# The Effect of Sex Hormones on Cardiometabolic Outcomes in Men and Women with Diabetes: The Look AHEAD (Action for Health in Diabetes) Study

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $704,335

## Abstract

Although women and men have about an equal prevalence of type 2 diabetes (DM), DM imposes a clinically
significant excess relative risk of coronary heart disease (44% higher), stroke (27% higher) and vascular
dementia (19% higher) in women compared to men. Understanding these sex differences could inform
research to improve DM outcomes for both women and men. Postulated reasons for the “female disadvantage”
include an adverse cardiometabolic profile (particularly greater obesity) and disparities in aggressiveness of
CV preventive treatments (e.g. use of statins). In addition, differences in endogenous sex hormones, including
estradiol (E2), testosterone (T) and sex hormone binding globulin (SHBG), may contribute to the excess risk
for women conferred by DM. Although lifestyle changes (diet, exercise and weight loss) are the cornerstone of
diabetes management, it is not known if weight loss and healthier lifestyle can modulate the trajectory of sex
hormones over time, and the role of these hormonal changes on cardiometabolic risk factors. The Action for
Health In Diabetes (Look AHEAD) Study was a randomized controlled trial among 5,145 overweight individuals
with obesity and type 2 diabetes designed to evaluate the effect of an Intensive Lifestyle Intervention (ILI)
compared to a control group on incident CVD events. A major strength of Look AHEAD is its capacity to
address questions of causation, because study participants were followed over 8 years (~3000 with
longitudinal biospecimens for sex hormone measurements), with significant and well-characterized alterations
in weight and with adjudicated clinical outcomes. In this proposal, we will first analyze the stored biospecimens
for sex hormones (E2, T), SHBG and albumin. We will then 1) Test whether the ILI improves endogenous sex
hormones over time and whether the effect of ILI is moderated by sex; 2) Evaluate the longitudinal
associations between endogenous sex hormones and cardiometabolic risk factors (HbA1c, lipid levels, body
mass index and weight, waist circumference, body composition, blood pressure) (primary outcomes); 3) Test
the effect of the time-trajectory of endogenous sex hormones on improving cardio-metabolic risk factors and
long term DM outcomes (i.e. CVD, stroke, chronic kidney disease and vascular dementia) over 8 years of
followup, and whether differences exist by sex. Our overall hypothesis is that ILI improves the sex hormone
profile, and that an unfavorable sex hormone profile, i.e. high free T in women and low free T in men, is
associated with an adverse cardiometabolic risk profile. Ultimately, understanding the biological role of sex
hormones in DM could target treatments, particularly lifestyle modification, and inform the prevention of CVD
and other DM complications, to reduce DM-related morbidity and mortality for both women and men.

## Key facts

- **NIH application ID:** 10102514
- **Project number:** 1R01DK127222-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Wendy Lynet Bennett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $704,335
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102514

## Citation

> US National Institutes of Health, RePORTER application 10102514, The Effect of Sex Hormones on Cardiometabolic Outcomes in Men and Women with Diabetes: The Look AHEAD (Action for Health in Diabetes) Study (1R01DK127222-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102514. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*