrospective cohort study of a stratified random sample (n=1500) of all individuals diagnosed with type 1 diabetes before age 15 years during 1970-99 in Finland. The sampling frame was the database of the Finnish Institute for Health and Welfare. Individuals with an atypical clinical course, presentation of non-diabetic kidney disease, insufficient albumin excretion rate measurements, or unavailable medical records were excluded (final sample n=1430). Study participants were followed up until death, the event of interest (moderate or severe albuminuria or kidney failure), or the most recent event-free date. Medical records retrieved up to Dec 31, 2020 were systematically reviewed for albuminuria determinations. Moderate and severe albuminuria were categorised on the basis of international reference limits (two of three consecutive urine samples). Kidney failure was defined as dialysis treatment or kidney transplant. Cohorts defined by calendar year of diabetes diagnosis (1970-79, 1980-89, and 1990-99) were assessed. Patterns of duration-specific incidences were evaluated by fitting generalised additive models to the data, which were split into multiple observations of half-year duration. Cumulative incidences were calculated with Kaplan-Meier analysis. In analyses with kidney failure as the endpoint, competing risk for mortality was incorporated. FINDINGS: In our stratified random sample, 462 individuals were diagnosed with diabetes in 1970-79, 481 were diagnosed in 1980-89, and 487 were diagnosed in 1990-99. The incidence rate pattern of severe albuminuria changed over time; a peak at 15-19 years since diabetes onset in the 1970-79 cohort was not replicated in those diagnosed later. In the combined 1980-99 diagnosis-year cohorts, the incidence rate rose during the first 14 years after diabetes onset, after which it levelled off to a plateau. Between the 1970-79 and 1980-89 diabetes diagnosis cohorts, the cumulative incidence of severe albuminuria had approximately halved (hazard ratio [HR] 0·55 [95% CI 0·42-0·72] with the 1970-79 cohort as reference, p<0·0001), whereas, between the 1980-89 and 1990-99 cohorts, no further decrease was observed (HR 0·83 [0·54-1·26] with the 1980-89 cohort as reference, p=0·38). The 25-year cumulative incidence for severe albuminuria was 26·8% (22·6-30·8) in the 1970-79 diagnosis cohort, 12·0% (9·0-15·0) in the 1980-89 cohort, and 10·8% (6·7-14·6) in the 1990-99 cohort. 15 years after onset of severe albuminuria, cumulative progression rate from severe albuminuria to kidney failure was 35·2% (27·4-43·0) in the 1970-79 cohort and 35·6% (24·3-47·0) in the 1980-99 cohorts combined (Gray's test p=0·37). In the cohorts with data on moderate albuminuria (1980-89 and 1990-99), cumulative incidence of moderate albuminuria showed no calendar effect between the earlier and later cohorts (HR 0·99 [0·78-1·28] with the 1980-89 cohort as reference, p=0·97). The incidence rate of moderate albuminuria increased until 10 years after diabetes onset, then remained mostly stable until starting to decrease at around 25 years after diabetes onset. INTERPRETATION: Our analyses show that the cumulative incidence of severe albuminuria has decreased between 1970-79 and 1980-99; however, whether this decrease solely denotes a delay in albuminuria, or also a true prevention of albuminuria, needs to be investigated further. Nevertheless, diabetic kidney disease remains a significant complication of type 1 diabetes. Due to the robust association of diabetic kidney disease with premature mortality, novel therapies to improve prognosis are needed. FUNDING: Folkhälsan Research Foundation, Medical Society of Finland, Wilhelm and Else Stockmann Foundation, Finnish Diabetes Research Foundation, Waldemar von Frenckell Foundation, Liv och Hälsa Society, Academy of Finland, and Novo Nordisk Foundation. TRANSLATIONS: For the Finnish and Swedish translations of the abstract see Supplementary Materials section.

Apolipoprotein C-III predicts cardiovascular events and mortality in individuals with type 1 diabetes and albuminuria.

OBJECTIVES: We studied apolipoprotein C-III (apoC-III) in relation to diabetic kidney disease (DKD), cardiovascular outcomes, and mortality in type 1 diabetes. METHODS: The cohort comprised 3966 participants from the prospective observational Finnish Diabetic Nephropathy Study. Progression of DKD was determined from medical records. A major adverse cardiac event (MACE) was defined as acute myocardial infarction, coronary revascularization, stroke, or cardiovascular mortality through 2017. Cardiovascular and mortality data were retrieved from national registries. RESULTS: ApoC-III predicted DKD progression independent of sex, diabetes duration, blood pressure, HbA1c , smoking, LDL-cholesterol, lipid-lowering medication, DKD category, and remnant cholesterol (hazard ratio [HR] 1.43 [95% confidence interval 1.05-1.94], p = 0.02). ApoC-III also predicted the MACE in a multivariable regression analysis; however, it was not independent of remnant cholesterol (HR 1.05 [0.81-1.36, p = 0.71] with remnant cholesterol; 1.30 [1.03-1.64, p = 0.03] without). DKD-specific analyses revealed that the association was driven by individuals with albuminuria, as no link between apoC-III and the outcome was observed in the normal albumin excretion or kidney failure categories. The same was observed for mortality: Individuals with albuminuria had an adjusted HR of 1.49 (1.03-2.16, p = 0.03) for premature death, while no association was found in the other groups. The highest apoC-III quartile displayed a markedly higher risk of MACE and death than the lower quartiles; however, this nonlinear relationship flattened after adjustment. CONCLUSIONS: The impact of apoC-III on MACE risk and mortality is restricted to those with albuminuria among individuals with type 1 diabetes. This study also revealed that apoC-III predicts DKD progression, independent of the initial DKD category.

The pattern-recognition molecule H-ficolin in relation to diabetic kidney disease, mortality, and cardiovascular events in type 1 diabetes.

H-ficolin recognizes patterns on microorganisms and stressed cells and can activate the lectin pathway of the complement system. We aimed to assess H-ficolin in relation to the progression of diabetic kidney disease (DKD), all-cause mortality, diabetes-related mortality, and cardiovascular events. Event rates per 10-unit H-ficolin-increase were compared in an observational follow-up of 2,410 individuals with type 1 diabetes from the FinnDiane Study. DKD progression occurred in 400 individuals. The unadjusted hazard ratio (HR) for progression was 1.29 (1.18-1.40) and 1.16 (1.05-1.29) after adjustment for diabetes duration, sex, HbA1c, systolic blood pressure, and smoking status. After adding triglycerides to the model, the HR decreased to 1.07 (0.97-1.18). In all, 486 individuals died, including 268 deaths of cardiovascular causes and 192 deaths of complications to diabetes. HRs for all-cause mortality and cardiovascular mortality were 1.13 (1.04-1.22) and 1.05 (0.93-1.17), respectively, in unadjusted analyses. These estimates lost statistical significance in adjusted models. However, the unadjusted HR for diabetes-related mortality was 1.19 (1.05-1.35) and 1.18 (1.02-1.37) with the most stringent adjustment level. Our results, therefore, indicate that H-ficolin predicts diabetes-related mortality, but neither all-cause mortality nor fatal/non-fatal cardiovascular events. Furthermore, H-ficolin is associated with DKD progression, however, not independently of the fully adjusted model.