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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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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Viscous Fiber Supplements in Diabetes Control: Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

Viscous Fiber Supplements in Diabetes Control: Results from a Systematic Review and Meta-analysis of Randomized Controlled Trials

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

According to the recent 2019 American Diabetes Association (ADA) Standards of Medical Care in Diabetes, people with diabetes should increase their intake of viscous fiber from sources such as oats, legumes, and citrus to help regulate blood glucose levels and lower risk of cardiovascular disease1. Viscous fibers are described as such because they increase viscosity in the human gut, thereby reducing the rate at which carbohydrates are digested and the glucose molecules from them absorbed.  These effects occur because the viscous solution impedes the ability of digestive enzymes to reach starch molecules and slows the rate at which glucose molecules reach the brush border in the intestinal lumen, where absorption can occur.  The result is flattening of the postprandial glycemic and insulinemic responses.  While these acute effects are well established, the longer-term impacts of viscous fibers on glycemic control markers are not well known2.

 

In a systematic review and meta-analysis, Jovanovski2 investigated the effect of viscous dietary fiber supplementation on markers of glycemic control in people with type 2 diabetes (T2D).  A comprehensive literature search on MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through June 15, 2018 identified 2,716 potential RCTs.  After reviewing the studies based on the inclusion/exclusion criteria, 27 studies (n = 1,394) were identified for the review and meta-analysis.  Inclusion criteria were: ≥3 weeks in duration, studied viscous fiber supplementation (β-glucan, guar gum, konjac, psyllium, pectin, xanthan gum, locust bean gum, alginate, agar) compared to an appropriate control (i.e., fiber-free supplement or one containing insoluble fiber, background diet, or placebo), and included at least one glycemic measurement (glycated hemoglobin [HbA1c], fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance [HOMA-IR], or fructosamine).

 

The median age of subjects was 60 years (range 48-67) and they had a median body mass index of 27 kg/m2 (range 26-32 kg/m2).  The median dose of viscous fibers in the studies was 13.1 g/day (range 2.55-21.0 g/day) and the median study duration was 8 weeks (range 3-52 weeks).

 

Compared to control groups, inclusion of viscous fiber in the diet was associated with significant reductions in HbA1c, fasting blood glucose and HOMA- IR. 

 

  • HbA1c: mean difference (MD) -0.58% 95% confidence interval (CI) -0.88%, -0.28%; p = 0.0002;
  • Fasting blood glucose: MD -14.8 mg/dL 95% CI -23.8, -5.59; p = 0.001
  • HOMA-IR: MD -1.89 95% CI -3.45, -0.33; p = 0.02.

 

There were no differences between viscous fiber groups and controls for fasting insulin (MD -2.53 µU/mL 95% CI -5.41, 0.35; p = 0.08) or fructosamine (MD -0.12 mmol/L 95% CI -0.39, 0.14; p = 0.37).  Only 2 studies reported fructosamine, so this finding should be interpreted with caution.  There was no evidence of a significant dose-response effect.  Results for HbA1c, fasting glucose, fasting insulin, and HOMA-IR were graded moderate for certainty of evidence, while fructosamine was graded low.

 

Comment.  Viscous fiber intake, through consumption of food sources such as legumes, whole fruits (e.g., apples and pears) and whole grain oats and barley, as well as dietary supplementation with products such as psyllium (e.g., Metamucil®), methylcellulose (e.g., Citrucel®) or konjac (e.g., Lipozene®), appears to have several benefits regarding cardiometabolic health.  For those with T2D, this meta-analysis shows evidence to support favorable effects on glycemic control and insulin sensitivity.  More research is needed to establish more clearly whether all viscous fibers enhance insulin sensitivity, or whether this property is limited to those with certain characteristics, such colonic fermentability or content of specific bioactive compounds3,4.  Evidence from other sources also shows that viscous fiber lowers the circulating cholesterol level, likely by trapping cholesterol and bile acids, thus preventing their absorption/reabsorption3.  In addition, viscous fibers appear to play a role in appetite regulation, enhancing satiety after meal5.

 

The meta-analysis by Jovanovski and colleagues shows that inclusion of viscous fiber in the diet produces clinically meaningful improvements in glycemic control for patients with T2D.  Based on this, as well as evidence for other benefits (cholesterol lowering and enhanced satiety), inclusion of viscous fiber from foods and/or supplements should be considered an important component of the management plan for patients with T2D.

 

References

  1. American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(Supplement 1): S103-S123.

 

  1. Jovanovski E, Khayyat R,  Zurbau A,  et al. Should viscous fiber supplements be considered in diabetes control? Results from a systematic review and meta-analysis of randomized controlled trials. Diabetes Care. 2019 Jan; doi:10.2337 [Epub ahead of print].

 

  1. Weickert MO, Pfeiffer AFH. Impact of dietary fiber consumption on insulin resistance and the prevention of type 2 diabetes. J Nutr. 2018;148:7-12.

 

  1. Kärkkäninen O, Lankinen MA, Vitale M, et al. Diets rich in whole grains increase betainized compounds associated with glucose metabolism. Am J Clin Nutr. 2018;108:971-979.

 

  1. Rebello CJ, Chu YF, Johnson WD, et al. The role of meal viscosity and oat ß–glucan characteristics in human appetite control: a randomized crossover trial. Nutr J. 2014;13:49.

 

 

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Comparing the Effectiveness of Second-line Antidiabetic Medications on Cardiovascular Events in Patients with Type 2 Diabetes Mellitus

Comparing the Effectiveness of Second-line Antidiabetic Medications on Cardiovascular Events in Patients with Type 2 Diabetes Mellitus

By Mary R Dicklin, PhD and Kevin C Maki, PhD, CLS, FNLA

 

Cardiovascular disease is the leading cause of morbidity and mortality among patients with type 2 diabetes (T2D).1  Metformin is widely recommended as first-line therapy, but metformin alone may be inadequate for achieving glycemic control, or may not be tolerated, in which case clinicians have several second-line antidiabetic medication (ADM) prescription options.2  The second-line ADMs include sulfonylureas (SFUs), thiazolidinediones (TZDs), insulin, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose-cotransporter 2 (SGLT-2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors.3  Understanding how these ADMs differ in their effects on cardiovascular outcomes may assist clinicians in preventing comorbidities in patients with diabetes.

 

Results were recently published from a large, retrospective cohort study that examined major adverse cardiovascular events among insured adults with T2D who had recently started therapy with a second-line ADM after either taking metformin alone or not having received prior ADM.4  Nationwide U.S. administrative claims data were used from 2011-2015.  The primary outcome of the study was time to first cardiovascular event (defined as the composite of hospitalization for congestive heart failure, stroke, ischemic heart disease or peripheral artery disease) after starting a second-line ADM.  Patients were censored after either their first cardiovascular event, discontinuation of insurance coverage, transition of medical claims data coding from the International Classification of Diseases 9th revision to the 10th revision, or two years of follow up.

 

Among the 132,737 adults evaluated in this study, SFUs were used by 47.6%, DPP-4 inhibitors by 21.8%, basal insulin by 12.2%, GLP-1 receptor agonists by 8.6%, TZDs by 5.6% and SGLT-2 inhibitors by 4.3%.4  During the 169,384 person-years of follow-up there were 3480 incident cardiovascular events.  After adjusting for patient, prescriber and health plan characteristics, the risk of composite cardiovascular events according to second-line ADM was determined.  DPP-4 inhibitors were considered to have a neutral effect on cardiovascular outcomes, based on previous clinical trial evidence.5-7  Thus, DPP-4 inhibitor use was the referent (1.0) in the Cox proportional hazard regression analysis.4  The hazard ratios (95% confidence intervals) were:

  • DPP-4 inhibitors: 1.00 (reference)
  • GLP-1 receptor agonists: 0.78 (0.63-0.96)
  • SGLT-2 inhibitors: 0.81 (0.57-1.53)
  • TZDs: 0.92 (0.76-1.11)
  • SFUs: 1.36 (1.23-1.49)
  • Basal insulin: 2.03 (1.81-2.27)

 

Higher cardiovascular risk was associated with use of SFUs or basal insulin.  The risk associated with GLP-1 receptor agonist use was lower than with DPP-4 inhibitor use, but this finding was not statistically significant in all of the sensitivity analyses.  The risks associated with SGLT-2 inhibitors and TZDs were not significantly different from DPP-4 inhibitors.

 

Recent randomized clinical trials that have evaluated the cardiovascular risk associated with newer ADMs have also suggested reduced cardiovascular events.8,9  Unlike those randomized trials, in which most of the participants already had cardiovascular disease, just 5.5% of participants in this observational study had a history of prior cardiovascular events, although cardiovascular risk factors, such as dyslipidemia (61.6%) and hypertension (70.1%), were present in the majority of subjects.

 

In summary, these results suggest that, with regard to managing cardiovascular comorbidity in their patients with T2D, after metformin, clinicians may consider prescribing any of the newer ADMs (i.e., GLP-1 receptor agonists, SGLT-2 inhibitors and DPP-4 inhibitors) that were shown to be similarly associated with lower cardiovascular risk, instead of SFUs or basal insulin, which were associated with greater cardiovascular risk.

 

References:

  1. American Diabetes Association. 10. Cardiovascular disease and risk management: Standard of medical care in diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S102-S123.
  2. American Diabetes Association. 3. Prevention or delay of type 2 diabetes: Standards of medical care in diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S29-S33.
  3. Thrasher J. Pharmacologic management of type 2 diabetes mellitus: available therapies. Am J Cardiol. 2017;120:S4-S16.
  4. O’Brien MJ, Karam SL, Wallia A, et al. Association of second-line antidiabetic medications with cardiovascular events among insured adults with type 2 diabetes. JAMA Network Open. 2018;1:e1816125.
  5. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.
  6. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-242.
  7. White WB, Kupfer S, Zannad F, et al. Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial. Diabetes Care. 2016;39:1267-1273.
  8. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2018; Epub ahead of print.
  9. Sposito AC, Berwanger O, de Carvalho LSG, Saraiva JFK. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Cardiovasc Diabetol. 2018;17:157.
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Summary of Results from a Trial of a Novel Selective PPARɑ Modulator, Pemafibrate, on Lipid and Glucose Metabolism in Patients with Type 2 Diabetes and Hypertriglyceridemia1

Summary of Results from a Trial of a Novel Selective PPARɑ Modulator, Pemafibrate, on Lipid and Glucose Metabolism in Patients with Type 2 Diabetes and Hypertriglyceridemia

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

 Background:

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death in persons with type 2 diabetes2 and the incidence of cardiovascular events is elevated in patients with type 2 diabetes compared with those without diabetes.3,4 Abnormalities in lipid metabolism often accompany type 2 diabetes mellitus and are associated with insulin resistance, including:

  • Elevated triglyceride (TG) levels with delayed clearance of TG-rich lipoproteins from the circulation;
  • Reduced high-density lipoprotein cholesterol (HDL-C) levels;
  • An increased proportion of small, dense low-density lipoprotein (LDL) particles.

Several large-scale clinical trials, including the Collaborative Atorvastatin Diabetes Study (CARDS) and a Cholesterol Treatment Trialists’ (CTT) meta-analysis, have shown that effective management of dyslipidemia through LDL cholesterol (LDL-C)-lowering therapy with statins results in reduced cardiovascular risk in patients with diabetes.5,6 Other studies in people with diabetes have also identified risk factors for developing coronary heart disease including the Japan Diabetes Complication Study (JDCS), which noted high LDL-C and TG levels as risk factors, and the UK Prospective Diabetes Study (UKPDS), which showed that high LDL-C and low HDL-C are associated with elevated cardiovascular disease risk.7,8

Studies with fibrates have shown the expected decreases in TG and increases in HDL-C, but have shown inconsistent results regarding reductions in ASCVD risk in patients with type 2 diabetes. A meta-analysis completed by our group9 showed evidence that fibrates and other drugs that primarily lower TG and TG-rich lipoproteins (omega-3 fatty acid concentrates and niacin) reduce ASCVD events in participants with elevated TG, particularly if also accompanied by low HDL-C.

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor alpha (PPARɑ) modulator approved for the treatment of dyslipidemia.10 Ishibashi et al. performed a dose-finding phase 2 trial of pemafibrate in patients with atherogenic dyslipidemia (elevated TG and low HDL-C) and noted significant reductions in TG and increases in HDL-C with rates of adverse events (AEs) similar to placebo. Because type 2 diabetes and atherogenic dyslipidemia often coexist, many of the patients who receive treatment with pemafibrate (once approved for marketing) are expected to also have type 2 diabetes. This summary reports on the initial 24-week treatment period for a Phase III clinical trial comparing the effects of pemafibrate and placebo in patients with elevated TG and type 2 diabetes. The primary end point of the study was the percentage change in fasting serum TG level from baseline to the end point of 24 weeks. Secondary endpoints included the percentage changes or changes from baseline in fasting and postprandial lipid-related and glycemic parameters. The primary safety end points were the incidence rates of AEs and adverse drug reactions after the study drug usage.

 Methods:

This was a multicenter, placebo-controlled, randomized, double-blind, parallel group study that was completed in 34 medical institutions in Japan from February 20, 2014 through April 30, 2015. Subjects were eligible for the study if they met the following criteria:

  • Men and postmenopausal women age ≥20 years;
  • Type 2 diabetes with glycated hemoglobin (HbA1c) ≥6.2% and TG ≥150 mg/dL (1.7 mmol/L);
  • ≥12 weeks of dietary or exercise guidance before the first screening visit.

This study included participants who were randomly assigned to receive twice daily placebo (n = 57), 0.2 mg/day pemafibrate (n = 54), or 0.4 mg/day pemafibrate (n = 55) for 24 weeks. Pemafibrate is available in 0.1 mg tablets.

 Results:

Fasting serum TG significantly decreased by ~45% with pemafibrate compared with placebo (p<0.001, see table).

 

 

Fasting TG, mg/dL, mean ± standard deviation

 

Baseline

Week 24

Placebo

  284.3 ± 117.6

240.0 ± 92.2

0.2 mg/day pemafibrate

240.3 ± 93.5

129.0 ± 71.5

0.4 mg/day pemafibrate

260.4 ± 95.9

135.8 ± 71.2

Percentage changes in fasting serum TG levels from baseline to 24 weeks were -10.8% (p < 0.01), -44.3% (p < 0.001) and -45.1% (p <0.001) for placebo, 0.2 mg/day and 0.4 mg/day, respectively. The pemafibrate groups also had significantly reduced levels of non-HDL-C, remnant lipoprotein cholesterol, apolipoprotein (Apo) B100, Apo B48 and Apo C3, and significantly increased HDL-C and Apo A1 levels. LDL-C was not significantly affected by treatment with pemafibrate. The 0.2 mg/day pemafibrate group had significant reductions in homeostasis model assessment (HOMA)-insulin resistance scores compared with placebo, but no significant alterations vs. placebo were seen in fasting plasma glucose, fasting insulin, glycoalbumin or HbA1c. Rates of AEs and adverse drug reactions were similar between the two pemafibrate groups and the placebo group.

 Comment:

This is the first report of long-term (24 weeks) efficacy and safety of pemafibrate in subjects with type 2 diabetes and hypertriglyceridemia. In this study, which was conducted in Japan, pemafibrate lowered TG levels by ~45%, which was apparent within the first month of the treatment period and maintained over the entire treatment period. An ASCVD event trial with pemafibrate commenced enrollment in 2017, the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial, and is expected to complete in 2022 (https://clinicaltrials.gov/ct2/show/NCT03071692).

References:

  1. Araki E, Yamashita S, Arai H, et al. Effects of pemafibrate, a novel selective PPARalpha modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial. Diabetes Care. 2018;41(3):538-546.
  2. Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720-1732.
  3. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-234.
  4. Mulnier HE, Seaman HE, Raleigh VS, et al. Risk of myocardial infarction in men and women with type 2 diabetes in the UK: a cohort study using the General Practice Research Database. Diabetologia. 2008;51(9):1639-1645.
  5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685-696.
  6. Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117-125.
  7. Sone H, Tanaka S, Tanaka S, et al. Serum level of triglycerides is a potent risk factor comparable to LDL cholesterol for coronary heart disease in Japanese patients with type 2 diabetes: subanalysis of the Japan Diabetes Complications Study (JDCS). J Clin Endocrinol Metab. 2011;96(11):3448-3456.
  8. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316(7134):823-828.
  9. Maki KC, Guyton JR, Orringer CE, Hamilton-Craig I, Alexander DD, Davidson MH. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10(4):905-914.

10.       Ishibashi S, Yamashita S, Arai H, et al. Effects of K-877, a novel selective PPARalpha modulator (SPPARMalpha), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis. 2016;249:36-43.

female scientist

CVD-REAL Results Suggest that Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors are, Indeed, Real

CVD-REAL

CVD-REAL Results Suggest that Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors are, Indeed, Real

By Kevin C Maki, PhD

 Background

In 2015, the release of the Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial results generated significant surprise and controversy.1 The investigators randomly assigned 7,020 patients with type 2 diabetes mellitus (T2D) to receive 10 or 25 mg/d of empagliflozin or placebo.  Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that reduces renal reabsorption of glucose and sodium, thus increasing urinary losses and reducing the plasma glucose concentration.  The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in the pooled empagliflozin group compared with the placebo group.

The EMPA-REG OUTCOME results showed a 14% reduction (p = 0.04) in the primary outcome in the empagliflozin group.  Despite significant reductions in blood pressure, glycated hemoglobin and body weight, there were no differences between the groups in myocardial infarction or stroke.  However, there were substantial reductions (p ≤ 0.002) in death from cardiovascular causes (38%) and hospitalization for heart failure (35%).

More recently, the results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) program were released in which data were pooled from two placebo-controlled studies of another SGLT-2 inhibitor, canagliflozin, involving 10,142 patients with T2D at high cardiovascular risk.2  The outcome for the primary composite, which was the same as that in EMPA-REG OUTCOME, showed that canagliflozin treatment was associated with a significant 14% reduction, a result that was essentially identical to that in the EMPA-REG OUTCOME study overall.  However, there were some differences between the results for individual components of the composite.

 

Outcome EMPA-REG OUTCOME (empagliflozin) CANVAS

(canagliflozin)

Hazard Ratio (95% Confidence Interval)
Primary Composite 0.86 (0.74-0.99) 0.86 (0.75-0.97)
Death from Cardiovascular Causes 0.62 (0.49-0.77) 0.87 (0.72-1.06)
Non-fatal Myocardial Infarction 0.87 (0.70-1.09) 0.85 (0.69-1.05)
Non-fatal Stroke 1.24 (0.92-1.67) 0.90 (0.71-1.15)
Hospitalization for Heart Failure 0.65 (0.50-0.85) 0.67 (0.52-0.87)
Death from Any Cause 0.68 (0.57-0.82) 0.87 (0.74-1.01)

The notable differences are for death from cardiovascular causes (38% reduction vs. non-significant 13% reduction) and death from any cause (32% reduction vs. non-significant 13% reduction), for which the results with empagliflozin appeared more favorable, and non-fatal stroke (non-significant 24% increase vs. non-significant 10% reduction), for which the results appeared more favorable for canagliflozin. Or course, such differences could easily be due to random variation, so additional studies are needed with these and other agents in the SGLT-2 inhibitor class.  Large-scale randomized, controlled clinical trials are expensive and time consuming, so it is useful to look at results in the real world for patients prescribed these medications in clinical practice.  Results from such investigations need to be viewed with caution because they are more susceptible to various types of bias and confounding than results from randomized trials.  Nevertheless, they can be useful for evaluating risks and benefits of drug therapies and to further evaluate hypotheses generated from clinical trial data, such as whether there are differences in cardiovascular outcomes between agents in the SGLT-2 inhibitor class.

Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) Methods and Results3

Data were collected from medical claims in the US and several countries in the EU.  A propensity score was used to adjust for SGLT-2 inhibitor initiation.  Hazard ratios were calculated for hospitalization for heart failure, all-cause mortality, and incidence of either outcome among those taking SGLT-2 inhibitors compared with other glucose-lowering drugs (GLD).

Data were included for more than 300,000 patients, half of whom took an SGLT-2 inhibitor and half of whom took other GLDs.  Canagliflozin was the most commonly used SGLT-2 inhibitor (53% of exposure), followed by dapagliflozin (42% of exposure) and empagliflozin (5% of exposure).  Canagliflozin was the most commonly used SGLT-2 inhibitor in the US (76%), whereas dapagliflozin was the most commonly used in Europe (92%); 87% of subjects had no known cardiovascular disease at baseline.

Over 190,164 person-years of follow-up, hazard ratios for hospitalization for heart failure (0.61, 95% CI 0.51-0.73), death (0.49, 0.41-0.57) and either outcome (0.54, 0.48-0.60) were all significantly below the null, indicating that incidence rates for these outcomes were 39-51% lower for SGLT-2 inhibitors compared with other GLDs.  Sensitivity analyses were consistent with the main results, with no evidence of significant heterogeneity across type of SGLT-2 inhibitor or country.

Comment

The results of the CVD-REAL investigation support the hypothesis that use of the SGLT-2 inhibitor class reduces risks for heart failure and death in patients with T2D.  The mechanisms responsible for these benefits, which are generally confirmatory (significant reductions or trends) for those observed in the EMPA-REG OUTCOME and CANVAS trials, are not well understood.  The SGLT-2 inhibitor class does not differ markedly from other GLD classes regarding effects on glycemic control.  Additional research will be needed to elucidate mechanisms responsible, which may have implications for the application of this drug class to other high-risk groups who do not have T2D.

References:

  1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
  2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. 2017; Jun 12. [Epub ahead of print].
  3. Kosiborod M, Cavendar MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249-259.

 

 

 

FOURIER

MB Clinical Academy Releases its First Two Educational Programs

MB Clinical Academy

MB Clinical Academy Releases its First Two Educational Programs

MB Clinical Academy produces educational materials to help clinicians, clinical research professionals and students more effectively manage the cardiometabolic health of their patients/clients, and to understand the strengths and limitations of the available evidence, including gaps that can be filled with future studies.

We have just completed two new programs, which will be available for purchase and download during the week of July 10, 2017.

Short Course

Diet and Prevention of Type 2 Diabetes Mellitus:  Beyond Weight Loss and Exercise

This short course will review the evidence for dietary factors in the prevention of type 2 diabetes mellitus (T2D).  It contains three modules that will cover:

  • Module 1: Epidemiology and pathophysiology of T2D
  • Module 2: Predictors of T2D risk and effects of interventions on incidence
  • Module 3: Summary of the associations and mechanisms through which diet may affect T2D risk, with an emphasis on insulin sensitivity and glycemic load

Short Course

Interpreting Efficacy Results from Cardiovascular Outcomes Trials

Cardiovascular outcomes trials are integral to evidence-based medicine, and they are the most effective means for demonstrating that an intervention reduces major adverse cardiovascular events.  A sound understanding of the fundamentals of clinical study design and statistical methodology is essential for the interpretation of efficacy results from cardiovascular outcomes trials.  However, most clinicians have not had extensive training on how to interpret measures of association and statistical procedures used to assess the efficacy of interventions intended to reduce cardiovascular event risk.  This course will review of the following concepts and their use in cardiovascular outcomes studies:

  • Measures of cardiovascular event incidence
    1. Relative risk
    2. Hazard ratio
    3. Odds ratio
  • Comparing event rates and treatment effects
    1. Relative risk reduction
    2. Absolute risk reduction
    3. Number needed to treat (or harm)
  • Pitfalls when making comparisons between cardiovascular outcomes trials, including the three most important questions
    1. Who was studied (risk profile)?
    2. What outcomes were assessed?
    3. Over what time period?
  • Additional factors to consider in the interpretation of findings from cardiovascular outcomes trials
    1. Evaluating the roles of chance, bias and confounding
    2. Factors affecting validity and generalizability
    3. Assessing the potential for type I and type II statistical errors

We expect that those who purchase these programs will find them informative and practical.  If you have suggestions for future programs, don’t hesitate to send us an email:  info@mbclinicalresearch.com.

 

MB Clinical Academy

Mendelian Randomization – Nature’s Clinical Trial – is Providing New Insights About the Causes and Potential Treatments for Cardiometabolic Diseases

Mendelian Randomization

Mendelian Randomization – Nature’s Clinical Trial – is Providing New Insights About the Causes and Potential Treatments for Cardiometabolic Diseases

By Kevin C. Maki, PhD

In a recent issue of JAMA Cardiology, Lyall and colleagues1 report that a score based on 97 genetic variants related to body mass index (BMI) was associated with increased risks for hypertension [odds ratio (OR) per 1-SD higher genetically-driven BMI of 1.64, 95% confidence interval (CI) 1.48-1.83], type 2 diabetes mellitus (OR 2.53; 95% CI 2.04-3.13) and coronary heart disease (CHD; OR 1.35; 95% CI 1.09-1.69).  Notably, the genetic BMI score was not associated with stroke risk.

Because the genetic score provides a measure of exposure over a lifetime to genetic variants that increase BMI, it is a relatively unconfounded marker that is less likely to be influenced by reverse causality than BMI itself.  Genotypes are assigned randomly when passed from parents to offspring during meiosis.2 The population genotype distribution should therefore be unrelated to the distribution of confounding variables.2  Accordingly, Mendelian randomization can be thought of as experiments of nature, similar to what is accomplished through randomization in a clinical trial.  The new results from Lyall et al.1 add evidence to support a causal relationship between increased BMI and cardiometabolic diseases.

Results reported in another recent paper by Dale and colleagues3 using Mendelian randomization also suggest causal roles for abdominal (waist-hip ratio adjusted for BMI; WHRadjBMI) and total adiposity (BMI) regarding risks for CHD and type 2 diabetes mellitus.  Each 1-SD higher WHRadjBMI (about 0.08 U) was associated with an excess risk of CHD (OR 1.48; 95% CI 1.28-1.71), similar to findings for BMI (SD about 4.6 kg/m2; OR 1.36; 95% CI, 1.22-1.52). WHRadjBMI, but not BMI, was associated with higher risk of ischemic stroke (OR 1.32; 95% CI, 1.03-1.70).  For type 2 diabetes mellitus, both variables had significant associations: OR 1.82 (95% CI 1.38-2.42) per 1-SD higher WHRadjBMI and OR 1.98 (95% CI 1.41-2.78) per 1-SD higher BMI.  These results are consistent with those reported by Lyall et al.1

Prior studies using Mendelian randomization have provided evidence for and against causality for several potentially modifiable risk factors for cardiometabolic diseases.  Evidence for causality has been provided for various lipoprotein-related variables and risks for atherosclerotic cardiovascular disease, including:4

  • Low-density lipoprotein cholesterol;
  • Triglycerides and triglyceride-rich lipoprotein cholesterol;
  • Lipoprotein (a).

Evidence against direct causality has been produced through Mendelian randomization for:4

  • High-density lipoprotein cholesterol;
  • C-reactive protein.

However, it should be noted that for high-density lipoprotein cholesterol and C-reactive protein, lack of association should not be interpreted to mean that these are not important risk indicators, only that the levels of these variables likely reflect other processes that are more directly involved in causal pathways.

The real promise of Mendelian randomization is to identify novel, modifiable targets for which new therapies can be developed.  This process was nicely illustrated by the identification of proprotein convertase subtilisin kexin type 9 (PCSK9) variants as predictors of CHD risk5, which ultimately led to the development of a new class of pharmaceuticals, the PCSK9 inhibitors.6

References:

  1. Lyall DM, Celis-Morales C, Ward J, et al. Association of body mass index with cardiometabolic disease in the UK Biobank: a Mendelian randomization study. JAMA Cardiol. July 5, 2017 [Epub ahead of print].
  2. Thanassoulis G, O’Donnell CJ. Mendelian randomization: nature’s randomized trial in the post-genome era. JAMA. 2009;301:2386-2387.
  3. Dale CE, Fatemifar G, Palmer TM, et al. Causal associations of adiposity and body fat distribution with coronary heart disease, stroke subtypes, and type 2 diabetes mellitus: a Mendelian randomization study. Circulation. 2017;135:2373-2388.
  4. Lacey B, Herrington WH, Preiss D, Lewington S, Armitage J. The role of emerging risk factors in cardiovascular outcomes. Curr Atheroscler Rep. 2017;19:28.
  5. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-1272.
  6. Durairaj A, Sabates A, Nieves J, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and its inhibitors: a review of physiology, biology, and clinical data. Curr Treat Options Cardio Med. 2017;19:58.
Mendelian Randomization