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Effect of Pioglitazone on Left Ventricular Diastolic Function

Diastolic function begins to decline in early stages of type 2 diabetes.

Cardiovascular disease is a major risk factor for patients with type 2 diabetes. Of the cases in which patients with type 2 diabetes experience heart failure, half will result in mortality within the next 5 years. A major concern is that most patients who have diabetes in conjunction with diastolic dysfunction, are asymptomatic. Previous studies have suggested that pioglitazone enhances insulin sensitivity in the skeletal, liver, and adipose tissues. However, limited research is available on how pioglitazone affects insulin sensitivity in cardiac tissue and how this is associated with cardiac function. Because myocardial insulin resistance is thought to be a risk factor for cardiac dysfunction and coronary atherosclerosis, it is important that the relation between pioglitazone and myocardial insulin sensitivity be further studied in diabetes patients.

A recent 6-month study aimed to determine how patients with type 2 diabetes are impacted by pioglitazone in regard to insulin sensitivity in cardiac tissue, and left ventricular diastolic function. 12 patients with type 2 diabetes were included in the treatment group, and 12 patients with normal glucose tolerance were included in the control group. The patients with diabetes were either on metformin therapy, metformin and sulfonylurea therapy, or no therapy. Despite having diabetes, all participants in the treatment group were healthy and normally active. 10 out of the diabetic patients were on statin therapy and 10 were on antihypertensive therapy.

Parameters obtained at baseline included HbA1c, fasting plasma glucose and, insulin and lipid levels. An oral glucose tolerance test was used to determine glucose, insulin, and C-peptide levels. DEXA was used to obtain total body fat and lean mass. Patients then returned for an MRI, within a week following the oral glucose tolerance test to analyze left ventricular diastolic and systolic function. 3 to 7 days following the MRI, patients returned once again for a euglycemic insulin clamp with positron emission tomography to measure whole body (primarily skeletal muscle) and cardiac tissue insulin sensitivity. MRI’s and euglycemic insulin clamp with positron emission tests were conducted both at baseline prior to treatment and after treatment of pioglitazone. Patients with diabetes were to take pioglitazone 15 mg daily for 2 weeks, followed by 30 mg daily for 2 weeks, then 45 mg daily for the remainder of the study. Prior to treatment, patients were given dietary recommendations. Follow-up was conducted every 2 to 4 weeks.

At the 6-month follow-up, the patient with diabetes taking pioglitazone saw a significant reduction in HbA1c (6.7 ± 1.3 to 5.6 ± 0.8%; P<0.01), fasting plasma glucose (149 ± 48 to 112 ± 23 mg/dL; P<0.05), fasting plasma free fatty acids (0.52 ± 0.17 to 0.30 ± 0.14 mm/L; P<0.01), and both systolic blood pressure (124 ± 12 to 117 ± 10 mmHg) and diastolic blood pressure (80 ± 9 to 73 ± 9 mmHg) (P<0.05). Patients taking pioglitazone also experienced a significant increase in whole body insulin (primarily skeletal muscle) stimulated glucose uptake (3.4 ± 1.3 to 5.8 ± 2.1 mg/kg · min; P<0.01), Matsuda index of insulin sensitivity during oral glucose tolerance test (2.8 ± 1.9 to 5.8 ± 3.4; P<0.01), myocardial glucose uptake (0.24 ± 0.14 to 0.42 ± 0.13 µmol/min · g; P<0.01), and myocardial blood flow (0.95 ± 0.16 to 1.10 ± 0.25 mL/min · g; P<0.05).

It was also found that systolic function parameters were significantly increased from baseline in patients taking pioglitazone. There was an increase in stroke volume (37.7 ± 7.3 to 41.7 ± 8.5 mL/m2; P<0.05), and ejection fraction (60.7 ± 5.1 to 65.6.0 ± 6.9%; P<0.05), and a small reduction in resting heart rate. There was also a significant improvement in diastolic dysfunction after treatment. Transmitral early diastolic relation/atrial contraction ratio (1.04 ± 0.28 to 1.25 ± 0.38; P<0.01), and peak left ventricular filling rate (171 ± 52 to 212 ± 54 mL/s · m2; P<0.01) both increased.

Overall, the study showed that type 2 diabetes patients  without cardiovascular disease taking pioglitazone, experienced an improvement in both systolic and diastolic function. It was also determined that increased systolic and diastolic function is associated with an increase in both myocardial and skeletal muscle insulin sensitivity. Pioglitazone proved beneficial on all measured cardiac function parameters. The study also demonstrated that diastolic function begins to decline in the early stages of type 2 diabetes. The study did have positive findings but limitations should be considered. There were very few participants enrolled in the study, only diabetic patients without cardiovascular disease were included, and radiolabeled glucose was not utilized so glucose uptake may have been less accurate.

Practice Pearls:

  • Patients with type 2 diabetes who do not yet have cardiovascular disease had a significant increase in left ventricular diastolic function and systolic function with pioglitazone treatment.
  • Enhanced diastolic and systolic function was greatly associated with enhanced whole body (primarily skeletal muscle) and myocardial insulin sensitivity.
  • Diastolic function begins to decline in early stages of type 2 diabetes and these patients may benefit from pioglitazone.

Reference:

Clarke GD, Solis-Herrera C, Molina-Wilkins M, et al. Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes. Diabetes Care. 2017; 40: 1530-1536.

Graciela Nieto, Pharm. D. Candidate 2018, LECOM School of Pharmacy