Cardiovascular risks in patients with type 2 diabetes using pioglitazone or sulfonylureas: personalized care approach.
Patients with type 2 diabetes and cardiovascular disease are recommended anti-diabetic medications that are proven to be useful in reducing cardiovascular risks. Unless contraindicated or not tolerated, metformin is the gold standard, first line therapy for treating patients with type 2 diabetes. Anti-diabetic drug classes such as sulfonylureas (SUs), Thiazolidinediones (TZDs), etc. can be used as add-ons to help intensify therapy and work synergistically with metformin. SUs and TZDs are both commonly prescribed and affordable, suitable treatment options regarding supported efficacy and adverse effects. Pioglitazone, in the TZD class, has previously shown to have protection against cardiovascular risks. According to a study published in The Journal of Clinical Endocrinology and Metabolism, pioglitazone and metformin has shown better cardiovascular protection for patients recently diagnosed with type 2 diabetes who have a fairly low risk for cardiovascular complications.
Per clinical guidelines and recent research, sodium-glucose cotransporter (SGLT) 2 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists are recommended to be used in patients with type 2 diabetes with cardiovascular disease, due to proven cardiovascular benefits. However, there have been no studies assessing the cardiovascular benefit of anti-diabetic medications in patients with type 2 diabetes who rarely have clinical evidence of cardiovascular disease. Researchers, using the RECursive Partitioning and AMalgamation (RECPAM) method, aimed to evaluate the long-term cardiovascular effects of pioglitazone or sulfonylureas in patients with type 2 diabetes with pretreatment cardiovascular risk.
Sulfonylureas are classified into 2 generations: first-generation and second-generation. Currently used are the second-generation sulfonylureas (Glyburide, Glipizide, Glimepiride, Gliclazide), while the first-generation sulfonylureas are no longer used (Tolbutamide, Chlorpropamide, Tolazamide) due to severe hypoglycemia episodes. This class of drugs are considered long-acting insulin secretagogues, which binds to sulfonylurea (SUR1) receptors on pancreatic beta cells to enhance insulin secretion, therefore lowering glucose levels in the blood. Pioglitazone is a thiazolidinedione, which activates peroxisome proliferator-activated receptor-g (PPAR-g) nuclear receptors to increase glucose uptake and utilization in peripheral tissues. Pioglitazone is the only TZD that has shown to have cardiovascular benefit in patients with type 2 diabetes.
For the study, published in The Journal of Clinical Endocrinology and Metabolism, 2,820 patients from the previous TOSCA.IT trial were divided into four different subgroups based on outcome risk of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization. Each group’s outcomes were evaluated off the effect of pioglitazone and SUs. The average age of participants was 62 years old. At baseline, the body mass index (BMI) was 30 kg/m2 and 8.5 years was the average duration patients had type 2 diabetes. 11.2% of the participants reported previous cardiovascular disease.
With gender being the first splitting variable, females had the lowest cardiovascular risk (class 1, reference), compared to the other 3 classes involved of only males. Classes were separated by urinary albumin-to-creatinine ratio (UACR) and BMI: class 2 with UACR ≤9 mg/g, class 3 with UACR >9 mg/g and BMI ≤28.8 kg/m2, and class 4 (highest risk for cardiovascular disease) UACR >9 mg/g and BMI >28.8 kg/m2 (HR 5.58, 95%CI 3.32-9.69). Higher BMI, waist circumference, triglycerides, blood pressure, and UACR and lower HDL cholesterol all characterized Class 4 with greater insulin resistance than other classes. Metformin and pioglitazone in class 4 showed significant lower occurrence of cardiovascular risk than sulfonylureas (HR 0.48; 95% CI 0.25-0.76). Other classes showed no significant differences between the two drugs.
The study has shown that add-on pioglitazone to metformin, compared to SU, is effective in cardiovascular protection, when cardiovascular risk is low in patients newly diagnosed with type 2 diabetes. Although current practice guidelines do not recommend the use of SUs or TZDs as add-ons for patients with cardiovascular disease initially, personalized care approaches can still benefit patients. Anti-diabetic medication regimens are patient-centered, based off the patient’s needs on affordability, tolerance, and adverse effects with drugs. Pioglitazone is affordable, effective, and an overall a safe drug to use in patients with lower cardiovascular risks.
- Pioglitazone, compared to sulfonylureas, can be used as an alternate add-on to SGLT-2 inhibitors and GLP-1 agonists when initiating anti-diabetic medication therapy to patients with lower cardiovascular risks.
- Pioglitazone showed better cardiovascular protection for men with higher BMI, waist circumference, triglycerides, blood pressure, and UACR and lower HDL cholesterol.
- Sulfonylureas have not been proven to lower occurrence of cardiovascular risks.
Rice, Tyler. “Cardiovascular Effects of Pioglitazone and Sulfonylureas in Type 2 Diabetes.” Endocrinology Advisor, 21 May 2019, www.endocrinologyadvisor.com/home/topics/diabetes/type-2-diabetes/cardiovascular-effects-of-pioglitazone-and-sulfonylureas-in-type-2-diabetes/.
Vaccaro, et al. “Cardiovascular Effects of Pioglitazone or Sulphonylureas According to Pretreatment Risk: Moving towards Personalized Care.” OUP Academic, Oxford University Press, 6 May 2019, academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2019-00361/5485080?redirectedFrom=fulltext.
Emma Kammerer, L|E|C|O|M Bradenton School of Pharmacy, PharmD Candidate