1. IRIS Trial
Insulin Resistance Intervention after Stroke

2. DM prevention and risk of recurrent stroke and MI
IRIS
DM prevention and risk of recurrent stroke and MI

3. Diabetes Prevention
In IRIS, at baseline, about 42% of the 3876 total patients had impaired fasting glucose (IFG) of 100 to 125 mg/dl (as defined by the American Diabetes Association), while 14% met the World Health Organization/International Diabetes Federation IFG criteria ( mg/dl), and two-thirds had HbA1c levels of 5.7% or greater. Just over half had at least three components of the metabolic syndrome.

4. Diabetes Prevention
At 1 year, fasting plasma glucose was reduced significantly in the pioglitazone group (from 98.2 to 95.1 mg/dL) but remained unchanged in the placebo group (P < for between-group difference). Homeostasis model assessment of insulin resistance (HOMA-IR) also dropped significantly with pioglitazone compared with placebo (P < ).

5. Diabetes Prevention
Over an average 4.8 years, there was a 3.9% absolute risk reduction in progression to diabetes with pioglitazone compared with placebo (hazard ratio, 0.48), with greater risk reductions seen among those meeting the ADA definition of IFG at baseline (8.5% vs 0.8%), those with baseline HbA1c 5.7% or greater compared with below (5.6% vs 1.0%), and HOMA-IR 4.6 or above vs below (6.3% vs 1.4%).

6. The main IRIS finding- that pioglitazone reduced by a significant 24% the risk for recurrent stroke or myocardial infarction (MI) in people with insulin resistance, no frank diabetes, and a recent history of stroke or transient ischemic attack- were presented earlier this year at the International Stroke Conference 2016 and simultaneously published in the New England Journal of Medicine.

7. In the new analysis, progression to diabetes-a pre specified secondary end point of IRIS -occurred in 3.8% of the 1939 individuals randomized to 45 mg/day of pioglitazone compared with 7.7% of the 1937 receiving placebo, a significant 52% reduction in the time to diabetes onset (P < ).

8. Pioglitazone Slows Progression to Type 2 Diabetes: More IRIS Data

9. In the new analysis, The prevention of diabetes and secondary stroke seen together in IRIS is "the first time [both have been] shown in one trial with one drug, although they are not necessarily linked,"

10. Pioglitazone is the only oral type 2 diabetes drug with clear anti atherosclerosis effects .... Should the role of this inexpensive, generic medication in type 2 diabetes management be reassessed?
Also, Should the neurology community consider the potential role of pioglitazone for secondary stroke prevention?"

11. Ralph A DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center, San Antonio, and ACT NOW lead author, believes the time is right to take another look at pioglitazone. And regarding the new IRIS data, Dr DeFronzo said: "I think pioglitazone, particularly in lower doses .. .is an ideal drug for prevention of diabetes, adding, "Personally, I think it is the second-best drug for treating people with diabetes."

12. The additional risk of fractures is about one for every 100 patients using the drug for 1 year, "so it's not a large signal. One might think that preventing a stroke or an Ml is more important, but that depends on several factors, including how severe the fracture vs the stroke/MI is.

13. ln IRIS we did not see a hip-fracture signal, which is gratifying
ln IRIS we did not see a hip-fracture signal, which is gratifying. Nonetheless it needs to be incorporated into decision making with the patient."

14. Revisiting the Use of Pioglitazone in the Treatment of Type 2 Diabetes

15. Tabla . Attributes that Make Pioglitazona Attractive
- An Inexpensive generic
- Lowers A1 c as much as any oral agent
- Causes no significant hypoglycemia as monotherapy
- Has been used for a long time- no surprises expected
- Easy to use - 1 pill once daily anytime
- Can be combined with any other therapy
- The responsiveness is very durable over the years
- Has a beneficial effect of lipids (improves HDL, TG, and LDL particles)
- Beneficial effect on markers of CVD (IVUS, CIMT)
- Beneficial impact on CVD outcomes (PRO active, IRIS)
Beneficial effect on beta-cell function
Effective even in patients with a low eGFR

16. Tabla . Attributes that Make Pioglitazona less Attractive:
- Weight gain
* Manageable with using lower doses (15, 30 mg), avoiding use with insulin, combining with GLP-1 RA and/or SGL T2 inhibitor
* Fat is subcutaneous, not visceral (fewer metabolic consequences)
- Fluid retention
* Manageable as above
* Avoid use in New York Class Ill and IV CHF
- Bone fractures
* Avoid use in high-risk patients
* Atypical fractures, rare
- Overcoming the history of bad press

17. We therefore propose that pioglitazone be reconsidered in the therapeutic armamentarium for T2D, to address CVD in patients with insulin resistance, used in the lower doses of 15 to 30 mg. Such an approach may go a long way in mitigating the excess CVD events associated with T2D and provide an affordable alternative therapy, especially in individuals whose renal function limits the choices of therapies.

18. thiazolidinedione in people who have
“Do not commence or continue a
thiazolidinedione in people who have
evidence of heart failure, or who are at
higher risk of fracture.

20. What to do