Effects of pioglitazone on risks for cardiovascular events and diabetes in patients with prediabetes and a history of stroke or transient ischemic attack

Effects of pioglitazone on risks for cardiovascular events and diabetes in patients with prediabetes and a history of stroke or transient ischemic attack

By Aly Becraft, MS and Kevin C Maki, PhD

 

Insulin resistance is an established risk factor for stroke and other adverse cardiovascular events.1,2 As many as 50% of patients with stroke or transient ischemic attack have insulin resistance without being classified as having diabetes.3 Furthermore, insulin resistance is associated with cardiovascular risk factors such as increased blood pressure, elevated levels of triglycerides and inflammatory markers and reduced high-density lipoprotein concentration.4 Pioglitazone is an insulin-sensitizing medication that works to lower insulin resistance by activating peroxisome proliferator-activated receptors (PPAR)-γ, and slightly activating PPAR-α, which have potential cardioprotective effects by promoting fatty acid uptake and oxidation.5-9 In the Insulin Resistance Intervention After Stroke (IRIS) trial, pioglitazone was shown to reduce the risk of stroke or myocardial infarction (MI) by 24% compared to placebo in patients with insulin resistance and a history of stroke or transient ischemic attack.10 Treatment with pioglitazone also reduced new-onset diabetes by half.10

Spence and colleagues published a post-hoc analysis of the IRIS trial to investigate the effect of pioglitazone in those patients with good adherence (taking ≥80% of the protocol dose over the duration of the study) and with prediabetes defined using the American Diabetes Association (ADA) definition.11 In the IRIS trial, patients were enrolled based on their homeostasis model assessment of insulin resistance (HOMA-IR) score,10 which is not routinely measured in clinical practice, whereas the ADA definition considers patients to have prediabetes if their glycated hemoglobin (HbA1c) level is 5.7-6.4% or fasting plasma glucose level is 100-125 mg/dL.  The primary outcome was recurrent fatal or nonfatal stroke or myocardial infarction. Secondary outcomes included stroke; acute coronary syndrome; the composite of stroke, MI, hospitalization for heart failure; and the progression to diabetes.

In the IRIS trial, patients were randomized to receive either 15 mg/d pioglitazone titrated up to a maximum dose of 45 mg/d, or a matched placebo. In this analysis, 2885 of the 3876 participants enrolled in the IRIS trial were classified as have prediabetes; 1456 were in the pioglitazone group and 1429 in the placebo group. Among these, 1454 were also classified as having good adherence; 644 were in the pioglitazone group and 810 were in the placebo group. Median follow-up time was 4.8 years.

In those patients with ADA-defined prediabetes and good adherence, the relative risk reductions (RRR) with pioglitazone vs. placebo were 40% for stroke + MI, 33% for stroke, 52% for acute coronary syndrome, and 38% for stroke + MI + hospitalization for heart failure. The relative risk for new-onset diabetes was also reduced by 80% for pioglitazone vs. placebo. Adverse events in the pioglitazone group included weight gain of ≥10% of body weight (29.8% vs. 12% in placebo group; p < 0.001), edema (29.2% vs. 21.6% in placebo group; p < 0.001), and serious bone fractures (3.6% vs. 2.8% in placebo group; p = 0.08). These adverse effects were also observed in the full IRIS trial analysis.12

 

Comment: An initial requirement of enrollment in the IRIS trial was HOMA-IR score ≥3; therefore, the findings from this trial can only be extended to patients with prediabetes that meet this criterion. That said, this post-hoc analysis provides evidence that patients with prediabetes and established stroke or transient ischemic attack have improved clinical outcomes when treated early, particularly when adherence to treatment is high. Edema was a large contributor to weight gain observed with pioglitazone treatment, which may be less with lower dosages than were used in this trial. For instance, a dose of 7.5 mg/d has been associated with low incidence of weight gain and edema.12 The IRIS investigators conclude that the benefit of pioglitazone treatment demonstrated in this and in the original analysis10 appear to outweigh the observed risks. Additional research is warranted to assess the effects of lower dosage pioglitazone therapy for cardiovascular risk reduction in a wider range of patients than were studied in IRIS.

 

References:

  1. Kernan WN, Inzucchi SE, Viscoli CM, et al. Insulin resistance and risk for stroke. Neurology. 2002;59:809-815.
  2. Burchfiel CM, Curb JD, Rodriguez BL, Abbott RD, Chiu D, Yano K. Glucose intolerance and 22-year stroke incidence. The Honolulu Heart Program. Stroke. 1994;25:951-957
  3. Kernan WN, Inzucchi SE, Viscoli CM, et al. Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke. Neurology. 2003;60:1447-1451.
  4. Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest. 2006;116:1813-1822.
  5. Lee M, Saver JL, Liao HW, Lin CH, Ovbiagele B. Pioglitazone for secondary stroke prevention: a systematic review and meta-analysis. Stroke. 2017;48:388-393.
  6. Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106-1118.
  7. Spencer M, Yang L, Adu A, et al. Pioglitazone treatment reduces adipose tissue inflammation through reduction of mast cell and macrophage number and by improving vascularity. PLoS One. 2014;9:e102190.
  8. Zhang MD, Zhao XC, Zhang YH, et al. Plaque thrombosis is reduced by attenuating plaque inflammation with pioglitazone and is evaluated by fluorodeoxyglucose positron emission tomography. Cardiovasc Ther. 2015;33:118-126.
  9. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409-435.
  10. Kernan WN, Viscoli CM, Furie KL, et al; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321-1331.
  11. Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, Furie KL, Lovejoy AM, Young LH, Kernan WN. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial. JAMA Neurol. 2019; Epub ahead of print.
  12. Adachi H, Katsuyama H, Yanai H. The low dose (7.5 mg/day) pioglitazone is beneficial to the improvement in metabolic parameters without weight gain and an increase of risk for heart failure. Int J Cardiol. 2017;227:247-248.
Photo by Louis Reed

Redefining a Healthful Diet: New Results from the Largest Observational Study Ever Conducted on Nutrition and Heart Health Challenge Current Advice

Redefining a Healthful Diet: New Results from the Largest Observational Study Ever Conducted on Nutrition and Heart Health Challenge Current Advice

By Orsolya M. Palacios, RD, PhD and Kevin C. Maki, PhD

Background
Cardiovascular disease is a major cause of morbidity and mortality worldwide.  Its relationship to healthful diet and lifestyle practices has been an area of active research for decades since these represent modifiable behaviors that have the potential to affect cardiovascular disease risk and overall health.  Within dietary recommendations, health authorities advise reducing total and saturated dietary fats while increasing carbohydrates from whole grains, as well as intakes of fruits, vegetables, nuts, seeds and legumes (DGA, 2015). These recommendations are based on studies that have been mostly observational in nature and conducted in high-income countries such as the U.S. and those in Western Europe.  The advice to lower saturated fat intake and replace it with unsaturated fat sources stems largely from the linear relationship between saturated fat intake and a low-density lipoprotein cholesterol (LDL-C) level.  LDL-C is a risk factor for cardiovascular disease, and thus, the working concept is that reducing saturated fat intake reduces LDL-C levels which, in turn, reduce cardiovascular disease risk.  In conjunction with lowering saturated fat intake, health authorities recommend reducing intakes of animal products such as meat and dairy products to accommodate higher intake of plant foods.  However, the advice to increase fruit, vegetable and legume intake also stems from observational studies conducted mainly in high-income nations.  Research on the associations of fruit, vegetable and legume intakes with health outcomes in other nations is sparse and inconclusive.

The dietary habits of populations within wealthy countries are generally one of excess, which significantly differs from the dietary habits of populations in low- and middle-income countries, where intake of certain nutrients, including adequate intake of complete proteins, may be sub-optimal.  Furthermore, dietary habits are strongly rooted in cultural practices, which can also vary greatly among countries, regardless of income status.  Since cardiovascular disease is a leading cause of morbidity and mortality in low- and middle-income countries as well, understanding the link between currently recommended dietary patterns, cardiovascular disease events and/or mortality in more globally-represented populations is crucial in providing accurate and meaningful guidelines for healthful food consumption.

 Methods
The Prospective Urban Rural Epidemiology (PURE) study was conducted to address this topic.  Researchers recruited individuals aged 35 to 70 years of age in 18 low-income, middle-income and high-income countries between January 1, 2003 and March 31, 2013 to participate in the PURE prospective cohort study to assess the association between total mortality and major cardiovascular events and diet choices.  Habitual dietary intake data was analyzed from 135,355 individuals using validated food frequency questionnaires, which documented energy intake from fat (including total, saturated, monounsaturated and polyunsaturated fat), carbohydrate and protein as well as daily intake of fruit, vegetable and legume servings.  Demographic information, socioeconomic status, lifestyle, physical activity, health history and medication use questionnaires were also distributed and assessed.  Trained physicians using standard definitions completed standardized case-report forms to report mortality and major cardiovascular events.  The primary outcomes in this study were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke and heart failure) and secondary outcomes were all myocardial infractions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality.

To assess associations between macronutrient energy contribution and cardiovascular disease events and/or mortality, participants were categorized into quintiles based on the dietary percentage of energy from total fat, individual fats, carbohydrates and protein; hazard ratios (HRs) were calculated using a multivariable Cox frailty model.  To assess the associations between daily fruit, vegetable and legume servings and cardiovascular disease events and/or mortality, Cox frailty models with random effects were also employed and HRs calculated.

Results
Median follow up of participants was 7.4 years during which time 5796 deaths and 4784 major cardiovascular disease events were recorded.  Regarding macronutrient intake, higher carbohydrate intake was associated with a significantly higher total mortality risk for the highest quintile versus the lowest quintile, but there was no significant association between carbohydrate intake and cardiovascular disease, myocardial infarction, stroke or cardiovascular disease mortality.

Results from this study indicate that total fat, as well as saturated, monounsaturated and polyunsaturated fats all were significantly associated with a lower risk of mortality for the highest quintile versus the lowest quintile of total and individual fat intake.  Specifically, the HR for the highest versus the lowest quintile of fat intake was 0.77 (95% confidence interval [CI] 0.67-0.87) for total fat, 0.86 (95% CI 0.76-0.99) for saturated fat, 0.81 (95% CI 0.71-0.92) for monounsaturated fat, and 0.80 (95% CI 0.71-0.89) for polyunsaturated fat.  For cardiovascular disease events, the highest quintile of saturated fat intake was associated with a significantly lower risk of stroke (HR 0.79, 95% CI 0.64-0.98) compared to the lowest quintile of saturated fat intake.  Neither total fat nor any of the individual fats were associated with myocardial infarction risk or cardiovascular disease mortality.

Like total fat, the highest quintile versus the lowest quintile of total protein intake was significantly and inversely associated with total mortality risk (HR 0.88, 95% CI0.77-1.00) and non-cardiovascular disease mortality (HR 0.85, 95% CI 0.73-0.99).  Animal protein intake was associated with a significantly lower risk of total mortality whereas plant protein intake had no significant association with total mortality.

Total Fat HR (5th Quintile vs. 1st Quintile) 95% CI P-trend
Total Mortality 0.77 0·67–0·87 <0.0001
CVD Mortality 0.92 0·72–1·16         0.50
Non-CVD Mortality 0.70 0·60–0·82       <0.0001
Major CVD Events 0.95 0·83–1·08         0.33
Saturated Fat HR (1st Quintile vs. 5th Quintile) 95% CI P-trend
Total Mortality 0.86 0·76–0·99 0.0088
CVD Mortality 0.83 0·65–1·07         0.20
Non-CVD Mortality 0.86 0·73–1·01 0.0108
Major CVD Events 0.95 0·83–1·10         0.49
Fruits, Vegetables & Legumes HR (< 1 serving/day vs. 3-4 servings/day) 95% CI P-trend
Total Mortality 0.78 0.69–0.88 0.0001
CVD Mortality 0.81 0.65–1.02 0.0568
Non-CVD Mortality 0.77 0.66–0.89 0.0038
Major CVD Events 1.06 0.92–1.22 0.1301

Abbreviations: CVD, cardiovascular disease; HR, hazard ratio

Adapted from: Ramsden et al. Lancet (2017) S0140 (17)32241-9; Toledo et al.  Lancet (2017) S0140-6736(17)32251-1.

The mean fruit, vegetable and legume intake was 3.91 (standard deviation 2.77) daily servings.  When the researchers assessed the links between fruit, vegetable and legume intakes and outcomes, they found that higher fruit, vegetable and legume intake was significantly inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality and total mortality after adjustments for age, sex and random effects.  However, these effects were diminished after multivariable adjustments.  The HR for total mortality was lowest for those consuming three to four daily servings of fruit, vegetables and legumes (HR 0.78, 95% CI 0.69-0.88) compared to the reference group, who consumed less than one serving of these foods per day.  Higher intakes of fruits, vegetables and legumes were not associated with further lowering of risk.  When assessed independently, fruit intake was associated with lower mortality, including total mortality, cardiovascular mortality and non-cardiovascular mortality.  Raw vegetables were strongly linked to lower mortality risk whereas cooked vegetables had a modest association with lower risk.  Legume intake was inversely associated with non-cardiovascular death and total mortality.

Comment

To date, the PURE study is the largest observational study to assess the link between nutrient intakes, food group intakes, cardiovascular disease events (including death) and overall mortality.  It encompassed data from over 135,000 participants in 18 countries across five continents from low-, mid- and high-income nations.  The results of this study align with some general recommendations (e.g,. emphasize consumption of fruits, vegetables and legumes) but are in conflict with some others.  For example, health authorities recommend increasing intakes of fruits, vegetables and legumes at the expense of animal foods (DGA, 2015).  However, the results of this study suggest that the association between increased fruit, vegetable and legume intake plateaus after three to four daily servings, and the median fruit, vegetable and legume intake among participants was already 3.9 daily servings.  Thus, as a whole, participants were theoretically obtaining the maximal benefit from intake of these foods and the incremental benefit beyond the median level of intake in the populations studied is uncertain.  The study’s finding that higher energy intake from animal protein is linked to reduced total mortality, while plant proteins, such as those found in legumes, showed no significant association, does not align with the some aspects of the current Dietary Guidelines for Americans (DGA, 2015).  Although it recommends an increase in seafood, The Dietary Guidelines for Americans also recommends strategies such as using legumes, nuts and seeds in place of meat and poultry in mixed dishes to attain protein needs and to increase vegetable intake while cutting back on foods such as some meats, poultry and cheeses to help lower saturated fat intake (DGA, 2015).

However, the PURE study results challenge the emphasis on reducing intake of saturated fat.  Higher energy intake from fat and each individual type of fat, including saturated fat, was associated with lower total mortality, as well as lower risk for some cardiovascular disease events.  Carbohydrate energy intake either showed no association on assessed outcomes or was associated with an increased risk for mortality.  However, it should be emphasized that intakes of saturated fats were generally low, with mean values ranging from 5.7% in China to 10.9% in Europe and North America.  Across countries, total and saturated fat intakes are positively associated with socioeconomic status.  Thus, in countries with higher intakes of total and saturated fat, and thus lower intakes of carbohydrate, higher socioeconomic status, with resulting access to higher quality healthcare, is a potential confounder.

Taken together, the results from PURE raise questions about current dietary guidance, which is largely based on results from observational studies completed in the U.S. and Europe.  Unfortunately, very few randomized, controlled trials have been completed to assess the influence of dietary guidance on long-term health and disease incidence.  While difficult and expensive, these are essential for fully evaluating the potential benefits and risks of dietary recommendations (Maki, 2014).  The strongest recommendations should be limited to those instances where results from randomized, controlled trials align with findings from observational studies.  While the results from PURE are at odds with some current dietary recommendations, they are consistent with the age-old adage “everything in moderation.”

 PURE Study References

Dehghan M, Mente A, Zhang X, et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study.  Lancet. 2017; S0140-6736(17)32252-3.

Miller V, Mente A, Dehghan M, et al. Fruit, vegetable, and legume intake, and cardiovascular disease and deaths in 18 countries (PURE): a prospective cohort study.  Lancet. 2017; S0140-6736(17)32253-5.

Ramsden CE, Domenichiello AF. PURE study challenges the definition of a healthy diet: but key questions remain.  Lancet. 2017; S0140-6736(17)32241-9.

Toledo E, Martinez-Gonzalez MA. Fruits, vegetables, and legumes: sound prevention tools.  Lancet. 2017; S0140-6736(17)32251-1.

Additional References

Maki KC, Slavin JL, Rains TM, Kris-Etherton PM.  Limitations of observational evidence: implications for evidence-based dietary recommendations.  Adv Nutr. 2014;5(1)7-14.

U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. December 2015. Available at https://health.gov/dietaryguidelines/2015/guidelines/.

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