The Sapienza University Mortality and Morbidity Events Rate (SUMMER) Study in Diabetes

Background Mortality rate of diabetic patients is about twice as much that of non-diabetic individuals of similar age; this makes diabetes a leading risk factor for mortality, especially of cardiovascular origin, which accounts for 2.9 million global events yearly. Such scenario is expected to further deteriorate, given that the prevalence of type 2 diabetes mellitus (T2DM), by far the most common form of diabetes comprising more than 90% of all diabetic individuals, is increasing worldwide. Predicting such devastating event is, therefore, urgently needed in order to target aggressive prevention strategies in high risk T2DM patients.

Aims This observational study is aimed at identifying new molecular promoters of all-cause mortality in patients with T2DM.

Secondary endpoints are to identify in these individuals molecular markers of

• cardiovascular mortality;
• myocardial infarction;
• stroke;
• dialysis.

Other pre-specified endpoints are to assess in these subjects:

• LADA;
• severe hypoglycemic episodes;
• revascularization procedures;
• hospitalization for heart failure;
• other co-morbidities (cancer - at follow-up only, liver disease, chronic obstructive pulmonary disease, autoimmune and endocrine disorders, other - non-diabetic - renal diseases, fractures, cognitive impairment).

Patients A total of 5,000 patients with T2DM of both sexes will be recruited. Measures The following parameters will be recorded as exposure variables at baseline.

• Age, BMI, waist circumference, systolic and diastolic pressure;
• Lifestyle habits, including diet, physical activity (both by validated questionnaires) and smoking.
• Menopausal state (for women).
• Family history of diabetes (3 consecutive generations).
• Family history of cardiovascular disease (first degree relatives).
• Diabetes duration.
• Severe (requiring assistance) hypoglycemic episodes (per year).
• Myocardial infarction, stroke, ulcer/gangrene/amputation, coronary and peripheral revascularization, hospitalization for heart failure, dialysis (at follow-up only).
• Glucose, HbA1c, creatinine, uric acid, total and HDL cholesterol, triglycerides, high sensitive C reactive protein, testosterone, Vitamin D, uric acid levels, white blood cells counting, urinary albumin creatinine ratio (ACR)
• Current glucose-, lipid-, blood pressure-lowering and anti-platelet or anti-coagulant treatment.
• Other relevant treatments (steroids, NSAIDs, immunomodulators, androgens, estrogens, anti-fracturative therapy).
• Main co-morbidities (cancer, chronic liver disease, chronic obstructive pulmonary disease, autoimmune and endocrine disorders, other - non-diabetic - renal diseases, fractures, cognitive impairment).

The following parameters will be assessed at baseline only:

• GADAs (by a radiobinding assay using in vitro translated [35S] methionine-labelled GAD65) and IA-2 antibodies (by radioimmunoprecipitation assays) to identify subjects with LADA.
• Genomic (common and rare variants in genes of interest according to a pathway-centric approach by means of Affymetrix platforms), transcriptomic (differential levels of mRNA by GeneChip Human Gene 1.0 ST Array from Affymetrix) and metabolomic by a combination of ultra-pressure liquid chromatography and gas chromatography coupled to mass spectrometry) analysis.

Measurements of testosterone, Vitamin D, GADAs and IA-2 antibodies as well as gnomic, transcriptomic and metabolomic analysis will be centralized.

Time schedule Recruitment of patients will last approximately 3 years. The enrolled patients will be followed for at least 5 years with yearly visits and telephone calls or consultation of death records in case of drop-out for unknown reasons.

Inclusion criteria

Type 2 diabetes mellitus

Exclusion criteria

• Severe psychiatric illnesses
• End-stage renal disease and dialysis
• Cirrhosis
• Any active cancer