Pioglitazone, the go-to therapy

Many drugs have CV benefits, reduce HA1c, have metabolic effects, and improve NASH/NAFLD in people with diabetes. Still, pioglitazone, an SGLT2 inhibitor, seems to be one of the cheap drugs and has many functions with more significant benefits than risk. There are a lot of CV trials conducted like the EMPAREG and CANVAS.

The PROactive is a meta-analysis published regarding whether pioglitazone reduces the risk of macrovascular complications in patients with type 2 diabetes mellitus (DM) and high risk for macrovascular complications compared to placebo. It was a Prospective, randomized, placebo-controlled, multi-center (321 centers in 19 European countries) trial with 5,238 participants divided into two arms, Pioglitazone arm (n=2,605) and Placebo arm (n=2,633). The enrollment period was from 2001 to 2002, and the mean follow-up time was 34.5 months. Demographics include people of age 61.9 years, 67% male, 98% white race, BMI of 30.7±4.7 kg/m2, T2DM- time since first diagnosis 8 (4-13) years, HbA1c 7·8 (7.0-8.9)% and are on one oral antihyperglycemic agent 30%, two oral antihyperglycemic agent 25%, insulin and 1 or 2 oral antihyperglycemic agents 30%, BP with systolic 144±18 mm Hg and diastolic 83±10 mm Hg, LDL-C  2.9 (2.3-3.5) mmol/L; HDL-C: 1·1 (0.9-1.3) mmol/L; triglyceride: 1.8 (1.3-2.6) mmol/L. Other medical histories: microvascular complications 43%, active smoker 13%, hypertension 75%. Macrovascular disease criteria: MI 47%, stroke 19%, PCI or CABG 31%, ACS 14%, CAD 48%, PAD 19%, ≥2 macrovascular disease criteria 47%. Primary outcome: all-cause mortality, non-fatal MI (including silent MI), stroke, ACS, endovascular or surgical intervention in the coronary or leg arteries, and above-ankle amputation. Using Kaplan Meier, statistical analysis was conducted to examine the MACE endpoints in both arms.  

Primary outcomes indicated all-cause mortality, non fatal MI (including silent MI), stroke, ACS, endovascular or surgical intervention in the coronary or leg arteries, and above-ankle amputation was 514 vs. 572 patients (HR 0·90, 95% CI 0·80-1·02, P=0·095) in the pioglitazone vs placebo arm respectively. Secondary outcomes indicated that all-cause mortality, non-fatal MI, and stroke301 vs. 358 patients (HR 0.84; 95% CI 0.72-0.98; P=0.027),All-cause mortality177 vs. 186 patients (HR 0.96; 95% CI 0.78-1.18; P=NS)Non-fatal MI119 vs. 144 first events (HR 0.83; 95% CI 0.65-1.06; P=NS, Stroke86 vs. 107 first events (HR 0.81; 95% CI 0.61-1.07; P=NS),Major leg amputation26 vs. 26 first events (HR 1.01; 95% CI 0.58-1.73; P=NS,ACS56 vs. 72 first events (HR 0.78; 95% CI 0.55-1.11; P=NS), Coronary revascularization169 vs. 193 first events (HR 0.88; 95% CI 0.72-1.08; P=NS),Leg revascularization 80 vs. 65 first events (HR 1.25; 95% CI 0.90-1.73; P=NS).

Increased risk of bone fractures was reported in individuals treated with TZDs, mostly in postmenopausal women on the distal long bone of hand and feet related to trauma. Because one study did reveal an increased risk of bone fracture in men, and the other showed no risk in either. With that said, it is still recommended to use caution in post-menopausal women with osteoporosis.

Pioglitazone was also shown to be a potent insulin sensitizer. Knowing the main defect in T2DM patients are insulin resistance and beta-cell failure, pioglitazone improves insulin sensitivity, corrects multiple components of IRS, ameliorates lipotoxicity, and protects against atherosclerotic CVD, an excellent agent for the treatment of NAFLD and NASH.Adverse events included any serious events: 46% vs 48% of patients (P=0.110) Endpoint events: 15% vs 16% of patients (P=0.123), Non-endpoint events: 41% vs 44% of patients (P=0.09)Heart failure: 11% vs. 8% of patients (P<0.0001) in pioglitazone vs placebo. The higher the weight gain, the less the HA1c and the greater the insulin secretions and sensitivity; all these are dose-dependent. Weight gain can be minimized by not exceeding 30mg/day or by combining with metformin or a GLP agonist. The FDA recommended a prospective study should be done to see if there was a potential risk of having bladder cancer while using pioglitazone. The results revealed no significant risk. However, the FDA still recommends using caution while using pioglitazone in patients with diabetes who have active bladder cancer or a history of it.

Pioglitazone is the only drug with a potential beneficial effect on insulin sensitivity and beta-cell function, leading to a long-term reduction in HA1c. This drug also corrects components of the metabolic syndrome and is effective in treating NASH/NAFLD.

Practice Pearls:

• Since pioglitazone causes weight gain, these will be watchful for it can worsen symptoms of HF in patients.
• It will be great to consider pioglitazone if the patient has cardiovascular disease because pioglitazone is cardioprotective.
• Pioglitazone is cheaper than other anti-diabetic drugs with the same properties.

Citation.

DeFronzo, Ralph A et al. “Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes.” Diabetes & vascular disease research vol. 16,2 (2019): 133-143. doi:10.1177/1479164118825376