Aims: To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. Methods: Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD‐free status. Results: Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD‐free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all‐cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75–2.33) and HR 2.05 (95% CI 1.82–2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all‐cause mortality risk: HRs 3.91 (95% CI 3.02–5.07) and 3.14 (95% CI 2.90–3.40), respectively. Conclusion: In a large multinational study of >750 000 CVRD‐free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.

OBJECTIVE: Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m2) received subcutaneous injections of IDeg(A) (600 μmol/L; n = 59), IDeg(B) (900 μmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS: At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52–1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65–1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25–0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44–1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments. CONCLUSIONS: In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10⁻⁸) with GDM, mapping to/near MTNR1B (P = 4.3 × 10⁻⁵⁴), TCF7L2 (P = 4.0 × 10⁻¹⁶), CDKAL1 (P = 1.6 × 10⁻¹⁴), CDKN2A-CDKN2B (P = 4.1 × 10⁻⁹) and HKDC1 (P = 2.9 × 10⁻⁸). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

The difference in diabetes susceptibility by ethnic background is poorly understood. The aim of this study was to assess the association between adiposity and diabetes in four ethnic minority groups compared with Norwegians, and take into account confounding by socioeconomic position. Data from questionnaires, physical examinations and serum samples were analysed for 30-to 60-year-olds from population-based cross-sectional surveys of Norwegians and four immigrant groups, comprising 4110 subjects born in Norway (n = 1871), Turkey (n = 387), Vietnam (n = 553), Sri Lanka (n = 879) and Pakistan (n = 420). Known and screening-detected diabetes cases were identified. The adiposity measures BMI, waist circumference and waist-hip ratio (WHR) were categorized into levels of adiposity. Gender-specific logistic regression models were applied to estimate the risk of diabetes for the ethnic minority groups adjusted for adiposity and income-generating work, years of education and body height used as a proxy for childhood socioeconomic position. The age standardized diabetes prevalence differed significantly between the ethnic groups (women/men): Pakistan: 26.4% (95% CI 20.1-32.7)/20.0% (14.9-25.2); Sri Lanka: 22.5% (18.1-26.9)/20.7% (17.3-24.2), Turkey: 11.9% (7.2-16.7)/12.0% (7.6-16.4), Vietnam: 8.1% (5.1-11.2)/10.4% (6.6-14.1) and Norway: 2.7% (1.8-3.7)/6.4% (4.6-8.1). The prevalence increased more in the minority groups than in Norwegians with increasing levels of BMI, WHR and waist circumference, and most for women. Highly significant ethnic differences in the age-standardized prevalence of diabetes were found for both genders in all categories of all adiposity measures (p < 0.001). The Odds Ratio (OR) for diabetes adjusted for age, WHR, body height, education and income-generating work with Norwegians as reference was 2.9 (1.30-6.36) for Turkish, 2.7 (1.29-5.76) for Vietnamese, 8.0 (4.19-15.14) for Sri Lankan and 8.3 (4.37-15.58) for Pakistani women. Men from Sri Lanka and Pakistan had identical ORs (3.0 (1.80-5.12)). A high prevalence of diabetes was found in 30-to 60-year-olds from ethnic minority groups in Oslo, with those from Sri Lanka and Pakistan at highest risk. For all levels of adiposity, a higher susceptibility for diabetes was observed for ethnic minority groups compared with Norwegians. The association persisted after adjustment for socioeconomic position for all minority women and for men from Sri Lanka and Pakistan.

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: Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT‐2i CVOTs of a general T2D population. Methods: T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE‐TIMI 58, EMPA‐REG OUTCOME, VERTIS‐CV) by the total T2D population. Results: In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV‐preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE‐TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2‐, 3‐ and 4‐fold higher compared to the CANVAS (34%), EMPA‐REG OUTCOME (21%) and VERTIS‐CV (17%) trials, respectively. Conclusions: In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE‐TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries.