SGLT2 Inhibition With Empagliflozin in Patients With Type 2 Diabetes Mellitus: Influences on Left Ventricular Mass, Function, and Cardiac Lipid Content
Overview
- Phase
- Phase 4
- Intervention
- Empagliflozin
- Conditions
- Diabetes Mellitus Type 2
- Sponsor
- Hannover Medical School
- Enrollment
- 7
- Locations
- 1
- Primary Endpoint
- change in left ventricular mass
- Status
- Terminated
- Last Updated
- 7 years ago
Overview
Brief Summary
Patients with type 2 diabetes mellitus are exposed to an excessive heart failure risk secondary to left ventricular hypertrophy and impaired diastolic filling, a condition not addressed by currently available treatments. The abnormality results from obesity-induced volume overload, increased blood pressure, and myocardial fat accumulation. By improving metabolism, body weight, and blood pressure, Empagliflozin addresses the root causes of type 2 diabetes-associated myocardial disease. We will assess left ventricular mass, function, and lipid content in patients with type 2 diabetes mellitus using cardiac magnetic resonance imaging and spectroscopy as well as echocardiography before and after empagliflozin or glimepiride treatment. We expect to observe improvements in left ventricular mass, function, and fat content with empagliflozin. The results of the study will help to position empagliflozin as an antidiabetic agent with the added value of protecting the heart.
Detailed Description
Overview of Medical Indication Type 2 diabetes mellitus is associated with increased heart failure risk. The increased risk results in part from poor glycemic control and obesity, but concomitant arterial hypertension may also contribute. In the Framingham Heart Study, heart failure risk increased by 5% in men and by 7% in women with each 1 kg/m2 increment in body mass index (BMI). Compared with normal weight subjects, obese subjects had a doubling of heart failure risk. Given the rapid increase in the prevalence of obesity and type 2 diabetes mellitus, the number of heart failure patients is likely to increase sharply. Evidence Heart failure in obesity is explained by increased left ventricular mass and impaired left ventricular diastolic filling rather than systolic dysfunction. Obesity is associated with volume expansion and increased cardiac output. Arterial blood pressure also increases with increasing obesity. In addition, type 2 diabetes mellitus may directly elicit abnormalities in myocardial metabolism and function through intramyocardial triglyceride deposition and lipotoxicity. In a study from our group, obese women with insulin resistance showed increased myocardial lipid accumulation compared with obese insulin-sensitive women, and intramyocardial lipids were reduced by dietary weight loss. Finally, intramyocardial lipids are associated with impaired diastolic function in patients with type 2 diabetes mellitus. Myocardial insulin resistance may also contribute to heart failure, because genetic deletion of cardiac insulin receptors in mice worsens catecholamine-mediated myocardial injury. Heart failure risk may be further exacerbated through obesity-induced neurohumoral activation and systemic inflammation. Inflammatory cytokines are elevated in heart failure and modulate cardiac remodelling through various mechanisms including myocardial hypertrophy, fibrosis, and apoptosis. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new drug class for the treatment of type 2 diabetes mellitus. SGLT2 inhibitors may be particularly suitable in improving cardiac structure and function because they substantially improve systemic glucose metabolism, lower blood pressure, and reduce body weight. These effects reduce sympathetic vasomotor tone, and renin-angiotensin-system activity. Thus, SGLT2 inhibitors including empagliflozin ameliorate metabolic and hemodynamic risk factors tightly linked with left ventricular hypertrophy and heart failure risk. Recently published outcome data suggest a beneficial effect of empagliflozin on heart failure hospitalisation rates and on overall cardiovascular mortality in patients with type 2 diabetes and previously diagnosed cardiovascular disease. Study Rationale Patients with type 2 diabetes mellitus are exposed to an excessive heart failure risk secondary to left ventricular hypertrophy and impaired diastolic filling, a condition not addressed by currently available treatments. The abnormality results from obesity-induced volume overload, increased blood pressure, and myocardial fat accumulation. By improving metabolism, body weight, and blood pressure, empagliflozin addresses the root causes of myocardial disease associated with type 2 diabetes-. We will assess left ventricular mass, function, and lipid content in patients with type 2 diabetes mellitus before and after 24 weeks treatment with metformin plus empagliflozin or glimepiride. We expect to observe improvements in left ventricular mass, function, and fat content with empagliflozin. The results of the study will help to understand the mechanisms of cardioprotective effects of empagliflozin that have been revealed recently.
Investigators
Eligibility Criteria
Inclusion Criteria
- •women and men ≥40 and \<80 years of age
- •patients with type 2 diabetes mellitus on stable anti-diabetic treatment for the last 3 months; at screening the following treatment conditions are allowed:
- •metformin + sulfonylurea with HbA1c ≥6.5% and ≤9.0%
- •metformin monotherapy with HbA1c ≥7.5% and ≤ 9.0%
- •metformin + dipeptidylpeptidase-IV inhibitor with ≥6.5% and ≤9.0%
- •waist circumference ≥80 cm in women or ≥94 cm in men
- •office blood pressure ≤150/95 mm Hg with a stable dose of a maximum of 4 antihypertensive medications for the last 3 months (24h ambulatory blood pressure measurement (ABPM) is allowed to check accuracy of office values; inclusion with 24h mean blood pressure ≤145/90 mm Hg is possible)
- •women without childbearing potential defined by:
- •at least 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral oophorectomy
- •hysterectomy
Exclusion Criteria
- •diabetes mellitus type 1
- •uncontrolled diabetes mellitus type 2 with fasting glucose \> 13.3 mmol/l confirmed on a second day
- •previous treatment with insulin, glucagon-like peptide-1 analogues, or pioglitazone during the last year before screening
- •previous treatment with empagliflozin
- •acute illness at screening or randomization according to judgement by the investigator or patient
- •known or suspected hypersensitivity to empagliflozin, glimepiride or any excipients; known or suspected hypersensitivity to sulfonylureas or sulfonamides
- •history of multiple severe hypoglycemic episodes
- •any condition prohibiting MRI studies (e.g. metal implants, claustrophobia, body weight too high) including any suspected reaction after contrast agent application
- •patient actively attempted to lose weight or experienced unintentional clinically significant weight loss during the last 3 months
- •bariatric surgery or other gastrointestinal surgery procedures that induce chronic malabsorption
Arms & Interventions
Empagliflozin
25 mg/d empagliflozin + matching glimepiride placebo for 24 weeks.
Intervention: Empagliflozin
Glimepiride
2 or 4 mg/d glimepiride+ matching empagliflozin placebo for 24 weeks.
Intervention: Glimepiride
Outcomes
Primary Outcomes
change in left ventricular mass
Time Frame: baseline and 24 weeks
change in left ventricular mass determined by cardiac MRI as the difference between 24 weeks and baseline
Secondary Outcomes
- change in left ventricular end-diastolic volume(baseline and 24 weeks)
- change in intramyocardial lipid content(baseline and 24 weeks)
- change in fasting plasma glucose concentration(baseline and 24 weeks)
- change in diastolic function(baseline and 24 weeks)
- change in HbA1c(baseline and 24 weeks)
- change in left ventricular end-systolic volume(baseline and 24 weeks)
- change in left ventricular function(baseline and 24 weeks)
- change ambulatory blood pressure(baseline and 24 weeks)
- change in fasting serum insulin concentration(baseline and 24 weeks)
- change in body fat mass(baseline and 24 weeks)
- change in body weight(baseline and 24 weeks)
- change in waist circumference(baseline and 24 weeks)