AIMS/HYPOTHESIS: We aimed to describe the shape of observed relationships between risk factor levels and clinically important outcomes in type 2 diabetes after adjusting for multiple confounders. METHODS: We used retrospective longitudinal data on 246,544 adults with type 2 diabetes from 600 practices in the Clinical Practice Research Datalink, 2006-2012. Proportional hazards regression models quantified the risks of mortality and microvascular or macrovascular events associated with four modifiable biological variables (HbA1c, systolic BP, diastolic BP and total cholesterol), while controlling for important patient and practice covariates. RESULTS: U-shaped relationships were observed between all-cause mortality and levels of the four biometric risk factors. Lowest risks were associated with HbA1c 7.25-7.75% (56-61 mmol/mol), total cholesterol 3.5-4.5 mmol/l, systolic BP 135-145 mmHg and diastolic BP 82.5-87.5 mmHg. Coronary and stroke mortality related to the four risk factors in a positive, curvilinear way, with the exception of systolic BP, which related to deaths in a U-shape. Macrovascular events showed a positive and curvilinear relationship with HbA1c but a U-shaped relationship with total cholesterol and systolic BP. Microvascular events related to the four risk factors in a curvilinear way: positive for HbA1c and systolic BP but negative for cholesterol and diastolic BP. CONCLUSIONS/INTERPRETATION: We identified several relationships that support a call for major changes to clinical practice. Most importantly, our results support trial data indicating that normalisation of glucose and BP can lead to poorer outcomes. This makes a strong case for target ranges for these risk factors rather than target levels. ; Kontopantelis, Evangelos Springate, David A Reeves, David Ashcroft, Darren M Rutter, Martin Buchan, Iain Doran, Tim Diabetologia. 2014 Dec 16.