Benefits of Pioglitazone Plus Insulin For Type 2

Combination pioglitazone plus insulin dual therapy reduces mortality by 50%.

Type 2 diabetes is a metabolic disease characterized by having high levels of blood glucose. The primary causes are persistent insulin resistance and progressive failure of pancreatic beta cells. Uncontrolled type 2 diabetes can lead to a combination of long-term illnesses including kidney disease, cardiovascular (CV) disease, retinopathy, and peripheral neuropathy. Monotherapy is the primary choice of management. Most individuals suffering from type 2 diabetes require treatment with anti-hyperglycemic medications to control the high levels of glucose. Patients with type 2 will eventually need a combination of antihyperglycemic medications to control their diabetes, especially if their A1C level is 9 or 10. Therefore, selecting appropriate medications to be used in combination therapy is very crucial in this disease state.

Pioglitazone is an agent of Thiazolidines (TZD), an oral antidiabetic class, that exerts its action through a gamma form of peroxisome proliferator-activated nuclear receptor.  This PPAR receptor alters the transcription of several genes involved in glucose metabolism and energy balance, These genes code for lipoprotein, lipase, fatty acyl-CoA synthase, magic enzyme, glucokinase, and GLUT4 glucose transporter. They reduce insulin resistance in adipose tissue, muscle, and the liver. Associated with Type 2 diabetes, TZDs have the potential to benefit individuals suffering full insulin resistance syndrome and have potential benefits for secondary complications such as cardiovascular disease.

Proven methods of combining pioglitazone with insulin have shown effective results.  It is much more effective than just using monotherapy. The way this works is that adding pioglitazone and insulin speeds up the glucose-lowering effect with the slower glycemic-lowering effects of pioglitazone by itself. By combining the drugs, there is a strong possibility of having hypoglycemia frequently within 1 to 2 months of giving a patient the combination of drugs. 

The National Health Insurance Research Database in Taiwan conducted a retrospective study analyzing the overall incidence rates of all-cause mortality and CV events between 2,579 adults with type 2 diabetes prescribed insulin and pioglitazone compared to the same number of 2,579 with type 2 diabetes prescribed insulin but not pioglitazone therapy. From the data, the mean age was 62 and mean duration of diabetes was 6 years. 

The mortality rates of users with pioglitazone therapy vs. users without pioglitazone therapy were 15.02 and 30.26 per 1,000 person-years, respectively. The adjusted hazard ratio for pioglitazone therapy users and nonusers was 0.47(95% CI, 0.38-0.58). CV and non-CV death had an adjusted hazard ratio of 0.78 (95% CI, 0.51-1.19) and 0.5 (95% CI, 0.38-0.66), respectively. New-onset heart failure, hospitalization for coronary artery disease, or stroke showed no differences in mortality rates between the two groups

Chih-Cheng Hsu, MD, DrPH, deputy director of the Institute of Population Health Sciences, National Health Research Institutes, Taiwan, told Endocrine Today that the findings from this study showed that the combination therapy of insulin and pioglitazone lowered the risk for all-cause mortality. Hsu discussed how pioglitazone might be a beneficial agent in insulin therapy. Most patients with diabetes will eventually require a combination of drug therapy. In addition, clinicians must know when combination therapy is necessary and must consider many factors when selecting an appropriate combination that targets multiple pathophysiologic defects, which will be effective and avoid risks of hypoglycemia. 

Practice Pearls

• Pioglitazone and Insulin in combination reduce death by 50%.
• When Pioglitazone and Insulin are prescribed concurrently, a low dose of Pioglitazone should be started to avoid the risk of hypoglycemia.
• Thiazolidines can decrease cardiovascular risk in type 2 diabetes patients.

References for “Benefits of Pioglitazone Plus Insulin For Type 2”:

Metab, J Clin Endocrinol. “Pioglitazone Halves Mortality Risk in Insulin-Dependent Type 2 Diabetes.” Healio, https://www.healio.com/endocrinology/diabetes/news/online/{1017cb5e-983a-489a-a1d9-77c749c8c7e4}/pioglitazone-halves-mortality-risk-in-insulin-dependent-type-2-diabetes.

Divakaran S, et al. Diabetes Care. 2019;doi:10.2337/dc19-0998. October 4. “Diabetes Exacerbates Long-Term CV Risks after MI for Younger Adults.” Healio, https://www.healio.com/endocrinology/diabetes/news/online/{2858617d-beab-42fd-ac05-14348b7e0311}/diabetes-exacerbates-long-term-cv-risks-after-mi-for-younger-adults.

“What Is Insulin?” EndocrineWeb, https://www.endocrineweb.com/conditions/type-1-diabetes/what-insulin.

Taylor-Eugene Simmons, Florida A&M University, College of Pharmacy & Pharmaceutical Sciences, PharmD Candidate