IntroductionType 2 diabetes is characterized by considerable heterogeneity in its etiopathogenesis and clinical presentation. We aimed to identify clusters of type 2 diabetes in Asian Indians and to look at the clinical implications and outcomes of this clustering.Research design and methodsFrom a network of 50 diabetes centers across nine states of India, we selected 19 084 individuals with type 2 diabetes (aged 10–97 years) with diabetes duration of less than 5 years at the time of first clinic visit and performed k-means clustering using the following variables: age at diagnosis, body mass index, waist circumference, glycated hemoglobin, serum triglycerides, serum high-density lipoprotein cholesterol and C peptide (fasting and stimulated). This was then validated in a national epidemiological data set of representative individuals from 15 states across India.ResultsWe identified four clusters of patients, differing in phenotypic characteristics as well as disease outcomes: cluster 1 (Severe Insulin Deficient Diabetes, SIDD), cluster 2 (Insulin Resistant Obese Diabetes, IROD), cluster 3 (Combined Insulin Resistant and Deficient Diabetes, CIRDD) and cluster 4 (Mild Age-Related Diabetes, MARD). While SIDD and MARD are similar to clusters reported in other populations, IROD and CIRDD are novel clusters. Cox proportional hazards showed that SIDD had the highest hazards for developing retinopathy, followed by CIRDD, while CIRDD had the highest hazards for kidney disease.ConclusionsCompared with previously reported clustering, we show two novel subgroups of type 2 diabetes in the Asian Indian population with important implications for prognosis and management. The coexistence of insulin deficiency and insulin resistance seems to be peculiar to the Asian Indian population and is associated with an increased risk of microvascular complications.

The most common side effect of angiotensin converting enzyme inhibitor drugs (ACEi) is a cough. We conducted a genome wide association study (GWAS) of ACEi-induced cough among 7,080 subjects of diverse ancestries in the eMERGE network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1,595 cases and 5,485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (MAF=0.33, OR=1.3 [95%CI: 1.2–1.4], p=1.0×10−8). Replication for six SNPs in KCNIP4 was tested in a second eMERGE population (n=926) and in the GoDARTS cohort (n=4,309). Replication was observed at rs7675300 (OR=1.32 [1.01–1.70], p=0.04) in eMERGE and rs16870989 and rs1495509 (OR=1.15 [1.01–1.30], p=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 [1.15–1.32], p=1.9×10−9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

BackgroundThere are few observational studies evaluating the risk of AKI in people with type 2 diabetes, and even fewer simultaneously investigating AKI and CKD in this population. This limits understanding of the interplay between AKI and CKD in people with type 2 diabetes compared with the nondiabetic population.MethodsIn this retrospective, cohort study of participants with or without type 2 diabetes, we used electronic healthcare records to evaluate rates of AKI and various statistical methods to determine their relationship to CKD status and further renal function decline.ResultsWe followed the cohort of 16,700 participants (9417 with type 2 diabetes and 7283 controls without diabetes) for a median of 8.2 years. Those with diabetes were more likely than controls to develop AKI (48.6% versus 17.2%, respectively) and have preexisting CKD or CKD that developed during follow-up (46.3% versus 17.2%, respectively). In the absence of CKD, the AKI rate among people with diabetes was nearly five times that of controls (121.5 versus 24.6 per 1000 person-years). Among participants with CKD, AKI rate in people with diabetes was more than twice that of controls (384.8 versus 180.0 per 1000 person-years after CKD diagnostic date, and 109.3 versus 47.4 per 1000 person-years before CKD onset in those developing CKD after recruitment). Decline in eGFR slope before AKI episodes was steeper in people with diabetes versus controls. After AKI episodes, decline in eGFR slope became steeper in people without diabetes, but not among those with diabetes and preexisting CKD.ConclusionsPatients with diabetes have significantly higher rates of AKI compared with patients without diabetes, and this remains true for individuals with preexisting CKD.

AimsA genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.Methods and resultsIn the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34–2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07–1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05–2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10–1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16–1.54).ConclusionThis study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.