Cardiovascular Safety of Oral Semaglutide in Patients with Type 2 Diabetes

Cardiovascular Safety of Oral Semaglutide in Patients with Type 2 Diabetes

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

Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 2 diabetes (T2D), therefore it is required that all new glucose-lowering therapies demonstrate no increase in cardiovascular risk with treatment.1  Glucagon-like-peptide-1 (GLP-1) receptor agonists have shown cardiovascular safety and in some cases, such as for semaglutide, benefit.2,3  The GLP-1 receptor agonists approved to date are administered subcutaneously, but a new oral semaglutide was recently developed, and the Peptide Innovation for Early Diabetes Treatment (PIONEER) 6 trial was conducted to rule out an excess in cardiovascular risk among patients with T2D treated with this product.4

PIONEER 6 was an event-driven, randomized, double-blind trial in which 3,183 patients with high CVD risk (≥50 y of age with established CVD or chronic kidney disease or ≥60 y of age with CVD risk factors only) were treated with 14 mg/day oral semaglutide or placebo.4  The primary outcome was the first occurrence of a major cardiovascular event (e.g., death from CVD, nonfatal myocardial infarction [MI], nonfatal stroke).

The mean age of the subjects was 66 y.  Subjects that were ≥50 y of age with either CVD or chronic kidney disease accounted for 2,695 (84.7%) of the subjects. The median time in the trial was 15.9 months with 61 of 1591 patients (3.8%) in the semaglutide and 76 of 1592 patients (4.8%) in the placebo group experiencing a major cardiovascular event.  Consistent with previous GLP-1 receptor agonist cardiovascular outcomes trials, this study demonstrated that oral semaglutide was non-inferior to placebo for the primary outcome (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.57-1.11) thus confirming that there is no excess CVD risk with oral semaglutide treatment.  The results for the individual components of the primary outcome and deaths from any cause are shown in the table below.

Table:  Major CVD outcomes in patients with high CVD risk receiving either oral semaglutide or placebo.

Primary Outcomes

Oral Semaglutide (n = 1591)

Placebo

 (n = 1592)

HR (95% CI)

 

 

                                            n (%)

 

Death from cardiovascular causes

15 (0.9%)

30 (1.9%)

0.49 (0.27-0.92)

Nonfatal MI

37 (2.3%)

31 (1.9%)

1.18 (0.73-1.90)

Nonfatal stroke

12 (0.8%)

16 (1.0%)

0.74 (0.35-1.57)

Death from any cause

23 (1.4%)

45 (2.8%)

0.51 (0.31-0.84)

 

Glycated hemoglobin was decreased with semaglutide compared to placebo (mean change from baseline to end of the trial, -1.0 vs. -0.3, respectively).  Body weight was also decreased from baseline to the end of the study by 4.2 kg with semaglutide compared to 0.8 kg with placebo.  Systolic blood pressure was also lower with semaglutide, compared to placebo, and there was a modest lowering of low-density lipoprotein cholesterol and triglycerides with semaglutide.

Comment.  These results showed that oral semaglutide has a similar cardiovascular safety profile to the subcutaneous form of semaglutide, and that the cardiovascular risk profile of oral semaglutide is not inferior to the cardiovascular risk profile of placebo.  It is notable that there were statistically significant reductions in secondary outcomes of cardiovascular and total mortality.  Because some patients may be reluctant to take an injectable medication, an orally administered GLP-1 receptor agonist may be an attractive alternative for patients with T2D.  Additional research is warranted to further investigate potential cardiovascular and mortality benefits of this agent.

 

References

  1. American Diabetes Association. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S103-S123.

 

  1. Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6:105-113.

 

  1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcome sin patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.

 

  1. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019; Epub ahead of print.

 

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The Effects of Nutritional Supplements and Dietary Interventions on All-Cause Mortality and Cardiovascular Outcomes

The Effects of Nutritional Supplements and Dietary Interventions on All-Cause Mortality and Cardiovascular Outcomes

By Aly Becraft, MS and Kevin C Maki, PhD

 

Despite scientific uncertainty surrounding the benefits of dietary supplements, many U.S. adults use them, along with various dietary interventions, with the belief that they will improve their overall health (1).  Khan et al. (2) recently published a systematic review to assess the effect of various nutritional supplements and dietary interventions on cardiovascular outcomes.  The criteria for inclusion were randomized controlled trials (RCTs) and meta-analyses of RCTs that assessed the effect of nutritional supplements (vitamins, minerals, dietary supplements) or dietary interventions on all-cause mortality and cardiovascular outcomes in adults and written in English.  The main outcome of interest was all-cause mortality and secondary outcomes included cardiovascular mortality, myocardial infarction (MI), stroke, and coronary heart disease (CHD).  From these criteria, 942 articles were identified, and after initial title and abstract screening, 140 full-text articles remained to be reviewed for eligibility.  Ultimately, 9 systematic reviews and 4 new RCTs were included, comprising a total of 105 meta-analyses, 24 interventions (16 types of nutritional supplements and 8 dietary interventions), 277 RCTs and 922,129 participants.  A list of these interventions is shown in Table 1 and the significant findings from the present analysis are summarized in Table 2.

 

Table 1. List of interventions analyzed in Khan et al. (2)

Nutritional Supplements

Dietary Interventions

Antioxidants

Mediterranean diet

Vitamin B6

Reduced dietary fat

Vitamin B3 or niacin

Modified dietary fat

Vitamin B complex

Reduced saturated fat

Carotene

Reduced salt (hypertensive)

Selenium

Reduced salt (normotensive)

Vitamin E

Increased omega-3 α-linolenic acid

Vitamin A

Increased omega-6 PUFA

Vitamin C

 

Vitamin D

 

Calcium and calcium plus vitamin D

 

Folic acid

 

Iron

 

Omega-3 long-chain PUFA

 

Multivitamins

 

Abbreviation: PUFA, polyunsaturated fatty acids

 

 

 

Table 2. Summary of statistically significant findings from Khan et al. (2)

 

Intervention

RR (95% CI)

P-value

Certainty

All-cause mortality

Reduced salt intake in normotensive patients

0.90 (0.85 to 0.95)

0.01

Moderate

Cardiovascular mortality

Reduced salt intake in hypertensive patients

0.67 (0.46 to 0.99)

0.04

Moderate

MI

Omega-3 LC-PUFA

0.92 (0.85 to 0.99)

0.03

Low

CHD

Omega-3 LC-PUFA

0.93 (0.89 to 0.98)

0.01

Low

Stroke

Folic acid

0.80 (0.67 to 0.96)

0.02

Low

Stroke

Calcium plus vitamin D

1.17 (1.05 to 1.30)

0.01

Moderate

Abbreviations: CHD, coronary heart disease; CI, confidence interval; LC-PUFA, long-chain polyunsaturated fatty acids; MI, myocardial infarction; RR, risk ratio

 

Comment.  Overall, the researchers found little evidence for nutritional supplements or dietary interventions to significantly reduce risk for all-cause mortality or cardiovascular outcomes, with some exceptions as outlined in Table 2.  Interventions associated with lower risks included reduced salt intake and lower total (normotensives) or cardiovascular mortality (hypertensives), omega-3 fatty acid supplementation and reduced risks for CHD and MI, and folic acid supplementation associated with lower risk for stroke. 

 

Of note, calcium plus vitamin D intake was associated with increased risk for stroke.  This finding could be related to hypercalcemia-mediated vascular calcification and/or effects on coagulation, although additional research is needed to more firmly establish causality and mechanistic explanations (3-5).

 

Certainty of evidence from this systematic review was low for most interventions due to low precision of estimates, qualitative and quantitative heterogeneity, and publication bias.  Regardless, these findings can be a useful resource for healthcare professionals who would like to recommend evidence-based nutritional interventions and provide a basis for future studies to explore the gaps in the currently available evidence base. 

 

References:

  1. Gahche JJ, Bailey RL, Potischman N, et al. Dietary supplement use was very high among older adults in the United States in 2011-2014. J Nutr. 2017;147:1968-76.
  2. Khan SU, Khan MU, Riaz H, et al. Effects of nutritional supplements and dietary interventions on cardiovascular outcomes: an umbrella review and evidence map. Ann Intern. 2019;E-pub ahead of print
  3. Chin K, Appel LJ, Michos ED. Vitamin D, calcium, and cardiovascular disease: A”D”vantageous or “D”etrimental? An era of uncertainty. Curr Atheroscler Rep. 2017;19(1):5.
  4. Anderson JJ, Kruszka B, Delaney JA, et al. Calcium intake from diet and supplements and the risk of coronary artery calcification and its progression among older adults: 10-year follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc. 2016;5(10).
  5. Heaney RP, Kopecky S, Maki KC, Hathcock J, MacKay D, Wallace TC. A review of calcium supplements and cardiovascular disease risk. Adv Nutr. 2012;3:763-771.

 

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Therapeutic potential of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) for management of patients with atherogenic dyslipidemia

Therapeutic potential of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) for management of patients with atherogenic dyslipidemia

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

 

Atherosclerotic cardiovascular disease (ASCVD) is associated with a significant public health burden around the world.  It is further exacerbated by chronic lifestyle-related diseases, such as visceral obesity, type 2 diabetes mellitus (T2D) and non-alcoholic fatty liver disease.  The morbidity and mortality of ASCVD is particularly high in low- and middle- income countries, which also have the largest number of people with obesity and diabetes.1-3  In these populations atherogenic dyslipidemia is a significant unmet clinical need.  Elevated plasma triglycerides (TG), with or without low levels of high-density lipoprotein cholesterol (HDL-C), are modifiable ASCVD risk factors, especially in insulin resistant conditions such as T2D.4

 

Some current ASCVD prevention guidelines recommend peroxisome proliferator-activated receptor alpha (PPARα) agonists (e.g., fibrates) for management of hypertriglyceridemia after statins.5  Unfortunately, these PPAR-α agonists have low potency and limited selectivity for PPARα.  They also have pharmacokinetic interactions and other side effects, including an increased risk of myopathy with gemfibrozil in combination with statin and reversible elevation in serum creatinine with fenofibrate, as well as liver enzyme elevation.6-9  Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα), which has a unique receptor-cofactor binding profile to identify the most potent molecules with PPARα-mediated effects while limiting unwanted side effects, has recently been developed.

 

Given the clear need for new therapeutic options for ASCVD, the Joint Consensus Panel from the International Atherosclerosis Society and the Residual Risk Reduction Initiative reviewed the scientific literature to help to determine if it is possible for pemafibrate to improve upon the beneficial lipid effects and safety profile demonstrated for PPARα agonists.10  In a randomized, double-blind clinical trial of 33 patients with atherogenic dyslipidemia, pemafibrate led to markedly decreased TG-rich lipoprotein levels and significantly increased concentrations of HDL-C, apolipoprotein (apo) A-I and apo-A-II, as well as improved markers of HDL function including pre-beta-HDL, smaller HDL particles (HDL3), and increased macrophage cholesterol efflux capacity.11  A pooled analysis of phase II/III studies showed that pemafibrate therapy over 12-24 weeks led to significant improvements in liver function tests (alanine aminotransferase, gamma glutamyl transferase, bilirubin).12  Also, unlike fenofibrate, pemafibrate did not elevate serum creatinine for up to 52 weeks in patients with or without pre-existing renal dysfunction.13  In general, the studies conducted to date have demonstrated that pemafibrate is well tolerated, especially with regard to renal and hepatic function, and that it may help in the management of atherogenic dyslipidemia, particularly by lowering elevated TG-rich lipoproteins and remnant cholesterol levels that are common in overweight patients with T2D.10

 

This Joint Consensus Panel concluded that pemafibrate, a SPPARMα agonist, represents a novel therapeutic class, distinct from fibrates according to its pharmacological activity, with a safe hepatic and renal profile.10  The Panel also recognized that the ongoing Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial of 10,000 patients with T2D, elevated TG, and low levels of HDL-C will help to determine if pemafibrate can be safely used to reduce residual cardiovascular risk.

 

References

  1. Joseph P, Leong D, McKee M, et al. Reducing the global burden of cardiovascular disease. Part 1: the epidemiology and risk factors. Circ Res. 2017;121:677–94.
  2. World Health Organization. Fact sheet. Obesity and overweight. http:// www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 21 Jan 2019.
  3. NCD Countdown 2030 collaborators. NCD Countdown 2030: worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet. 2018;392:1072–88.
  4. Varbo A, Freiberg JJ, Nordestgaard BG. Remnant cholesterol and myocardial infarction in normal weight, overweight, and obese individuals from the Copenhagen General Population Study. Clin Chem. 2018;64:219–30.
  5. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37:2315–81.
  6. Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf. 2006;5:145–56.
  7. Mychaleckyj JC, Craven T, Nayak U, et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care. 2012;35:1008–14.
  8. Davis TM, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia. 2011;54:280–90.
  9. Hedrington MS, Davis SN. Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver. Expert Opin Drug Metab Toxicol. 2018;14:671–7.
  10. Fruchart J-C, Santos RD, Aguilar-Salinas C, et al. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential. A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc Diabetol. 2019;18:71.
  11. Yamashita S, Arai H, Yokote K, et al. Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia. J Clin Lipidol. 2018;12:1267–79.
  12. Matsuba I, Matsuba R, Ishibashi S, et al. Effects of a novel selective peroxisome proliferator-activated receptor-α modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. J Diabetes Investig. 2018;9:1323–32.
  13. Yokote K, Yamashita S, Arai H, et al. A pooled analysis of pemafibrate Phase II/III clinical trials indicated significant improvement in glycemic and liver function-related parameters. Atheroscler Suppl. 2018;32:155.

 

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Serum Markers of Oxidative Stress to Assess Mortality Risk in Patients with Type 2 Diabetes

Serum Markers of Oxidative Stress to Assess Mortality Risk in Patients with Type 2 Diabetes

By Aly Becraft, MS and Kevin C Maki, PhD

Hyperglycemia is thought to result in increased reactive oxygen species (ROS) production and weakened antioxidant capacity,1 which can make patients with type 2 diabetes (T2D) susceptible to elevated oxidative stress. Current research relating diabetes complications and oxidative stress is lacking because ROS are difficult to measure directly;2 however, methods that indirectly quantify oxidative stress by measuring derivatives of reactive oxygen metabolites (d-ROMs) as a proxy for ROS production3 and total thiol levels (TTLs) as a proxy for reduction-oxidation (redox) status of blood4 are also available.

Xuan et al. recently published pooled results from two cohort studies in a meta-analysis to investigate the association of these oxidative stress biomarkers with incident major cardiovascular events, total cancer incidence, and cause-specific and all-cause mortality in patients with T2D.5 Diabetes sub-cohorts of the ESTHER and DIANA studies, conducted in Germany, were included. In the ongoing ESTHER cohort, to date, patient follow up visits have been conducted after 2, 5, 8, 11 and 14 years. Follow up in the DIANA study occurred after 4 and 7 years. For this meta-analysis, the 8-year follow-up data from the ESTHER cohort was used as baseline and the 11-year follow-up for repeated biomarker measurements. For the DIANA study, baseline and the 4-year follow-up data were used. Biomarker measurements were conducted on 1029 patients from the ESTHER cohort, of which 720 had repeated measurements. In the DIANA study, measurements of both biomarkers were performed for 1096 baseline study participants, and repeated measurement of d-ROMs was done for 738 participants.

In both cohorts, significantly increased d-ROMs levels were observed in females, current smokers, patients with T2D who had body mass index (BMI) ≥40 kg/m2, those not taking any antidiabetic medication, with insulin therapy, without lipid-lowering medication, with high total cholesterol levels, or with high C-reactive protein (CRP) levels. In addition, significantly lower TTLs in both cohorts were observed in females, alcohol abstainers, and patients with T2DM with BMI ≥40 kg/m2, without any antidiabetic medication, with insulin therapy, with antihypertensive therapy, with anticoagulant medication, with high CRP levels, with estimated glomerular filtration rate (eGFR), or with a history of myocardial infarction, heart failure, or hypertension. Both biomarkers were significantly associated with all-cause mortality in each of the cohorts; however, the associations with cancer mortality and major cardiovascular events were not statistically significant. Adjustment for disease and CRP concentration attenuated observed effect estimates. Subgroup analysis of all-cause mortality demonstrated strong associations with d-ROM levels among males and among patients with T2D with glycated hemoglobin <7%, age <70 years, BMI <30 kg/m2, and a history of coronary heart disease.

 

The results of this study support the notion that an imbalanced redox system may play a role in increasing premature mortality in patients with T2D. Other evidence supports such a role for oxidative stress,6-8 but it remains to be determined if oxidative stress is also involved in the development of cardiovascular disease and cancer in patients with T2D. Although this study was observational, and thus, the possibility of residual confounding cannot be disregarded, the results demonstrate the potential need for oxidative stress interventions in patients with T2D and illustrate the usefulness of using d-ROMs and TTLs as biomarkers to identify individuals with T2D who may be at increased risk for premature death.

 

References:

 

  1. Dincer A, Onal S, Timur S, et al. Differentially displayed proteins as a tool for the development of type 2 diabetes. Ann Clin Biochem. 2009;46:306–310.

 

  1. Stephens JW, Khanolkar MP, Bain SC. The biological relevance and measurement of plasma markers of oxidative stress in diabetes and cardiovascular disease. Atherosclerosis. 2009;202:321–329.

 

  1. Kotani K, Sakane N. C-reactive protein and reactive oxygen metabolites in subjects with metabolic syndrome. J Int Med Res. 2012;40:1074–1081.

 

  1. Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev. 2017;2017:6501046.

 

  1. Xuan Y, Gào X, Anusruti A, Holleczek B, Jansen EH, Muhlack DC, Brenner H, Schöttker B. Association of serum markers of oxidative stress with incident major cardiovascular events, cancer incidence and all-Cause mortality in type 2 diabetes patients: pooled results from two cohort studies. Diabetes Care. 2019;Epub ahead of print.

 

  1. Broedbaek K, Siersma V, Henriksen T, et al. Urinary markers of nucleic acid oxidation and long-term mortality of newly diagnosed type 2 diabetic patients. Diabetes Care. 2011;34:2594– 2596.

 

  1. Kjaer LK, Oellgaard J, Henriksen T, et al. Indicator of RNA oxidation in urine for the prediction of mortality in patients with type 2 diabetes and microalbuminuria: a post-hoc analysis of the Steno-2 trial. Free Radic Biol Med. 2018;129:247–255.

 

  1. Kjær LK, Cejvanovic V, Henriksen T, et al. Cardiovascular and all-cause mortality risk associated with urinary excretion of 8-oxoGuo, a biomarker for RNA oxidation, in patients with type 2 diabetes: a prospective cohort study. Diabetes Care. 2017;40:1771–1778.

 

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Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease

Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease

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

 

Cardiovascular disease (CVD) continues to be the leading cause of death around the world and it is directly associated with blood levels of low-density lipoprotein cholesterol (LDL-C).1,2  In many clinical trials and in clinical practice, statins have been shown to be effective for lowering LDL-C, in both primary and secondary prevention, and to reduce the risk of future CVD events.3-6  The multi-society American College of Cardiology and American Heart Association guidelines for cholesterol management suggest that an adequate LDL-C lowering response with an intermediate-intensity statin is ≥30% and is  ≥50% with higher-intensity statins.5  The National Institute for Health and Care Excellence (NICE) guidelines defined sub-optimal responders as patients on treatment with statins for primary prevention of CVD who fail to achieve >40% reduction in LDL-C within the 24 months of statin initiation.6

 

Previous studies have identified individual biological and genetic variability of LDL-C response to statin therapy, as well as variation in treatment adherence, yet there is a paucity of literature on the variation of LDL-C response to statins in the general population.7,8  To address this issue, Akyea et al. examined the change in LDL-C and future risk of CVD in primary care patients over 24 months in response to initiation of statin therapy.9

 

This prospective cohort included 165,411 primary care patients, who were free of CVD at the initiation of statin therapy.  The data were collected from the UK Clinical Practice Research Datalink (CPRD), which is considered representative of the general population in the UK in terms of age, sex, and ethnicity.  Over half (51.2%, n=84,609) of patients had a sub-optimal LDL-C response to statin therapy within 24 months.  During the 1,077,299 person-years of follow-up (median follow-up 6.2 years) there were 22,798 CVD events.  Of these CVD events 12,142 were reported among the sub-optimal responders and 10,656 among the optimal responders (as defined by NICE).  The rates of CVD in the sub-optimal and optimal responders were 22.6 and 19.7/1000 person-years, respectively.

 

Compared to optimal responders, sub-optimal responders had a hazard ratio (HR) for incident CVD of 1.17 (95% CI 1.13-1.20).  After adjusting for age and baseline untreated LDL-C, the sub-optimal vs. optimal responders had a HR of 1.22 (95% CI 1.19-1.25).  Consideration of competing risks (e.g., patients transferring out of the practice, death) led to a lower HR for sub-optimal responders of 1.13 (95% CI 1.10-1.16) and an adjusted HR of 1.19 (95% CI 1.16-1.23).  It is worth noting that in this cohort, a higher proportion of patients with sub-optimal responses were prescribed lower potency statins than those with an optimal response.

 

Comment.  Overall the results show that over half of the patients in this general population cohort did not achieve >40% LDL-C reduction over 24 months with statin therapy.  Patients with suboptimal LDL-C responses were at higher risk for future CVD events.  These findings further support the view that “lower is better” for LDL-C and suggest that patients with a suboptimal response to statin therapy should be identified and evaluated for possible additional intervention, which might include intensification of lifestyle therapies, counseling regarding adherence to the prescribed statin regimen, dose escalation, switching to a higher-potency statin, or adjunctive pharmacotherapy such as ezetimibe or a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.

 

 

References

  1. Nichols M, Townsend N, Scarborough P, et al. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J. 2014;35:2950–9.

  2. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–90.
  3. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;326:1423.

  4. Cholesterol Treatment Trialists’ (CTT) collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376:1670–81.

  5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol. 2018;Epub ahead of print.
  6. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. London: National Institute for Health and Care Excellence, 2016.
  7. Mega JL, Morrow DA, Brown A, et al. Identification of genetic variants associated with response to statin therapy. Arterioscler Thromb Vasc Biol. 2009;29:1310–5.

  8. Mann DM, Woodward M, Muntner P, et al. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother. 2010;44:1410–21.
  9. Akyea RK, Kai J, QUreshi N, Iyen B, Weng SF. Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease. Heart. 2019;Epub ahead of print.

 

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Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

By Aly Becraft, MS and Kevin C Maki, PhD

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was designed to assess the effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, canagliflozin, on renal outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease.1,2 This randomized, double-blind, placebo-controlled, multicenter clinical trial included patients of at least 30 years of age with an estimated glomerular filtration rate of 30 to <90 mL per minute per 1.73 m2 of body-surface area, albuminuria, and a glycated hemoglobin level of 6.5 to 12.0%. Patients were randomized to receive a 100 mg daily dose of canagliflozin or placebo added to renin-angiotensin-aldosterone blockade. The primary outcome was a composite of end stage renal disease (ESRD), doubling of the serum creatinine level for at least 30 days, or death from renal or cardiovascular (CV) disease. Secondary outcomes were tested hierarchically in the following order:

  1. composite of CV death or hospitalization for heart failure (HF)
  2. composite of CV death, myocardial infarction (MI) or stroke
  3. hospitalization for HF
  4. composite of ESRD, doubling of the serum creatinine level or renal death
  5. CV death
  6. death from any cause
  7. composite of CV death, MI, stroke, or hospitalization for HF or for unstable angina (UA)

 

The trial design was event driven; after a planned interim analysis, the trial was stopped early due to the requisite number of primary outcome events having been achieved. The final analysis included 4401 randomized patients and a median follow up time of 2.62 years. The results for the outcomes, including the hazard ratios (HR) and 95% confidence intervals (CI), are shown in the table below.


 

 

Outcome

Canagliflozin

(n = 2202)

Placebo

(n = 2199)

HR

(95% CI)

p-value

 

Events/1000 patient-years

   

Primary composite outcome

43.2

61.2

0.70

(0.59, 0.82)

0.00001

Secondary outcomes

  CV death or hospitalization for HF

31.5

45.4

0.69

(0.57, 0.83)

<0.001

  CV death, MI or stroke

38.7

48.7

0.80

(0.67, 0.95)

0.01

  Hospitalization for HF

15.7

25.3

0.61

(0.47, 0.80)

<0.001

  ESRD, doubling of serum creatinine level or renal death

27.0

40.4

0.66

(0.53, 0.81)

<0.001

  CV death

19.0

24.4

0.78

(0.61, 1.00)

0.05*

           

 

*No significant between-group difference in the risk of CV death was observed, so the differences in all subsequent outcomes in the hierarchical testing sequence were not formally tested.

 

Conclusion: Compared to placebo, canagliflozin lowered risk of kidney failure and CV events after a median follow-up of 2.62 years, supporting efficacy as a treatment option for renal and CV protection in patients with T2D and chronic kidney disease.

References:

  1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; Epub ahead of print.
  2. Ingelfinger JR, Rosen CJ. Clinical credence – SGLT2 inhibitors, diabetes, and chronic kidney disease. N Engl J Med. 2019; Epub ahead of print.

 

 

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Oral Semaglutide versus Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes

Oral Semaglutide versus Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes

By Aly Becraft, MS and Kevin C Maki, PhD

 

The PIONEER3 trial was designed to compare the efficacy, long-term adverse event profile, and tolerability of an orally administered formulation of the glucagon-like peptide 1 receptor agonist (GLP-1RA), semaglutide, with the widely-used dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, as an add on to metformin, with or without sulfonylurea, in patients with type 2 diabetes (T2D).1,2 This 78-week, phase 3a, randomized, double-blind, active-controlled, parallel-group trial included a total of 1864 patients with T2D and glycated hemoglobin (HbA1c) levels of 7.0% to 10.5%. Patients were randomized to receive either 3 mg/d (n = 466), 7 mg/d (n = 466), or 14 mg/d (n = 465) of semaglutide, or 100-mg/d sitagliptin (n = 467). The primary endpoint was change in HbA1c from baseline to week 26. The key secondary endpoint was change in body weight from baseline to week 26. Additional secondary endpoints included changes in HbA1c and body weight from baseline to weeks 52 and 78. The analysis evaluated both intention-to-treat and per-protocol samples.

Semaglutide at doses of 7 and 14 mg/d was found to be superior to sitagliptin for reducing HbA1c and body weight (see table, intention-to-treat results at week 26). Neither superiority nor non-inferiority with 3-mg/d semaglutide was demonstrated.

 

Estimated mean changes from baseline and estimated mean

(95% confidence interval) differences

from sitagliptin at week 26

 

Sitagliptin

Semaglutide

 

100 mg/d

3 mg/d

7 mg/d

14 mg/d

 HbA1c, %

-0.8

-0.6

-1.0

-1.3

 Difference from sitagliptin

0.2 (0.0, 0.3)

-0.3 (-0.4, -0.1)

-0.5 (-0.6, -0.4)

 Body Weight, kg

-0.6

-1.2

-2.2

-3.1

 Difference from sitagliptin

-0.6 (-1.1, -0.1)

-1.6 (-2.0, -1.1)

-2.5 (-3.0, -2.0)

 

At week 78, significantly (p<0.05) greater reductions in HbA1c were observed with the semaglutide dosage of 14 mg/d versus sitagliptin in both intention-to-treat and per protocol samples (-0.4% and -0.7%, respectively), but semaglutide 7 mg/d was greater only in the per protocol sample (-0.3%). Significantly (p<0.05) greater body weight reductions were observed with all three dosages of semaglutide versus sitagliptin at week 78 (estimated mean differences of -0.8, -1.7 and -2.1 kg for 3, 7 and 14 mg/d of semaglutide). In addition, significant reductions in fasting plasma glucose and mean self-measured whole-blood glucose were greatest in the the14-mg/d semaglutide group at weeks 26 and 78 compared with sitagliptin.

The overall proportions of patients with at least one adverse event were similar across all treatment groups. However, a greater incidence of discontinuation due to adverse events was reported with 14 mg/d of semaglutide (11.6%), while 3- and 7-mg/d dosages (5.6% and 5.8%, respectively) had comparable incidences of discontinuation to sitagliptin (5.2%).  The primary cause of discontinuation in all treatment groups was gastrointestinal adverse events; for a substantial proportion of patients in the 7- and 14-mg/d semaglutide groups, the onset of the event leading to discontinuation occurred during the dose escalation period.

Conclusion: Compared to sitagliptin, oral semaglutide at 7 and 14 mg/d further reduced HbA1c and body weight over 26 weeks.

References:

  1. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: The PIONEER 3 randomized clinical trial. JAMA. 2019; Epub ahead of print.
  2. Hirsch IB. The future of the GLP-1 receptor agonists. JAMA. 2019;321:1457-1458.

 

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Associations of Dietary Cholesterol and Egg Consumption with Incident Cardiovascular Disease and Total Mortality

Associations of Dietary Cholesterol and Egg Consumption with Incident Cardiovascular Disease and Total Mortality

Associations of Dietary Cholesterol and Egg Consumption with Incident Cardiovascular Disease and Total Mortality

 

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

 

Despite decades of research, the association between dietary cholesterol consumption, cardiovascular disease (CVD) and mortality remains controversial.  Adding to this controversy are the confusing recommendations in the 2015-2020 Dietary Guidelines for Americans.1,2  The Guidelines state that cholesterol is not a nutrient of concern for overconsumption, but also recommend that individuals should consume as little dietary cholesterol as possible while following a healthy eating pattern.  A meta-analysis of prospective cohort studies published in 2015 did not show statistically significant associations between dietary cholesterol consumption and incident CVD, coronary artery disease or stroke, although higher dietary cholesterol intake was associated with an increased level of low-density-lipoprotein cholesterol (LDL-C).3  Because a large chicken egg (~50 g) contains roughly 186 mg of cholesterol,4 limiting egg consumption has been recommended as a way to decrease dietary cholesterol and to possibly reduce the risk of CVD.

 

Zhong et al. recently published an analysis of the associations between intakes of dietary cholesterol and eggs with incident CVD and total mortality from the Lifetime Risk Pooling Project.5  The Lifetime Risk Pooling Project contains data from 6 cohorts in which usual dietary intake, fatal and nonfatal coronary heart disease, stroke, heart failure and CVD from other causes were assessed. The 6 cohorts were the Atherosclerosis Risk in Communities (ARIC) Study,6 Coronary Artery Risk Development in Young Adults (CARDIA) Study,7 Framingham Heart Study (FHS),8  Framingham Offspring Study (FOS),9 Jackson Heart Study (JHS)10 and the Multi-Ethnic Study of Atherosclerosis (MESA).11  The analysis included 29,615 participants (mean [standard deviation] age at baseline, 51.6 [13.5] years).5  There were 13,299 (44.9%) men and 9,204 (31.1%) subjects were black.  The median follow-up was 17.5 years (interquartile limits, 13.0-21.7; maximum, 31.3) during which there were 5,400 incident CVD events and 6,132 all-cause deaths. 

 

Dietary cholesterol and egg consumption showed linear associations with incident CVD and all-cause mortality (all P values for nonlinear terms, 0.19-0.83).  The addition of each 300 mg of dietary cholesterol per day was associated with higher risk of incident CVD (adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI], 1.09-1.26 and adjusted absolute risk difference [ARD] 3.24%, 95% CI 1.39%-5.08%).  The same increment of dietary cholesterol per day was also associated with higher risk of all-cause mortality (adjusted HR 1.18, 95% CI 1.10-1.26 and adjusted ARD 4.43%, 95% CI 2.51%-6.36%). Consumption of each additional half egg per day was associated with higher risk of incident CVD:  adjusted HR 1.06, 95% CI 1.03-1.10; adjusted ARD 1.11%, 95% CI 0.32%-1.89% and all-cause mortality:  adjusted HR 1.08, 95% CI 1.04-1.11; adjusted ARD 1.93%, 95% CI 1.10%-2.76%.

 

The associations between egg consumption and incident CVD (adjusted HR 0.99, 95% CI 0.93-1.05) and all-cause mortality (adjusted HR 1.03, 95% CI 0.97-1.09) were no longer significant after adjusting for dietary cholesterol consumption.  The associations between dietary cholesterol intake and incident CVD, as well as mortality, remained statistically significant after adjusting for traditional CVD risk factors (including non-high-density lipoprotein cholesterol [non-HDL-C] concentration), various nutrient intakes and measures of diet quality.

 

Comment.  This new analysis by Zhong et al. has several strengths, including a long follow-up period and the availability and analysis of a great deal of dietary information, such as indices of diet quality, including the Alternative Healthy Eating Index, a Dietary Approaches to Stop Hypertension score and a Mediterranean Diet index.  The supplemental material for the paper includes extensive information from sensitivity analyses.

 

Despite these strengths, the results are difficult to interpret, in our view, for several reasons.  First, adjustment for non-HDL-C level did not materially alter the association between dietary cholesterol intake and incident CVD.  This is curious because the presumed mechanistic link between dietary cholesterol intake and incident CVD is through the effect of dietary cholesterol to raise the circulating concentrations of LDL-C and non-HDL-C, which are well-established major CVD risk factors that are believed to be causally related to CVD incidence.  In a communication with the authors, we were told that adjustment for non-HDL-C and HDL-C levels had virtually no impact on the point estimates for CVD risk.  Data were missing for LDL-C for 900 subjects, so this was not assessed separately.  Given the lack of effect of adjustment for lipid levels, if the association between dietary cholesterol intake and CVD risk is causal, one must hypothesize mechanisms other than the effect of dietary cholesterol to raise atherogenic cholesterol (LDL-C and non-HDL-C) levels.

 

A second issue is that within the range of typical cholesterol intakes in the United States (<300 mg/d), no significant increases in risk for incident CVD or all-cause mortality were observed.  For example, for intakes of 200 to <300 mg/d compared to <100 mg/d, the HR for CVD in model 3 (adjusted for CVD risk factors and medication use) was 0.99, 95% CI 0.87-1.12 and for mortality was 0.95, 95% CI 0.84-1.06.  Therefore, the traditional recommendation to limit dietary cholesterol intake to <300 mg/d is supported by these analyses.

 

Finally, the relationship between cholesterol intake and non-CVD mortality is similar to that for all-cause mortality, with model 3 HR for all-cause mortality of 1.15 (95% CI 1.07-1.23) compared with 1.13 (95% CI 1.04-1.22) for non-CVD mortality (eFigure 5 in the supplemental material).  We are not aware of biologically plausible mechanisms that would explain an increase in non-CVD mortality as a consequence of higher dietary cholesterol intake.  Therefore, the possibility of residual confounding must be considered.

 

It is also notable that two other recent publications have reported on the association between egg consumption and incident CVD.  In the EPIC-Norfolk cohort,12 the top quintile of egg consumption (median 40 g/d) was associated with a non-significantly lower adjusted incidence of ischemic heart disease compared with the lowest quintile (HR 0.93, 95% CI 0.86-1.01), with a p-value for trend across quintiles of 0.37.  Also, in a large study in China with nearly 500,000 participants,13 those who consumed eggs daily had lower risks for incident CVD (HR 0.89, 95% CI 0.87-0.92) and ischemic heart disease (HR 0.88, 95% CI 0.84-0.93) than those who rarely or never consumed eggs, with significant inverse trends (p < 0.001) over the range of egg intake categories.  So, within the space of one year we have seen publications from observational studies reporting associations ranging from a significant inverse association, to no significant relationship, to a significant positive association of egg intake with incident CVD and/or ischemic heart disease.

 

Our view is that the available data show convincingly that higher dietary cholesterol intake modestly raises the level of LDL-C, a major CVD risk factor, with linear models indicating a rise of ~2 mg/dL of LDL-C for each increment of 100 mg/d of dietary cholesterol.3,14,15  The results from the Zhong et al. study do not suggest elevations in CVD incidence or mortality risk for intakes of dietary cholesterol below the traditional recommendation of <300 mg/d (i.e., for intake of 200-299 mg/d compared with <100 mg/d).5  Their results also showed that the relationship between egg consumption and CVD and mortality risk could be accounted for by the cholesterol content of eggs.  Therefore, we believe it is reasonable to suggest that whole eggs can be a part of a healthy dietary pattern, provided that total dietary cholesterol intake is not excessive, with the traditional recommendation being not to exceed 300 mg/d.  For those with hypercholesterolemia, it may be reasonable to further restrict dietary cholesterol intake.  The National Lipid Association recommendations for management of dyslipidemia suggest that dietary cholesterol be limited to <200 mg/d for those with hypercholesterolemia, and further restriction may be prudent for those who are known to be hyperresponders, i.e., those who have a larger than average increase in LDL-C in response to an increase in dietary cholesterol.16  Additional research will be needed to determine whether a dietary cholesterol intake >300 mg/d is causally related to adverse health outcomes, and, if so, what mechanisms account for these relationships.

 

References

  1. US Department of Health and Human Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th Edition. December 2015. https://health.gov/dietary guidelines/2015/guidelines/.
  2. Dietary Guidelines Advisory Committee. Scientific Report of the 2015 Dietary Guidelines Advisory Committee: Advisory Report to the Secretary of Health and Human Services and the Secretary of Agriculture. Washington, DC: US Dept of Agriculture, Agricultural Research Service; 2015.
  3. Berger S, Raman G, Vishwanathan R, et al. Dietary cholesterol and cardiovascular disease. Am J Clin Nutr. 2015;102:276-294.
  4. US Department of Agriculture. Agricultural Research Service, Nutrient Data Laboratory. USDA National Nutrient Database for Standard Reference, Release 28. Version Current: September 2015. https://ndb.nal.usda.gov/ndb/.
  5. Zhong VW, Van Horn L, Cornelis MC, et al. Associations of dietary cholesterol or egg consumption with incident cardiovascular disease and mortality. JAMA. 2019;321:1081-1095.
  6. The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) study: design and objectives. Am J Epidemiol. 1989;129:687-702.
  7. Friedman GD, Cutter GR, Donahue RP, et al. CARDIA: study design, recruitment, and some characteristics of the examined subjects. J Clin Epidemiol. 1988;41:1105-1116.
  8. Wong ND, Levy D. Legacy of the Framingham Heart Study: rationale, design, initial findings, and implications. Glob Heart. 2013;8:3-9.
  9. Feinleib M, Kannel WB, Garrison RJ, et al. The Framingham Offspring Study: design and preliminary data. Prev Med. 1975;4:518-525.
  10. Taylor HA Jr, Wilson JG, Jones DW, et al. Toward resolution of cardiovascular health disparities in African Americans. Ethn Dis. 2005;15(suppl 6):4-17.
  11. Bild DE, Bluemke DA, Burke GL, et al. Multi-Ethnic Study of Atherosclerosis: objectives and design. Am J Epidemiol. 2002;156:871-881.
  12. Key TJ, Appleby PN, Bradbury KE, et al. Consumption of meat, fish, dairy products, eggs and risk of ischemic heart disease: a prospective study of 7198 incident cases among 409,885 participants in the Pan-European EPIC cohort. Circulation. 2019; Epub ahead of print.
  13. Qin C, Lv J, Bian Z, et al. Associations of egg consumption with cardiovascular disease in a cohort study of 0.5 million Chinese adults. Heart. 2018;104:1756-1763.
  14. Vincent MJ, Allen B, Palacios OM, Haber LT, Maki KC. Meta-regression analysis of the effects of dietary cholesterol intake on LDL and HDL cholesterol. Am J Clin Nutr. 2019;109:7-
  15. Clarke R, Frost C, Collins R, Appleby P, Peto R. Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies. BMJ. 1997;314:112-117.
  16. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(6 Suppl):S1-S122.e1.

 

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Association of Long-term Consumption of Sugar-Sweetened and Artificially Sweetened Beverages with Total and Cause-specific Mortality

Association of Long-term Consumption of Sugar-Sweetened and Artificially Sweetened Beverages with Total and Cause-specific Mortality

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

In the United States, sugar sweetened beverages (SSBs) account for the largest source of added sugar in the diet 1,2.  These types of drinks (e.g., carbonated, noncarbonated, fruit, sports) have added caloric sweeteners like high fructose corn syrup, sucrose, or fruit juice concentrates.  Currently it is recommended that adults consume no more than 10% of their total energy intake from added sugar 3.

While consumption rates of SSBs had been declining in the US over the past 10 years, recent research has suggested a reversal in that trend, with increased consumption among adults of all ages averaging around 145 kcal/day (6% of energy)4.  In younger adults, SSBs are responsible for 9.3% of daily calories in men and 8.2% of daily calories in women 5-7.

Studies have shown a positive association between intake of SSBs and weight gain, as well as higher risks of type 2 diabetes, coronary heart disease and stroke 8-11.  Artificially sweetened beverages (ASBs) are used as alternatives to the calorically heavy SSBs, yet there has been little research on the long-term health effects of ASBs or on the relationship between SSB consumption and total mortality.

In an analysis of two ongoing prospective cohort studies, Malik et al. examined the association between intakes of SSBs and ASBs with total and cause-specific mortality 12.  The analysis included data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS).  The NHS study has been collecting data since 1976 and includes 121,700 female nurses, age 30-55 years at study entry.  The HPFS began in 1986 and includes 51,529 male health professionals, age 40-75 years at entry. 

Mean consumption of SSBs decreased in both cohorts over the follow-up periods, which were 34 years in the NHS and 28 years in the HPFS.  Intakes of SSBs and ASBs were inversely correlated in both the NHS (r = −0.06, P < 0.001) and the HPFS (r = −0.16, P < 0.001).  Overall, there were 36,436 deaths, including 7,896 from cardiovascular disease (CVD) and 12,380 from cancer during a total of 3,415,564 person-years of follow-up.

After adjusting for major diet and lifestyle factors, consumption of SSBs was associated with a higher risk of total mortality (Table).  SSBs were also associated with increased CVD mortality (hazard ratio comparing extreme categories of 1.31 [95% confidence interval, 1.15-1.50], P trend < 0.0001) and cancer mortality (1.16 [1.04-1.29], P trend = 0.0004).  ASB intake was associated with increased risk for total and CVD mortality only in the highest intake group (Table).  Interestingly, intake of ASBs was associated with total mortality in the NHS, but not the HPFS (P interaction = 0.01).  ASBs were not associated with cancer mortality in either cohort.

 

 

Table:  SSB and ASB Consumption and Mortality Risk (Total, CVD, Cancer)

Pooled Hazard Ratios (95% confidence intervals) from NHS and HPFS

 

<1/month

1-4/month

2-6/week

1-<2/d

>2/d

P trend

Total Mortality

SSB

1.0

 

1.01

(0.98, 1.04)

1.06

(1.03, 1.09)

1.14

(1.09, 1.19)

1.21

(1.13, 1.28)

<0.0001

ASB

1.0

 

0.96

(0.93, 0.99)

0.97

(0.95, 1.00)

0.98

(0.94, 1.03)

1.04

(1.02, 1.12)

0.01

CVD Mortality

SSB

1.0

1.06

(1.00, 1.12)

1.10

(1.04, 1.17)

1.19

(1.08, 1.31)

1.31

(1.15, 1.50)

<0.0001

ASB

1.0

0.93

(0.87, 1.00)

0.95

(0.89, 1.00)

1.02

(0.94, 1.12)

1.13

(1.02, 1.25)

0.02

Cancer Mortality

SSB

1.0

1.03 

(0.98, 1.08)

1.06

(1.01, 1.11)

1.12

(1.03, 1.21)

1.16

(1.04, 1.29)

0.0004

ASB

1.0

1.01

(0.96, 1.07)

0.99

(0.94, 1.04)

1.00

(0.93, 1.07)

1.04

(0.96, 1.12)

0.58

 

Comment.  Results from this study highlight the importance of minimizing SSB intake because consumption of SSBs has been consistently associated with adverse health outcomes and a less favorable cardiometabolic risk factor profile.8-11  Substituting ASBs for SSBs will help decrease added sugar intake, but it is important to note that the possible health impacts of long-term consumption have not been well documented.  It is uncertain whether the modest increases in total (4%) and CVD (13%) mortality associated with consuming ≥2 ASBs per day represent causal relationships.  Nevertheless, it is reasonable to recommend moderation in the consumption of these products.

 

References

  1. Hu FB, Malik VS. Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav. 2010;100:47–54.
  2. National Cancer Institute: Division of Cancer Control & Population Sciences. Epidemiology and Genomics Research Program. Sources of Calories from Added Sugars among the US population, 2005–2006. Updated April 20, 2018. http://riskfactor.cancer.gov/diet/foodsources/added_sugars/.
  3. S. Department of Health and Human Services and U.S. Department of 
Agriculture. 2015–2020 Dietary Guidelines for Americans. 8th Edition. December 2015. http://health.gov/dietaryguidelines/2015/guidelines/.
  4. Welsh JA, Sharma AJ, Grellinger L, Vos MB. Consumption of added sugars is decreasing in the United States. Am J Clin Nutr. 2011;94:726–734.
  5. Ogden CL, Kit BK, Carroll MD, Park S. Consumption of sugar drinks in the United States, 2005–2008. NCHS Data Brief. 2011:1–8. 

  6. Rosinger A, Herrick K, Gahche J, Park S. Sugar-sweetened beverage consumption among U.S. adults, 2011–2014. NCHS Data Brief. 2017:1–8. 

  7. Malik VS, Pan A, Willett WC, Hu FB. Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98:1084–1102.
  8. Malik VS, Popkin BM, Bray GA, Després JP, Willett WC, Hu FB. Sugar- sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis. Diabetes Care. 2010;33:2477–2483.
  9. Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89:1037–1042.
  10. de Koning L, Malik VS, Kellogg MD, Rimm EB, Willett WC, Hu FB. Sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men. Circulation. 2012;125:1735–41, S1.
  11. Bernstein AM, de Koning L, Flint AJ, Rexrode KM, Willett WC. Soda consumption and the risk of stroke in men and women. Am J Clin Nutr. 2012;95:1190–1199.
  12. Malik VS, Li Y, Pan A, De Koning L, Schernhammer E, Willett WC, Hu FB. Long-term consumption of sugar-sweetened and artificially sweetened beverages and risk of mortality in US adults.  2019;139: doi: 10.1161/circulationaha.118.037401.

 

 

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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.
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