Medication profiling in women with type 1 diabetes highlights the importance of adequate, guideline-based treatment in low-risk groups.

Effective treatment may prevent kidney complications, but women might be underprescribed. Novel, data-driven insights into prescriptions and their relationship with kidney health in women with type 1 diabetes may help to optimize treatment. We identified six medication profiles in 1164 women from the FinnDiane Study with normal albumin excretion rate based on clusters of their baseline prescription data using a self-organizing map. Future rapid kidney function decline was defined as an annual estimated glomerular filtration rate (eGFR) loss > 3 ml/min/1.73 m2 after baseline. Two profiles were associated with future decline: Profile ARB with the highest proportion of angiotensin receptor blockers (odds ratio [OR] 2.75, P = 0.02) and highly medicated women in profile HighMed (OR 2.55, P = 0.03). Compared with profile LowMed (low purchases of all), profile HighMed had worse clinical characteristics, whereas in profile ARB only systolic blood pressure was elevated. Importantly, the younger women in profile ARB with fewer kidney protective treatments developed a rapid decline despite otherwise similar baseline characteristics to profile ACE & Lipids (the highest proportions of ACE inhibitors and lipid-modifying agents) without a future rapid decline. In conclusion, medication profiles identified different future eGFR trajectories in women with type 1 diabetes revealing potential treatment gaps for younger women.

L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum.

OBJECTIVE: Vascular endothelial growth factor (VEGF) plays a key role in diabetic retinopathy (DR). Previously, we have reported an association between mutations in a gene coding for the L-type calcium channel subunit, VEGF and DR. L-type calcium channel blockers (LTCCBs) have been widely used as antihypertensive medication (AHM), but their association with VEGF and DR is still unclear. Therefore, we explored the effect of LTCCBs compared to other AHMs on VEGF concentrations in retinal cells and human serum. Furthermore, we evaluated the association between the use of LTCCBs and the risk of severe diabetic eye disease (SDED). RESEARCH DESIGN AND METHODS: Müller cells (MIO-M1) were cultured as per recommended protocol and treated with LTCCBs and other AHMs. VEGF secreted from cells were collected at 24 hours intervals. In an interventional study, 39 individuals received LTCCBs or other AHM for four weeks with a four-week wash-out placebo period between treatments. VEGF was measured during the medication and placebo periods. Finally, we evaluated the risk of SDED associated with LTCCB usage in 192 individuals from the FinnDiane Study in an observational setting. RESULTS: In the cell cultures, the medium VEGF concentration increased time-dependently after amlodipine (P<0.01) treatment, but not after losartan (P>0.01), or lisinopril (P>0.01). Amlodipine, but no other AHM, increased the serum VEGF concentration (P<0.05) during the interventional clinical study. The usage of LTCCB was not associated with the risk of SDED in the observational study. CONCLUSIONS: LTCCB increases VEGF concentrations in retinal cells and human serum. However, the usage of LTCCBs does not appear to be associated with SDED in adults with type 1 diabetes.

The many faces of hypertension in individuals with type 1 diabetes.

Several disturbed blood pressure (BP) patterns, including disparities between office and out-of-office BP measurements (such as white-coat and masked hypertension), disturbed circadian BP variability (such as abnormal dipping patterns and nocturnal hypertension) and treatment-resistant hypertension, are common in individuals with type 1 diabetes. Consequently, office or home BP measurements alone may not reflect real BP variation and may lead to inadequate diagnosis and treatment of hypertension. The early detection of these disturbed BP patterns is especially crucial in individuals with type 1 diabetes, as these patterns may indicate future development of adverse cardiovascular and renal outcomes. In this review we will describe these disturbed BP patterns and discuss recent findings on their prevalence and outcomes. We will also address critical areas for future research to determine the true prevalence and prognosis of disturbed BP patterns, and to optimize and improve the knowledge and management of high-risk individuals with type 1 diabetes and disturbed BP patterns.

Genetic Risk Score Enhances Coronary Artery Disease Risk Prediction in Individuals With Type 1 Diabetes.

OBJECTIVE: Individuals with type 1 diabetes are at a high lifetime risk of coronary artery disease (CAD), calling for early interventions. This study explores the use of a genetic risk score (GRS) for CAD risk prediction, compares it to established clinical markers, and investigates its performance according to the age and pharmacological treatment. RESEARCH DESIGN AND METHODS: This study in 3,295 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study (467 incident CAD, 14.8 years follow-up) used three risk scores: a GRS, a validated clinical score, and their combined score. Hazard ratios (HR) were calculated with Cox regression, and model performances were compared with the Harrell C-index (C-index). RESULTS: A HR of 6.7 for CAD was observed between the highest and the lowest 5th percentile of the GRS (P = 1.8 × 10-6). The performance of GRS (C-index = 0.562) was similar to HbA1c (C-index = 0.563, P = 0.96 for difference), HDL (C-index = 0.571, P = 0.6), and total cholesterol (C-index = 0.594, P = 0.1). The GRS was not correlated with the clinical score (r = -0.013, P = 0.5). The combined score outperformed the clinical score (C-index = 0.813 vs. C-index = 0.820, P = 0.003). The GRS performed better in individuals below the median age (38.6 years) compared with those above (C-index = 0.637 vs. C-index = 0.546). CONCLUSIONS: A GRS identified individuals at high risk of CAD and worked better in younger individuals. GRS was also an independent risk factor for CAD, with a predictive power comparable to that of HbA1c and HDL and total cholesterol, and when incorporated into a clinical model, modestly improved the predictions. The GRS promises early risk stratification in clinical practice by enhancing the prediction of CAD.

Resistant Hypertension and Risk of Adverse Events in Individuals With Type 1 Diabetes: A Nationwide Prospective Study.

OBJECTIVE: To estimate the risk of diabetic nephropathy (DN) progression, incident coronary heart disease (CHD) and stroke, and all-cause mortality associated with resistant hypertension (RH) in individuals with type 1 diabetes stratified by stages of DN, renal function, and sex. RESEARCH DESIGN AND METHODS: This prospective study included a nationally representative cohort of individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study who had purchases of antihypertensive drugs at (±6 months) baseline visit (1995-2008). Individuals (N = 1,103) were divided into three groups: 1) RH, 2) uncontrolled blood pressure (BP) but no RH, and 3) controlled BP. DN progression, cardiovascular events, and deaths were identified from the individuals' health care records and national registries until 31 December 2015. RESULTS: At baseline, 18.7% of the participants had RH, while 23.4% had controlled BP. After full adjustments for clinical confounders, RH was associated with increased risk of DN progression (hazard ratio 1.95 [95% CI 1.37, 2.79], P = 0.0002), while no differences were observed in those with no RH (1.05 [0.76, 1.44], P = 0.8) compared with those who had controlled BP. The risk of incident CHD, incident stroke, and all-cause mortality was higher in individuals with RH compared with those who had controlled BP but not beyond albuminuria and reduced kidney function. Notably, in those with normo- and microalbuminuria, the risk of stroke remained higher in the RH compared with the controlled BP group (3.49 [81.20, 10.15], P = 0.02). CONCLUSIONS: Our findings highlight the importance of identifying and providing diagnostic and therapeutic counseling to these very-high-risk individuals with RH.

Ambulatory blood pressure and arterial stiffness in individuals with type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to assess the use of ambulatory BP monitoring (ABPM) to identify the presence of masked, nocturnal and white-coat hypertension in individuals with type 1 diabetes, patterns that could not be detected by regular office-based BP monitoring alone. We also analysed associations between BP patterns and arterial stiffness in order to identify individuals at cardiovascular risk. METHODS: This substudy included 140 individuals with type 1 diabetes from the Helsinki metropolitan area, who attended the Finnish Diabetic Nephropathy Study (FinnDiane) Centre in Helsinki between January 2013 and August 2017. Twenty-four hour ABPM and pulse wave analysis were performed simultaneously using a validated non-invasive brachial oscillometric device (Mobil-O-Graph). Definitions of hypertension were based on the European Society of Hypertension guidelines. Masked hypertension was defined as normal office BP (BP obtained using a standardised automated BP device) but elevated 24 h ABPM, and white-coat hypertension as elevated office BP but normal 24 h ABPM. RESULTS: A total of 38% of individuals were normotensive and 33% had sustained hypertension, while 23% had masked and 6% had white-coat hypertension. About half of the cohort had increased absolute levels of night-time BP, half of whom were untreated. In the ambulatory setting, central BP and pulse wave velocity (PWV) were higher in participants with masked hypertension than in those with normotension (p ≤ 0.001). In a multivariable linear regression model adjusted for age, sex, BMI, antihypertensive treatment and eGFR, masked hypertension was independently associated with higher 24 h PWV (ß 0.50 [95% CI 0.34, 0.66]), but not with PWV obtained during resting conditions (adjusted ß 0.28 [95% CI -0.53, 1.10]), using normotension as the reference group. CONCLUSIONS/INTERPRETATION: ABPM analysis revealed that one-quarter of the participants with type 1 diabetes had masked hypertension; these individuals would not have been detected by office BP alone. Moreover, arterial stiffness was increased in individuals with masked hypertension. These findings support the use of ABPM to identify individuals at risk of cardiovascular disease.

Data-driven metabolic subtypes predict future adverse events in individuals with type 1 diabetes.

AIMS/HYPOTHESIS: Previously, we proposed that data-driven metabolic subtypes predict mortality in type 1 diabetes. Here, we analysed new clinical endpoints and revisited the subtypes after 7 years of additional follow-up. METHODS: Finnish individuals with type 1 diabetes (2059 men and 1924 women, insulin treatment before 35 years of age) were recruited by the national multicentre FinnDiane Study Group. The participants were assigned one of six metabolic subtypes according to a previously published self-organising map from 2008. Subtype-specific all-cause and cardiovascular mortality rates in the FinnDiane cohort were compared with registry data from the entire Finnish population. The rates of incident diabetic kidney disease and cardiovascular endpoints were estimated based on hospital records. RESULTS: The advanced kidney disease subtype was associated with the highest incidence of kidney disease progression (67.5% per decade, p < 0.001), ischaemic heart disease (26.4% per decade, p < 0.001) and all-cause mortality (41.5% per decade, p < 0.001). Across all subtypes, mortality rates were lower in women compared with men, but standardised mortality ratios (SMRs) were higher in women. SMRs were indistinguishable between the original study period (1994-2007) and the new period (2008-2014). The metabolic syndrome subtype predicted cardiovascular deaths (SMR 11.0 for men, SMR 23.4 for women, p < 0.001), and women with the high HDL-cholesterol subtype were also at high cardiovascular risk (SMR 16.3, p < 0.001). Men with the low-cholesterol or good glycaemic control subtype showed no excess mortality. CONCLUSIONS/INTERPRETATION: Data-driven multivariable metabolic subtypes predicted the divergence of complication burden across multiple clinical endpoints simultaneously. In particular, men with the metabolic syndrome and women with high HDL-cholesterol should be recognised as important subgroups in interventional studies and public health guidelines on type 1 diabetes.

Smoking and progression of diabetic nephropathy in patients with type 1 diabetes.

AIMS: To evaluate the effect of cumulative smoking on the development of diabetic nephropathy. METHODS: Study included 3613 patients with type 1 diabetes, participating in the Finnish Diabetic Nephropathy Study. The 12-year cumulative risk of microalbuminuria, macroalbuminuria and end-stage renal disease (ESRD) was estimated for current, ex- and nonsmokers. Cox regression analyses, with multivariable adjustments for other risk factors for diabetic nephropathy, were used to evaluate the risk at different stages of diabetic nephropathy based on the cumulative amount of smoking in pack-years. RESULTS: The 12-year cumulative risk of microalbuminuria was 18.9 % (95 % CI 14.6-23.0, P < 0.0001) for current smokers and 15.1 % (10.3-19.6, P = 0.087) for ex-smokers, compared with 10.0 % (7.8-12.1) for nonsmokers. The corresponding risks of macroalbuminuria were 14.4 % (95 % CI 10.8-17.9, P < 0.0001), 6.1 % (3.5-8.6, P = 0.082) and 4.7 % (3.0-6.4), respectively. The 12-year cumulative risk of ESRD was 10.3 % (95 % CI 8.4-12.4, P < 0.0001) for current smokers and 10.0 % (7.9-12.3, P < 0.0001) for ex-smokers, compared with 5.6 % (4.6-6.7) for nonsmokers. In the current smokers, one pack-year increased the risk of macroalbuminuria with a HR of 1.025 (1.010-1.041) and the risk of ESRD with a HR of 1.014 (1.001-1.026) compared with nonsmokers, in the fully adjusted model. In the ex-smokers, the risk of macroalbuminuria and ESRD was no different from the risk in nonsmokers after multivariable adjustment. CONCLUSIONS: Current smoking is a risk factor for the progression of diabetic nephropathy and the risk increases with the increasing dose of smoking. Ex-smokers seem to carry a similar risk of progression of diabetic nephropathy as nonsmokers.

The consequences of failure to achieve targets of guidelines for prevention and treatment of diabetic complications in patients with type 1 diabetes.

To study how the targets of glycemic, blood pressure (BP) and lipid control based on the American Diabetes Association (ADA) guidelines have been implemented, and to assess the risk of cardiovascular events (CVD) and mortality in patients with type 1 diabetes stratified by nephropathy (DN) status. A nationally representative cohort of patients with type 1 diabetes (N = 3,151) from the FinnDiane Study were included. CVD and deaths were identified from the national registers. The treatment targets were HbA1C <7 %, BP <140/80 mmHg and LDL cholesterol <2.6 mmol/l. About 63 % of the patients with DN and 34 % of the patients without DN reached none of the targets. With DN, the 10-year cumulative risk of CVD was 17.4 % (95 % CI 11.1-23.2) if BP was on target, 29.9 % (23.0-36.2, P = 0.03) if BP was not on target and 28.4 % (24.9-31.8, P = 0.009) in those who reached none of the targets. The corresponding figures were 3.8 % (2.7-4.8), 4.4 % (2.7-6.2, P = 0.3) and 8.1 % (6.4-9.8, P < 0.0001) for those without DN. In those with DN, the risk of CVD was higher if BP was not on target [hazard ratio (HR) 1.9 (1.1-3.3)], or none of the three targets [HR 2.2 (1.4-3.6)] were reached than if BP was on target. Although the risk of death without DN was higher in those who reached none of the targets (P = 0.003), after adjustment, no differences were observed between the groups. Failure to reach ADA treatment targets is associated with increased risk of mortality and CVD in patients with type 1 diabetes.

Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification.

AIMS/HYPOTHESIS: Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD. METHODS: We exploited a novel algorithm, 'Bag of Naive Bayes', whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK-Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US). RESULTS: Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case-control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno. CONCLUSIONS/INTERPRETATION: This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes.

AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Antihypertensive treatment and resistant hypertension in patients with type 1 diabetes by stages of diabetic nephropathy.

OBJECTIVE: To assess blood pressure (BP) control, antihypertensive treatment, and prevalence of resistant hypertension (RH) in patients with type 1 diabetes stratified by stage of diabetic nephropathy. RESEARCH DESIGN AND METHODS: This cross-sectional study included a nationally representative cohort of patients with type 1 diabetes (N = 3,678) from the Finnish Diabetic Nephropathy Study (FinnDiane). The data were linked to the Drug Prescription Register to obtain purchases of antihypertensive drugs 6 months prior to the baseline visit. The treatment targets were based on the American Diabetes Association guidelines. RH was defined as failure to reach BP target despite the use of three or more antihypertensive drugs of different classes (one of which was a diuretic). RESULTS: In patients with normal albumin excretion rate, 14.1% were on antihypertensive treatment and 74.6% of them had uncontrolled BP despite treatment. The corresponding figures were 60.5 and 71.2% for the microalbuminuric patients, 90.3 and 80.0% for the macroalbuminuric patients, 88.6 and 88.1% for dialysis, and 91.2 and 90.4% for kidney-transplanted patients. The prevalence of RH was 1.2% in the normoalbuminuric, 4.7% in the microalbuminuric, 28.1% in the macroalbuminuric, 36.6% in the dialysis, and 26.3% in the kidney transplant groups. Age (odds ratio 1.04 [95% CI 1.02-1.05]), estimated glomerular filtration rate (0.97 [0.96-0.97]), waist-to-hip ratio (1.44 [1.15-1.80]), triglycerides (1.19 [1.01-1.40]), microalbuminuria (2.58 [1.43-4.67]), and macroalbuminuria (5.61 [3.20-9.84]) were independently associated with RH. CONCLUSIONS: The prevalence of uncontrolled hypertension and RH increases with advanced diabetic nephropathy. These data suggest that there is an urgent need for improvement of antihypertensive treatment.

Longitudinal trends in use and costs of prescription medication in patients with type 1 diabetes: the impact of renal disease.

OBJECTIVE: We estimated trends in prescription medication costs in out-patients with type 1 diabetes by various stages of diabetic nephropathy (DN), before the development of end-stage renal disease, between 1995 and 2005. METHODS: Patients with normo- (n = 1,334), micro- (n = 206), and macroalbuminuria (n = 365) were identified from the Finnish Diabetic Nephropathy (FinnDiane) database. All purchases of medications were obtained from the Drug Prescription Register. RESULTS: The costs levels differed significantly (P < 0.0001) between all groups. The estimated annual costs per patient in 1995 were €1,310 (95% CI 1,230-1,400), €1,450 (1,300-1,600), and €1,770 (1,620-1,930) in the normo-, micro-, and macroalbuminuria groups, respectively. The corresponding costs in 2005 were €1,950 (1,830-2,080), €2,110 (1,910-2,320), and €2,900 (2,650-3,180). The costs increased in all groups over time (P < 0.0001). The annual average increase was 3.5%, 3.3%, and 5.2% in each group. After the generic substitution was introduced, the costs of agents acting on the renin- angiotensin system and lipid-modifying agents dropped, although the number of users increased at the same time. CONCLUSIONS: More severe stages of DN have a substantial impact on the costs, which suggests that early prevention and intensive treatment of renal disease may generate remarkable annual cost savings.

New susceptibility loci associated with kidney disease in type 1 diabetes.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ß1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Association testing of previously reported variants in a large case-control meta-analysis of diabetic nephropathy.

We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.