Unexplained Residual Risk In Type 2 Diabetes: How Big Is The Problem?

Sivaram Neppala, Jemema Rajan, Eric Yang, Ralph A. DeFronzo

Research output: Contribution to journalArticlepeer-review


Purpose of Review: What is new? Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes (T2D) individuals. Of the major risk factors for CVD, less than 10% of T2D people meet the American Diabetes Association/American Heart Association recommended goals of therapy. The present review examines how much of the absolute cardiovascular (CV) risk in type 2 diabetes patients can be explained by major CV intervention trials. Recent Findings: Multiple long-term cardiovascular (CV) intervention trials have examined the effect of specific target-directed therapies on the MACE endpoint. Only one prospective study, STENO-2, has employed a multifactorial intervention comparing intensified versus conventional treatment of modifiable risk factors in T2D patients, and demonstrated a 20% absolute CV risk reduction. Summary: If the absolute CV risk reduction in these trials is added to that in the only prospective multifactorial intervention trial (STENO-2), the unexplained CV risk is 44.1%. What are the clinical implications? Potential explanations for the unaccounted-for reduction in absolute CV risk in type 2 diabetes (T2D) patients are discussed. Hypothesis: failure to take into account synergistic interactions between major cardiovascular risk factors is responsible for the unexplained CV risk in T2D patients. Simultaneous treatment of all major CV risk factors to recommended AHA/ADA guideline goals is required to achieve the maximum reduction in CV risk.

Original languageEnglish (US)
Pages (from-to)623-633
Number of pages11
JournalCurrent Cardiology Reports
Issue number6
StatePublished - Jun 2024


  • Cardiovascular disease
  • Residual risk
  • Type 2 diabetes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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