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)


 (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.



  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.


Photo by Tbel Abuseridze

Meta-regression Characterizes the Relationships Between Changes in Dietary Cholesterol Intake and Plasma Low-density and High-density Lipoprotein Cholesterol Changes

Meta-regression Characterizes the Relationships Between Changes in Dietary Cholesterol Intake and Plasma Low-density and High-density Lipoprotein Cholesterol Changes

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


Our group recently collaborated with scientists from the University of Cincinnati to conduct meta-regression analyses that investigated the dose-response relationships between changes in dietary cholesterol intake and changes in lipoprotein-cholesterol levels.  The results from these analyses were presented in June at the American Society for Nutrition’s annual Nutrition 2018 meetings,1,2 and have also recently been accepted for publication in the American Journal of Clinical Nutrition.This summary is also available in the Fall 2018 Newsletter of MB Clinical Research.


Elevated low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor, and there is a strong inverse association between high-density lipoprotein cholesterol (HDL-C) concentration and cardiovascular risk.4  Dietary guidance generally recommends reducing intakes of saturated fatty acids (SFA) and trans fatty acids (TFA) to reduce LDL-C levels, but in recent years there has been a step back from making specific quantitative recommendations with regard to limiting dietary cholesterol intake.5,6  A key recommendation from the 2010 Dietary Guidelines was to limit consumption of dietary cholesterol to <300 mg/day, but this was not included in the 2015-2020 Dietary Guidelines, although they did explain that “this change does not suggest that dietary cholesterol is no longer important to consider when building healthy eating patterns.”6  The 2015 guidelines stated “Strong evidence from mostly prospective cohort studies but also randomized controlled trials has shown that eating patterns that include lower intake of dietary cholesterol are associated with reduced risk of CVD…”.6  However, the committee concluded that “More research is needed regarding the dose-response relationship between dietary cholesterol and blood cholesterol levels.  Adequate evidence is not available for a quantitative limit for dietary cholesterol specific to the Dietary Guidelines.” 6  The 2013 American Heart Association/American College of Cardiology Lifestyle Management Guideline also concluded “There is insufficient evidence to determine whether lowering dietary cholesterol reduces LDL-C.”5  One problem with the available evidence is that there are limited data examining how much of an impact on lipoprotein lipid levels is attributable to dietary cholesterol after controlling for intakes of dietary fatty acids (i.e., SFA, TFA, polyunsaturated fatty acids [PUFA] and monounsaturated fatty acids [MUFA]).


Therefore, the goal of these meta-regression analyses was to examine the impacts of changes in dietary cholesterol on lipoprotein cholesterol levels, after accounting for dietary fatty acids.1,2  This meta-regression examined results from 55 randomized controlled dietary intervention trials (n = 2652 subjects) using a Bayesian approach (with Markov chain Monte Carlo techniques) and adjustment for dietary fatty acids to determine the best fitting mathematical models to the data.7  No significant associations were observed between change in dietary cholesterol intake and change in triglyceride or very low density lipoprotein cholesterol level.


For LDL-C, the meta-regression results indicated a positive correlation using a linear model and two non-linear models (Michaelis-Menten and Hill models), even after accounting for intakes of SFA, PUFA, MUFA and, where possible, TFA.  The relationship was best characterized by the non-linear models across the full range of cholesterol changes (0-1500 mg/day).  A 100 mg/day dietary cholesterol change was predicted to be associated with an increase in LDL-C of ~ 4.5 mg/dL in LDL-C.  Baseline cholesterol intake was not a significant predictor of the LDL-C response to a change in dietary cholesterol.  The relationship between baseline LDL-C and LDL-C response was unclear, and needs further exploration.  For HDL-C, the meta-regression analyses did not indicate a clear relationship between the change in dietary cholesterol intake and the change in HDL-C levels when both men and women were included.  However, when analyzed according to sex, the linear model and the Michaelis-Menten non-linear model demonstrated an inverse relationship in men, and a positive relationship in women.  This suggests a possible interaction between sex and HDL-C response to dietary cholesterol.


Using the Mensink et al. equation, which is designed to calculate the effects of changes in carbohydrate and fatty acid intakes on serum lipid and lipoprotein levels, each 1% increase in SFA in exchange for carbohydrate is predicted to increase LDL-C by 1.23 mg/dL.8  These findings suggest that increasing dietary cholesterol by 100 mg/day or 200 mg/day would have effects comparable to increasing dietary SFA by 3.7% and 5.5%, respectively.


These results suggest that there is a clinically meaningful effect of dietary cholesterol on LDL-C concentration.  This finding from a pooled analysis of results from 55 studies aligns with those from the best-controlled individual studies, such as two published by Ginsberg et al.9,10  This dose-response analysis provides reference for clinicians and nutrition scientists on how changes in dietary cholesterol intake may impact plasma cholesterol levels, although considerable interindividual variability should be expected.9-11  The clinical implications of changes in HDL-C associated with increased dietary cholesterol intake remain uncertain.



  1. Vincent MJ, Allen B, Maki KC, Palacios OM, Haber LT. Non-linear models best characterize the relationship between dietary cholesterol intake and circulating low-density lipoprotein cholesterol levels. Presented at American Society of Nutrition’s Nutrition 2018 meetings, June 9-12, 2018, Boston MA.
  2. Palacios OM, Vincent MJ, Allen B, Haber LT, Maki KC. The effect of dietary cholesterol on high-density lipoprotein cholesterol levels in men and women: a meta-analysis of randomized controlled trials. Presented at American Society of Nutrition’s Nutrition 2018 meetings, June 9-12, 2018, Boston MA.
  3. Vincent MJ, Allen B, Palacios OM, Haber LT, Maki KC. Meta-regression analysis of the effects of dietary cholesterol intake on low- and high-density lipoprotein cholesterol. Am J Clin Nutr. 2018; In Press.
  4. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, Wilson DP, Brown WV. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8:473-488.
  5. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC Jr., Svetkey LP, Wadden TA, Yanovski SZ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle managemnet to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2960-2984.
  6. U.S. Department of Health and Human Services and U.S Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th edition. December 2015. Available at
  7. The Stan Development Team. RStan: the R interface to Stan. R package version 2.16.2. 2017. Available at
  8. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77:1146-1155.
  9. Ginsberg HN, Karmally W, Siddiqui M, Holleran S, Tall AR, Rumsey SC, Deckelbaum RJ, Blaner WS, Ramakrishnan R. A dose-response study of the effects of dietary cholesterol on fasting and postprandial lipid and lipoprotein metabolism in healthy young men. Arterioscler Thromb. 1994;14:576-586.
  10. Ginsberg HN, Karmally W, Siddiqui M, Holleran S, Tall AR, Blaner WS, Ramakrishnan R. Increases in dietary cholesterol are associated with modest increases in both LDL and HDL cholesterol in healthy young women. Arterioscler Thromb Vasc Biol. 1995;15:169- 178.
  11. Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, La Forge R, Daniels SR, Wilson DP, Morris PB, Wild RA, Grundy SM, Daviglus M, Ferdinand KC, Vijayaraghavan K, Deedwania PC, Aberg JA, Liao KP, McKenney JM, Ross JL, Braun LT, Ito MK, Bays HE, Brown WV, Underberg JA, NLA Expert Panel. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2. J Clin Lipidol. 2015;9(6 Suppl):S1-S122.
Photo by Kelly Sikkema

Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Steve Freed, RPh, CDE from Diabetes in Control conducted a terrific interview with Ralph DeFronzo, MD, who is an endocrinologist and Deputy Director of the Texas Diabetes Institute.  Dr. DeFronzo has been a pioneer in conducting studies to elucidate the pathophysiology of type 2 diabetes mellitus, and in the evaluation of treatment strategies that address the underlying defects.  Dr. DeFronzo recently surpassed 750 publications and it is difficult to overstate his influence on the field of diabetology.  The full interview on video and a transcript may be obtained at and

Below is a summary of Dr. DeFronzo’s key points.

  1. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two subtypes of prediabetes with different pathophysiologies:
    • IFG is characterized by hepatic insulin resistance and impaired first-phase insulin secretion;
    • IGT is characterized by skeletal muscle insulin resistance and impairment of second-phase insulin secretion.
  2. Progressive loss of pancreatic beta-cell function is the hallmark of progression from prediabetes to type 2 diabetes mellitus (T2D), and then to more severe T2D. Impairment of beta-cell response is due to a combination of dysfunction (hibernation) and loss of beta-cell mass.  This process can be arrested or slowed by drug therapies that have direct or indirect effects.
    • Direct effects – thiazolidinediones and GLP-1 agonists appear to have direct effects on the pancreas that help to preserve beta-cell mass, in part through reducing apoptosis.
    • Indirect effects – other drugs that lower glucose will reduce glucose toxicity, which, in turn, will improve beta-cell function and insulin sensitivity. DeFronzo believes that sulfonylureas should rarely be used and favors metformin and SGLT-2 inhibitors over other classes of glucose-lowering drugs.
  3. Recently published data support effects of three classes of hypoglycemic agents to reduce cardiovascular risk.
    • Pioglitazone (a thiazolidinedione) – the IRIS trial
    • SGLT-2 inhibitors – EMPA-REG Outcome and CANVAS
    • GLP-1 agonists – SUSTAIN-6 and LEADER
  4. DeFronzo advocates triple-therapy from early in the disease process (which can be costly) to address the underlying insulin resistance and arrest the progression of beta-cell impairment. This involves use of:
    • Pioglitazone (a thiazolidinedione),
    • A GLP-1 agonist,
    • Metformin or an SGLT-2 inhibitor.

Abbreviations:  CANVAS, Canagliflozin Cardiovascular Assessment Study; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; GLP-1, glucagon-like peptide-1; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IRIS, Insulin Resistance Intervention after Stroke; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SGLT-2, sodium-glucose cotransporter-2; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; T2D, type 2 diabetes mellitus.

Relevant references

Abdul-Ghani M, Migahid O, Megahed A, Adams J, Triplitt C, DeFronzo RA, Zirie M, Jayyousi A. Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: The QATAR Study. Diabetes Care. 2017;40:325-331. Erratum: 2017 June 14 [Epub ahead of print].

DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.

Kaul S. Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: A review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials. Diabetes Care. 2017;40:821-831.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 June 12 [Epub ahead of print].


Dr. Ralph Defronzo Interview