OBJECTIVE: Type 1 diabetes (T1D) and type 2 diabetes (T2D) increase risks of cardiovascular (CV) and renal disease (CVRD) compared with diabetes-free populations. Direct comparisons between T1D and T2D are scarce. We examined this by pooling full-population cohorts in Sweden and Norway. RESEARCH DESIGN AND METHODS: A total of 59,331 patients with T1D and 484,241 patients with T2D, aged 18–84 years, were followed over a mean period of 2.6 years from 31 December 2013. Patients were identified in nationwide prescribed drug and hospital registries in Norway and Sweden. Prevalence and event rates of myocardial infarction (MI), heart failure (HF), stroke, chronic kidney disease (CKD), all-cause death, and CV death were assessed following age stratification in 5-year intervals. Cox regression analyses were used to estimate risk. RESULTS: The prevalence of CV disease was similar in T1D and T2D across age strata, whereas CKD was more common in T1D. Age-adjusted event rates comparing T1D versus T2D showed that HF risk was increased between ages 65 and 79 years, MI between 55 and 79 years, and stroke between 40 and 54 years (1.3–1.4-fold, 1.3–1.8-fold, and 1.4–1.7-fold, respectively). CKD risk was 1.4–3.0-fold higher in T1D at all ages. The all-cause death risk was 1.2–1.5-fold higher in T1D at age >50 years, with a similar trend for CV death. CONCLUSIONS: Adult patients with T1D compared with those with T2D had an overall greater risk of cardiorenal disease (HF and CKD) across ages, MI and all-cause death at middle-older ages, and stroke at younger ages. The total age-adjusted CVRD burden and risks were greater among patients with T1D compared with those with T2D, highlighting their need for improved prevention strategies.

Aims: The aim of this study was to investigate the association between estimated glucose disposal rate (eGDR), a proxy for insulin resistance, and retinopathy or kidney disease, i.e. micro-, or macroalbuminuria, in young individuals with type 1 diabetes (T1D). Material and Methods: Using data from the Swedish pediatric registry for diabetes (SweDiabKids) and the registry for adults (NDR), all individuals with T1D with a duration of diabetes of less than 10 years between 1998 and 2017 were included. We calculated the crude incidence rates with 95% confidence intervals (CIs) and used multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) for two cohorts: retinopathy cohort or kidney disease cohort, stratified by eGDR categories: < 4, 4 to 5.99, 6 to 7.99, and ≥ 8 mg/kg/min (reference). Results: A total of 22 146 (10 289 retinopathy cohort, and 11 857 kidney disease cohort with an overlapping of 9575) children and adults with T1D (median age 21 years, female 42% and diabetes duration of 6 and 7 years, respectively for the cohorts) were studied. During a median follow-up of 4.8 years (IQR 2.6–7.7) there were 5040 (24.7%), 1909 (48.1%), 504 (52.3%) and 179 (57.6%) events for retinopathy in individuals with an eGDR ≥ 8, 7.99 to 6, 5.99 to 4, and < 4 mg/kg/min, respectively. Corresponding numbers for kidney disease was 1321 (6.5%), 526 (13.3%), 255 (26.8%) and 145 (46.6%). After multiple adjustments for different covariates, individuals with an eGDR 7.99 to 6, 5.99 to 4 and < 4 mg/kg/min, had an increased risk of retinopathy compared to those with an eGDR ≥ 8 mg/kg/min (adjusted HRs, 95% CIs) 1.29 (1.20 to 1.40); 1.50 (1.31 to 1.71) and 1.74 (1.41 to 2.14). Corresponding numbers for kidney disease was (adjusted HRs, 95% CIs) 1.30 (1.11 to 1.52); 1.58 (1.25 to 1.99) and 1.33 (0.95 to 1.86), respectively. Conclusions: eGDR, a proxy for insulin resistance, is associated with retinopathy and kidney disease in young adults with T1D. The risk of retinopathy increased with lower eGDR. The risk of kidney disease also increased with lower eGDR; however results show no association between the lowest eGDR and kidney disease. eGDR can be helpful to identify young T1D individuals at risk.

Aims: To investigate cardiovascular (CV) safety and event rates for dapagliflozin versus other glucose‐lowering drugs (GLDs) in a real‐world type 2 diabetes population after applying the main inclusion criteria and outcomes from the DECLARE‐TIMI 58 study. Methods: Patients with new initiation of dapagliflozin and/or other GLDs were identified in Swedish nationwide healthcare registries for the period 2013 to 2016. Patients were included if they met the main DECLARE‐TIMI 58 inclusion criteria: age ≥40 years and established CV disease or presence of multiple‐risk factors, e.g. men aged ≥55 years and women aged ≥60 years with hypertension or dyslipidaemia. Propensity scores for the likelihood of dapagliflozin initiation were calculated, then 1:3 matching was carried out. DECLARE‐TIMI 58 outcomes were hospitalization for heart failure (HHF) or CV‐specific mortality, and major adverse CV events (MACE; CV‐specific mortality, myocardial infarction, or stroke). Cox survival models were used to estimate hazard ratios (HRs). Results: After matching, a total of 28 408 new‐users of dapagliflozin and/or other GLDs were identified, forming the population for the present study (henceforth referred to as the DECLARE‐like cohort. The mean age of this cohort was 66 years, and 34% had established CV disease. Dapagliflozin was associated with 21% lower risk of HHF or CV mortality versus other GLDs (HR 0.79, 95% confidence interval [CI] 0.69‐0.92) and had no significant association with MACE (HR 0.90, 95% CI 0.79‐1.03). HHF and CV mortality risks, separately, were lower at HR 0.79 (95% CI 0.67‐0.93) and HR 0.75 (95% CI 0.57‐0.97), respectively. Non‐significant associations were seen for myocardial infarction and stroke: HR 0.91 (95% CI 0.74‐1.11) and HR 1.06 (95% CI 0.87‐1.30), respectively. Conclusion: In a real‐world population similar to those included in the DECLARE‐TIMI 58 study, dapagliflozin was safe with regard to CV outcomes and resulted in lower event rates of HHF and CV mortality versus other GLDs.

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are approved drugs for the treatment of hyperglycemia in patients with type 2 diabetes. These effects are mainly mediated by inhibiting endogenous glucagon-like peptide-1 (GLP-1) cleavage. Interestingly, gliptins can also improve stroke outcome in rodents independently from GLP1. However, the underlying mechanisms are unknown. Stromal cell-derived factor-1α (SDF-1α) is a DPP-4 substrate and CXCR4 agonist promoting beneficial effects in injured brains. However, SDF-1α involvement in gliptin-mediated neuroprotection after ischemic injury is unproven. We aimed to determine whether the gliptin linagliptin improves stroke outcome via the SDF-1α/CXCR4 pathway, and identify additional effectors behind the efficacy. Mice were subjected to stroke by transient middle cerebral artery occlusion (MCAO). linagliptin was administered for 3 days or 3 weeks from stroke onset. The CXCR4-antagonist AMD3100 was administered 1 day before MCAO until 3 days thereafter. Stroke outcome was assessed by measuring upper-limb function, infarct volume and neuronal survival. The plasma and brain levels of active GLP-1, GIP and SDF-1α were quantified by ELISA. To identify additional gliptin-mediated molecular effectors, brain samples were analyzed by mass spectrometry. Linagliptin specifically increased active SDF-1α but not glucose-dependent insulinotropic peptide (GIP) or GLP-1 brain levels. Blocking of SDF-1α/CXCR4 pathway abolished the positive effects of linagliptin on upper-limb function and histological outcome after stroke. Moreover, linagliptin treatment after stroke decreased the presence of peptides derived from neurogranin and from an isoform of the myelin basic protein. We showed that linagliptin improves functional stroke outcome in a SDF-1α/CXCR4-dependent manner. Considering that Calpain activity and intracellular Ca2+ regulate neurogranin and myelin basic protein detection, our data suggest a gliptin-mediated neuroprotective mechanism via the SDF-1α/CXCR4 pathway that could involve the regulation of Ca2+ homeostasis and the reduction of Calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke.