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.



  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

Potential Role of Nut Consumption for Improving Insulin Sensitivity : Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

Potential Role of Nut Consumption for Improving Insulin Sensitivity : Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD


Worldwide incidence and prevalence of type 2 diabetes mellitus (T2D) diabetes are increasing at alarming rates, largely following increases in incidence of overweight and obesity.  The World Health Organization reports that ~1.9 billion adults are overweight in 2019, including 600 million that are obese and thus at heightened risk for T2D1.  Overweight and obesity are associated with impaired whole-body insulin sensitivity (i.e., increased insulin resistance), which is believed to be the key pathophysiologic link to increased risk for T2D 2.


Many epidemiological studies have examined the association of nut consumption with risks for T2D and mortality.  Systematic reviews and meta-analyses of prospective cohort studies have suggested a reduction in T2D risk with regular nut consumption 3-5


Tindall and colleagues recently published a review of 40 randomized, controlled trials with a median duration of 3 months (N = 2,832 subjects), that examined the effects of consuming tree nuts and peanuts on glycemic markers, including homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin and glucose, and glycated hemoglobin (HbA1C) 6.  The median intake of nuts was 52 g/d (range: 20-113 g/d).


In pooled analyses, consumption of tree nuts or peanuts reduced both HOMA-IR (weighted mean difference [WMD] −0.23; 95% confidence interval [CI] −0.40, −0.06; I2 = 51.7%) and fasting insulin (WMD −0.40 μU/mL; 95% CI −0.73, −0.07 μU/mL; I2 = 49.4%) compared to the control conditions 6.  However, there were no effects of nut consumption on fasting blood glucose (WMD −0.52 mg/dL; 95% CI −1.43, 0.38 mg/dL; I2 = 53.4%) or HbA1C (WMD 0.02%; 95% CI −0.01%, 0.04%; I2 = 51.0%).
 Further analyses showed no associations between the dose of nuts/peanuts consumed and the mean difference between nut and control treatments for any of the measured outcomes.  Analysis by nut type showed no deviations from the main results.


Comment. While there were no effects of nut consumption on HbA1C or fasting glucose, there were statistically significant reductions in HOMA-IR and fasting insulin, suggesting improved insulin sensitivity.  Future studies are needed to help determine the mechanisms through which nut/peanut consumption affects insulin sensitivity. 



  1. World Health Organization. Global report on diabetes. Geneva, Switzerland: World Health Organization; 2016. 

  2. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–6.
  3. Afshin A, Micha R, Khatibzadeh S, Mozaffarian D. Consumption of nuts and legumes and risk of incident ischemic heart disease, stroke, and diabetes: a systematic review and meta-analysis. Am J Clin Nutr 2014;100(1):278–88. 

  4. Aune D, Keum N, Giovannucci E, et al. Nut consumption and risk of cardiovascular disease, total cancer, all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective studies. BMC Medicine 2016;14(1):207.
  5. Luo C, Zhang Y, Ding Y, et al. Nut consumption and risk of type 2 diabetes, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis. Am J Clin Nutr 2014;100(1):256–69. 

  6. Tindall AM, Johnston EA, Kris-Etherton PM, Petersen KS. The effect of nuts on markers of glycemic control: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2019;109:297–314.


Photo by Vitchakorn Koonyosying

No Additional Benefits on Cardiometabolic Risk Parameters of Reduced Red Meat or Increased Fiber Intake in an Energy-restricted Diet

No Additional Benefits on Cardiometabolic Risk Parameters of Reduced Red Meat or Increased Fiber Intake in an Energy-restricted Diet

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD


To date, results from epidemiological studies have suggested that a high intake of red meat is associated with a higher risk of developing type 2 diabetes (T2D) while high fiber intake is associated with a lower risk 1-5. Furthermore, high intakes of red meat have also been suggested to be linked to increased risks of cardiovascular disease (CVD) and mortality 6,7.  One of the main approaches for reducing risk of T2D and CVD is weight loss 8-10. Research findings have also suggested that cardiometabolic risk can be improved with dietary modification independent of weight loss 11,12.


Willman et al. completed a 6-month, randomized controlled dietary intervention trial to assess whether lower intake of meat or higher intake of dietary fiber would have additional benefits when incorporated into an energy-restricted diet 13.  Subjects were randomized to one of three groups with all groups being instructed to reduce their caloric intakes by 400 kcal/d below their weight-maintenance requirements and exercise 3 hours/week.  The control group just decreased their caloric intake.  The “no red meat” group avoided red meat, but was able to eat turkey, fish or chicken, and subjects in the “fiber” group increased their fiber intake to at least 40 g/day.  The researchers also analyzed 9-month follow-up data from the Tuebingen Lifestyle Intervention Program (TULIP) cohort, which included subjects (n = 229) at increased risk of diabetes 14.  The intervention in TULIP consisted of increased physical activity and decreased caloric intake.


All participants in the 6-month trial lost weight (mean 3.3 ± 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001), with no difference among the groups.  Similarly, liver fat content decreased (P < 0.001) with no differences among the groups.  The liver fat decrease correlated with the decrease in ferritin during intervention (r2 = 0.08, P = 0.0021). This association between ferritin and liver fat changes was confirmed in TULIP (P = 0.0084).


Comment.  Neither the absence of dietary red meat nor the increase in fiber intake had an additional effect beyond calorie restriction and exercise on risk markers for T2D or CVD.  These results confirm that weight loss can lead to improvement in glucose metabolism, body fat composition and liver fat content and do not indicate incremental benefits for restriction of red meat intake or increasing dietary fiber intake.  Additional research is needed to assess effects of these dietary factors during weight loss maintenance.



  1. The InterAct Consortium. Association between dietary meat consumption and incident type 2 diabetes: The EPIC-InterAct study. Diabetologia 2013;56:47–59.
  2. Fretts AM, Howard BV, McKnight B, et al. Associations of processed meat and unprocessed red meat intake with incident diabetes: The Strong Heart Family Study. Am J Clin Nutr 2012;95:752–8.
  3. Lajous M, Tondeur L, Fagherazzi G, et al. Processed and unprocessed red meat consumption and incident type 2 diabetes among French women. Diabetes Care 2012;35:128–30.
  4. Pan A, Sun Q, Bernstein AM, et al. Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. Am J Clin Nutr 2011;94:1088–96.
  5. Wittenbecher C, Mühlenbruch K, Kröger J, et al. Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes. Am J Clin Nutr 2015;101:1241–50.
  6. Etemadi A, Sinha R, Ward MH, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: Population based cohort study. BMJ 2017;357:1957.
  7. Sun Q. Red meat consumption and mortality: Results from 2 prospective cohort studies. Arch Intern Med 2012;172:555.
  8. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–50. 

  9. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393– 403. 

  10. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63:2985– 3023. 

  11. Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–90.
  12. Estruch R, Martínez-González MA, Corella D, et al. Effect of a high-fat Mediterranean diet on bodyweight and waist circumference: A prespecified secondary outcomes analysis of the PREDIMED randomised controlled trial. Lancet Diabetes Endocrinol 2016;4:666–76.
  13. Willmann C, Heni M, Linder K, et al. Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content: a randomized and controlled dietary intervention study. Am J Clin Nutr. 2019;109:288–96.
  14. Schmid V, Wagner R, Sailer C, et al. Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: Results from the TULIP study. Diabetologia 2017;60:2341– 51. 


Photo by Jez Timms

New Trial Suggests Light Therapy may be a Promising Intervention for Treatment of Depression with Type 2 Diabetes

New Trial Suggests Light Therapy may be a Promising Intervention for Treatment of Depression with Type 2 Diabetes

By Aly Becraft, MS; Kevin C Maki, PhD

One in 11 adults have diabetes worldwide,1 with an estimated 25% of people with diabetes also suffering from depression.2 Co-occurrence of these diseases has been shown to increase risk for diabetes complications,3 potentially due to a lack of motivation to properly manage the disease.4,5 Therefore, people with diabetes and depression need effective therapies for both conditions in order to remain properly treated.

Often, depression simultaneously occurs with impaired sleep, leading to biological rhythm disturbances.6 While pharmacological interventions can be successful, some antidepressant drugs may have unfavorable effects on glycemic control in people with type 2 diabetes (T2D).7 Light therapy is an alternative or adjunctive treatment for depression with minimal side effects.8 It is thought to act by modifying the phase relationships between the biological clock and the light-dark cycle to restore appropriate sleep-wake cycles9 and has proven effective for treating seasonal depression (seasonal affective disorder) as well as some cases of non-seasonal depression.10-12 In 2017, an estimated 12% of global health expenditures were spent on diabetes,1 thus, if efficacy can demonstrated, light therapy would be a cost-effective treatment for T2D patients suffering from depression. In addition to altering mood states, sleep deficiency may also be related to changes in glucose metabolism and decreased insulin sensitivity.13 Previous studies have reported that partial sleep deprivation induced insulin resistance in healthy subjects and patients with type 1 diabetes.13-15 Therefore, the restoration of biological rhythmicity in individuals with impaired sleep may have the potential to improve glucose regulation.

Brouwer et al., (2019) report results from a randomized, double-blind, placebo-controlled trial which was published in Diabetes Care and investigated whether mood and insulin sensitivity could be improved via light therapy in clinically depressed patients with T2D.16 In this parallel-arm study, a total of 79 adults with depression and T2D were included in the outcome measures. Forty received light therapy (broad-spectrum, white-yellow light, 10,000 lux), while 39 received placebo therapy (monochromatic green light, 470 lux). Light therapy was provided in the homes of participants over 4 weeks for 30 minutes each morning. Participants were assessed for changes in depressive symptoms, and a subset of participants who agreed to hyperinsulinemic-euglycemic clamp (HEC) procedure were evaluated for insulin sensitivity. Both measures were assessed at baseline and after the 4-week intervention. Several secondary measures were also evaluated including anxiety symptoms, diabetes stress, self-reported insomnia, objective sleep duration, sleep efficiency, and mid-sleep time, as well as glycated hemoglobin (HbA1C) levels, fasting blood glucose, self-reported hypo-glycemic events and body weight.

After the intervention, light therapy did not significantly reduce depressive symptoms, and similarly, had no effect on insulin sensitivity in the primary analysis. However, per-protocol analyses were conducted to exclude 13 participants that changed glucose-lowering medication during the protocol, which resulted in 51 remaining participants.  In the per-protocol analysis, participants had a 26% greater reduction in depressive symptoms in response to light therapy (P=0.031). In addition, subgroup analysis suggested that patients with higher insulin resistance responded positively to light therapy (P=0.017), and there was a trend toward positive response in patients using insulin vs non-insulin glucose lowering medication (P=0.094). No significant differences in secondary measures were found between the treatment and placebo groups.

Comment.  Overall, the results of this study were inconclusive, but the per-protocol analysis was suggestive of improvements in depressive symptoms, which is a hypothesis-generating finding that should be investigated in additional research. Furthermore, the reduction in depressive symptoms observed in patients with higher insulin resistance may indicate greater efficacy of light therapy in this subset. A similar observation by Dimitrova et al., (2017) suggested that higher BMI, a factor strongly associated with insulin resistance, may be a baseline predictor for light therapy response in patients with seasonal depression.17 Although improvements in insulin sensitivity have been previously demonstrated in two case studies in response to light therapy,18,19 this effect was not established in the present study. This study shows potential for light therapy as a treatment for depression with T2D, but more research is needed with larger samples, longer duration of therapy and/or greater daily light exposure to more fully evaluate the effects of this therapy.



  1. Cho NH, Shaw JE, Karuranga S, et al. International Diabetes Federation (IDF) diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. DiabetesRes Clin Pract. 2018;138:271-281.
  2. Goldney RD, Phillips PJ, Fisher LJ, Wilson DH. Diabetes, depression, and quality of life: a population study. Diabetes Care. 2004;27(5):1066-1070.
  3. Petrak F, Baumeister H, Skinner TC, et al. Depression and diabetes: treatment and health-care delivery. Lancet Diabetes Endocrinol. 2015;3:472-485.
  4. Gonzalez JS, Peyrot M, McCarl LA, et al. Depression and diabetes treatment nonadherence: a meta-analysis. Diabetes Care. 2008;31:2398-2403.
  5. Lin EH, Katon W, Von Korff M, et al. Relationship of depression and diabetes self-care, medication adherence, and preventive care. Diabetes Care. 2004;27:2154-2160.
  6. van Mill JG, Hoogendijk WJ, Vogelzangs N, et al. Insomnia and sleep duration in a large cohort of patients with major depressive disorder and anxiety disorders. J Clin Psychiatry. 2010;71:239-246.
  7. Deuschle M. Effects of antidepressants on glucose metabolism and diabetes mellitus type 2 in adults. Curr Opin Psychiatry. 2013;26:60-65.
  8. Wirz-Justice A, Benedetti F, Terman M. Chronotherapeutics for affective disorders: a clinician's manual for light and wake therapy, 2nd. Karger Medical and Scientific Publishers. 2013.
  9. Wirz-Justice A. Biological rhythm disturbances in mood disorders. Int Clin 2006;21:S11-5.
  10. Tuunainen A, Kripke DF, Endo T. Light therapy for non-seasonal depression. Cochrane Database Syst Rev. 2004;(2):CD004050.
  11. Perera S, Eisen R, Bhatt M, et al. Light therapy for non-seasonal depression: systematic review and meta-analysis. BJPsych Open. 2016;2:116-126.
  12. Mårtensson B, Pettersson A, Berglund L, Ekselius L. Bright white light therapy in depression: a critical review of the evidence. J Affect Disord. 2015;182:1-7.
  13. Spiegel K, Tasali E, Leproult R, Van Cauter E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol. 2009;5(5):253.
  14. Donga E, van Dijk M, van Dijk JG, et al. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J Clin Endocrinol Metab. 2010;95(6):2963-2968.
  15. Donga E, van Dijk M, van Dijk JG, et al. Partial sleep restriction decreases insulin sensitivity in type 1 diabetes. Diabetes Care. 2010;33:1573-1577.
  16. Brouwer A, Nguyen HT, Rutters F, et al. Effects of light therapy on mood and insulin sensitivity in patients with type 2 diabetes and depression: results from a randomized placebo-controlled trial. Diabetes Care. 2019.
  17. Dimitrova TD, Reeves GM, Snitker S, et al. Prediction of outcome of bright light treatment in patients with seasonal affective disorder: discarding the early response, confirming a higher atypical balance, and uncovering a higher body mass index at baseline as predictors of endpoint outcome. J Affect Disord. 2017;222: 126-132.
  18. Nieuwenhuis RF, Spooren PF, Tilanus JJ. Less need for insulin, a surprising effect of phototherapy in insulin-dependent diabetes mellitus. Tijdschr Psychiatr. 2009;51:693-697.
  19. Allen NH, Kerr D, Smythe PJ, et al. Insulin sensitivity after phototherapy for seasonal affective disorder. Lancet. 1992;339:1065-1066.



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Substituting a Type-4 Resistant Starch for Available Carbohydrate Reduces Postprandial Glucose, Insulin and Hunger: An Acute, Randomized, Double-Blind, Controlled Study

Substituting a Type-4 Resistant Starch for Available Carbohydrate Reduces Postprandial Glucose, Insulin and Hunger:  An Acute, Randomized, Double-Blind, Controlled Study1

 By Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD; Kevin C Maki, PhD


Dietary fiber (including a wide variety of nondigestible carbohydrates) is a noted shortfall nutrient in Western diets, despite the fact that appropriate consumption is associated with a broad range of health benefits.2,3 One of the benefits that has received considerable attention is blunting of postprandial blood glucose control. Researchers have established a benefit between consumption of viscous fibers and blood glucose excursions.4 When certain fibers, such as resistant starch (RS), are used in place of available carbohydrate in foods, less glucose is liberated through digestion, thus lowering the rate and quantity of glucose entering the bloodstream after a meal.5

It is important to note that there are different types of RS receiving varying levels of attention in clinical trials. These differences are outlined in the table below.

Type of RS


Amount of Research

Resistant starch type-2

Granular, native starch

Resistant to digestion

Majority of clinical research is in these 2 areas

Resistant starch type-3

Retrograded starch

Resistant to digestion

Resistant starch type-4 (RS4)

Chemically modified starch

Resists digestion by intestinal enzymes

Fewer clinical trials in this area

Among the types of RS4, phosphate distarch phosphate is the most frequently tested6-8, with fewer studies on hydroxypropyl distarch phosphate9,10 and only one study on acid hydrolyzed and heat treated RS4, to date.11

The primary aim of this study was to characterize the postprandial blood glucose response in healthy adults to a novel RS4 (acid hydrolyzed and heat treated maize-based RS) in a ready-to-eat baked good (scone), compared with the response to consumption of a scone made with a control starch. The secondary aims were to evaluate postprandial insulin response, satiety and gastrointestinal tolerance. It was hypothesized that the replacement of digestible carbohydrate from refined wheat flour with RS4 would reduce postprandial blood glucose.


This was a double-blind, randomized, controlled trial conducted at MB Clinical Research in Boca Raton, Florida, USA.

Main Entry Criteria:

  • Age 18-74 y
  • Men and women
  • Body mass index (BMI) 18.5-29.99 kg/m2
  • General good health
  • Fasting capillary glucose <100 mg/dL

The treatment fiber scone contained VERSAFIBE™ 2470 resistant starch (provided by Ingredion Incorporated, Bridgewater, NJ) as the primary fiber source. VERSAFIBE™ 2470 is a RS4 with 70% dietary fiber and is produced from food grade high-amylose maize starch. Acid hydrolysis and heat treatment both reduce the digestibility of this high-amylose maize starch resulting in increased RS4 and total dietary fiber in the finished product. There are no nonstarch polysaccharides present in VERSAFIBE™ 2470. The nutrition composition of the Fiber Scone and Control Scone are shown in the following table.


Per Serving, As-Eaten

Control Scone



Weight (g)



Calories (kcal)



Fat (g)



Saturated fat (g)



Protein (g)



Total Carbohydrates (g)



Available Carbohydrates (g)



Dietary Fiber (g)*



Sugars (g)



*VERSAFIBE™ 2470 resistant starch provided 16.5 g dietary fiber in the Fiber Scone

The subjects attended 3 study visits, one for screening and two test visits. At the test visits, subjects consumed the Control Scone or Fiber Scone (randomly assigned sequence) with 240 mL water.  Capillary glucose, plasma glucose and plasma insulin were measured pre-consumption and at t = -15, 15, 30, 45, 60, 90, 120 and 180 min ± 2 min, where t = 0 was the start of the study product consumption. Satiety visual analog scale (VAS) ratings were assessed pre-consumption and at 3 min intervals.  Questionnaires were used to assess Gastrointestinal (GI) Tolerability and product palatability at each test visit.


A total of 36 subjects were randomized in the study, and one was withdrawn due to non-compliance. Ultimately, 32 subjects were included in the glucose and insulin analyses and 35 were included in the satiety VAS, GI tolerability and palatability analyses.

Consumption of the Fiber Scone significantly reduced postprandial glucose and insulin incremental areas under the curve (43-45% reduction and 35-40% reduction, respectively, p<0.05 for both) as well as postprandial glucose and insulin maximum concentrations (8-10% and 22% reductions, respectively, p<0.05 for both).  Ratings of hunger and desire to eat were also significantly reduced following consumption of the Fiber Scone vs. the Control Scone during the 180 minutes after intake (p<0.05) and there were no GI side effects with the Fiber Scone compared with Control.


This study shows significant reductions in postprandial glucose and insulin levels associated with the replacement of refined carbohydrate with RS4 in healthy subjects. In addition, ratings of hunger and desire to eat were reduced after consumption of the RS4-containing food product, a first for this specific RS ingredient. Incorporation of a fiber such as RS4 into the diet has potential clinical and practical relevance due to favorable impacts on markers of cardiometabolic health.12,13


  1. Stewart ML, Wilcox ML, Bell M, Buggia MA, Maki KC. Type-4 resistant starch in substitution for available carbohydrate reduces postprandial glycemic response and hunger in acute, randomized, double-blind, controlled study. Nutrients. 2018;10(2).
  2. Dahl WJ, Stewart ML. Position of the Academy of Nutrition and Dietetics: Health implications of dietary fiber. J Acad Nutr Diet. 2015;115:1861-1870.
  3. Stephen AM, Champ MM, Cloran SJ, et al. Dietary fibre in Europe: current state of knowledge on definitions, sources, recommendations, intakes and relationships to health. Nutr Res Rev. 2017;30:149-190.
  4. Tosh SM. Review of human studies investigating the post-prandial blood-glucose lowering ability of oat and barley food products. European J Clin Nutr. 2013;67:310-317.
  5. Robertson MD. Dietary-resistant starch and glucose metabolism. Curr Opin Clin Nutr Metab Care. 2012;15:362-367.
  6. Haub MD, Hubach KL, Al-Tamimi EK, Ornelas S, Seib PA. Different types of resistant starch elicit different glucose reponses in humans. J Nutr Metab. 2010;2010.
  7. Al-Tamimi EK, Seib PA, Snyder BS, Haub MD. Consumption of cross-linked resistant starch (RS4(XL)) on glucose and insulin responses in humans. J Nutr Metab. 2010;2010.
  8. Martinez I, Kim J, Duffy PR, Schlegel VL, Walter J. Resistant starches types 2 and 4 have differential effects on the composition of the fecal microbiota in human subjects. PLoS One. 2010;5:e15046.
  9. Shimotoyodome A, Suzuki J, Kameo Y, Hase T. Dietary supplementation with hydroxypropyl-distarch phosphate from waxy maize starch increases resting energy expenditure by lowering the postprandial glucose-dependent insulinotropic polypeptide response in human subjects. Br J Nutr. 2011;106:96-104.
  10. Gentile CL, Ward E, Holst JJ, et al. Resistant starch and protein intake enhances fat oxidation and feelings of fullness in lean and overweight/obese women. Nutr J. 2015;14:113.
  11. Stewart ML, Zimmer JP. Post-prandial glucose and insulin response to high-fiber muffin top containing resistant starch type 4 in healthy adults: a double-blind, randomized, controlled trial. Nutrition. 2018 (in press).
  12. Maki KC, Pelkman CL, Finocchiaro ET, et al. Resistant starch from high-amylose maize increases insulin sensitivity in overweight and obese men. J Nutr. 2012;142:717-723.
  13. Marlatt KL, White UA, Beyl RA, et al. Role of resistant starch on diabetes risk factors in people with prediabetes: design, conduct, and baseline reuslts of the STARCH trial. Contemp Clin Trials. 2018;65:99-108.
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