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CME

Cardiovascular Outcomes With Antihyperglycemic Therapy: Past, Present, and Future Impact on Practice

  • Authors: Carol H. Wysham, MD; John E. Anderson, MD; Lawrence Blonde, MD; Serge A. Jabbour, MD
  • CME Released: 6/23/2016
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 6/23/2017
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Target Audience and Goal Statement

This activity is intended for diabetologists & endocrinologists, primary care physicians, and cardiologists.

The goal of this activity is to provide participants with an understanding of the importance of improving cardiovascular (CV) outcomes in diabetes management, and how recently reported CV outcomes data related to type 2 diabetes (T2D) therapies impact current and future clinical practice.

Upon completion of this activity, participants will be able to:

  1. Identify the link between diabetes, CVD, and risk
  2. Recognize the rationale for CV outcomes trials in patients with T2D
  3. Compare CV outcomes clinical data among older and modern classes of antihyperglycemic agents
  4. Assess effect of CV outcomes data on modern T2D practice


Disclosures

As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Moderator

  • Carol H. Wysham, MD

    Clinical Associate Professor of Medicine, University of Washington, Spokane, Washington

    Disclosures

    Disclosure: Carol H. Wysham, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Lilly; Janssen Pharmaceuticals, Inc.; Sanofi
    Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Lilly; Janssen Pharmaceuticals, Inc.; Novo Nordisk; Sanofi

    Dr Wysham does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Wysham does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Panelists

  • John E. Anderson, MD

    Internist, The Frist Clinic, Nashville, Tennessee

    Disclosures

    Disclosure: John E. Anderson, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Global Services LLC; Lilly; Sanofi
    Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Global Services LLC; Lilly; Pamlab, L.L.C.; Sanofi

    Dr Anderson does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Anderson does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Lawrence Blonde, MD

    Director, Ochsner Diabetes Clinical Research Unit, Department of Endocrinology, Diabetes and Metabolism, Associate Internal Medicine Residency Program Director, New Orleans, Louisiana

    Disclosures

    Disclosure: Lawrence Blonde, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; GlaxoSmithKline; Intarcia Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk; Sanofi
    Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals, Inc.; Merck & Co.; Novo Nordisk, Sanofi (Click here to enter...)
    Received grants for clinical research from: AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals, Inc.; Lexicon Pharmaceuticals, Inc.; Novo Nordisk; Merck & Co.; Sanofi

    Dr Blonde does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Blonde does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Serge Jabbour, MD

    Professor of Medicine; Director, Division of Endocrinology, Diabetes & Metabolic Diseases, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania

    Disclosures

    Disclosure: Serge A. Jabbour, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Lilly
    Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Lilly

    Dr Jabbour does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Jabbour does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Scientific Director

  • Anne G. Le, PharmD, RPh

    Senior Scientific Director, Medscape, LLC

    Disclosures

    Disclosure: Anne G. Le, PharmD, RPh, has disclosed no relevant financial relationships.

Editor

  • Eleanor Swift Yasgur, MA, LSW

    Teaneck, NJ

    Disclosures

    Disclosure: Eleanor Swift Yasgur, MA, LSW, has disclosed no relevant financial relationships.

CME Reviewer

  • Robert Morris, PharmD

    Associate CME Clinical Director, Medscape, LLC

    Disclosures

    Disclosure: Robert Morris, PharmD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Novo Nordisk; Sanofi
Served as a speaker or a member of a speakers bureau for: Merck; Novo Nordisk; Sanofi


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    Medscape, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Medscape, LLC staff have disclosed that they have no relevant financial relationships.

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CME

Cardiovascular Outcomes With Antihyperglycemic Therapy: Past, Present, and Future Impact on Practice

Authors: Carol H. Wysham, MD; John E. Anderson, MD; Lawrence Blonde, MD; Serge A. Jabbour, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME Released: 6/23/2016

Valid for credit through: 6/23/2017

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Editor's Note:

On June 13, 2016, during the American Diabetes Association 2016 Scientific Sessions, full results from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results -- A Long Term Evaluation (LEADER) trial was presented and published online in the New England Journal of Medicine by Steven Marso, MD, and colleagues. The degree of risk reduction for the 3-point major adverse cardiac event (MACE) components (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was 13% (occurring in 608 of 4668 patients taking liraglutide) vs 14.9% (in 694 of 4672 taking placebo) (P = .01 for superiority), including a 22% lower rate of cardiovascular death (4.7 vs 6.0%, P = .007) in adults with type 2 diabetes.

In addition, on June 14, 2016, microvascular outcomes data from the EMPA-REG OUTCOME trial of empagliflozin were presented and published online in the New England Journal of Medicine by Christoph Wanner, MD, and colleagues. Treatment with empagliflozin in this population of adults with type 2 diabetes and established cardiovascular disease led to a significant 38% relative risk reduction for the composite microvascular endpoint, which included time to first initiation of laser therapy for retinopathy, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy (hazard ratio [HR] = 0.62, 95% CI: 0.54, 0.70; P < .001) compared with placebo. Similar to the results for cardiovascular outcomes published in the New England Journal of Medicine in September 2015, the curves began to separate within approximately 3 months, with the benefit sustained throughout the trial. Empagliflozin also led to a significant 39% reduction in incident or worsening nephropathy (HR = 0.61; 95% CI: 0.53, 0.70; P < .001). Additional subanalyses presented during the Scientific Sessions suggest that empagliflozin reduced cardiovascular events regardless of age when starting treatment.

  • Cardiovascular Outcomes With Antihyperglycemic Therapy: Past, Present, and Future Impact on Practice

  • Slide 1.

    Slide 1.

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  • CV Outcomes in Type 2 Diabetes: Why Do We Care?

  • Slide 4.

    Slide 4.

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  • Complications of Diabetes[1-8]

    • Chronic complications lead to disability and death
    • Traditional microvascular complications are affected by glycemic control and illness duration
    • Death of patient with diabetes is commonly attributable to cardiovascular (CV) complications -- ie, stroke, cardiovascular disease (CVD)
    • Heart failure (HF) outcomes might be impacted by treatment

  • Slide 5.

    Slide 5.

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  • Diabetes Increases the Risk of a CV Event[9]

    • Patients with diabetes have a 2-fold higher rate of traditional coronary heart disease complications -- ie, death, heart attack, any form of stroke

  • Slide 6.

    Slide 6.

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  • Patients With Diabetes Presenting With ACS Have Poor Prognosis[10]

    • Patients with diabetes have an approximately 50% increase in rate of death from any cause after having an acute coronary syndrome (ACS)
    • The rate of cardiovascular death is increased by over 50%
    • The event rate for congestive heart failure (CHF) is higher than that for any other complications after ACS in patients with diabetes

  • Slide 7.

    Slide 7.

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  • CVD Drives Healthcare Costs in Patients With Diabetes[11]

    • Large database in a managed care organization analyzed to examine healthcare costs associated with the management of comorbidities in patients with diabetes
    • Patients with diabetes have dramatically higher healthcare costs associated with complications
    • The cost of pharmaceutical agents pales in comparison to the cost of medical complications

  • Slide 8.

    Slide 8.

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  • UKPDS: HbA1c and Rates for MI and Microvascular Complications[12]

    • In the UKPDS, for every 1% reduction in glycated hemoglobin (HbA1c), there was an approximate 14% reduction in risk of CV endpoints
    • In long-term CV trials, no impact of tight glycemic control on CV outcomes has been observed, especially in the randomized, controlled component of studies

  • Slide 9.

    Slide 9.

    (Enlarge Slide)
  • Impact of Intensive Therapy in Diabetes in Major Clinical Trials[13]

    • The impact of intensive therapy on cardiovascular outcomes has been examined in a number of open-label observational studies
    • Patients in these trials had 10 to 20 years of follow-up
    • Reductions in rates of myocardial infarction (MI) were seen in the DCCT and UKPDS trials
    • Reductions in rates of MI were not seen in the ACCORD or ADVANCE trials
    • In recent long-term follow-up of the VADT study, intensive control of HbA1c led to significant reduction in MI rates

  • Slide 10.

    Slide 10.

    (Enlarge Slide)
  • VADT: Intensive Therapy Group: Relationship of Diabetes Duration and HR for CVD Events[14]

    • In the VADT study, a clear association between risk of MI and tight control of HbA1c was observed
    • Patients with diabetes duration <15 years experienced a reduction in risk of CVD

  • Slide 11.

    Slide 11.

    (Enlarge Slide)
  • RACED Substudy of VADT: Effect of Glycemic Control on CVD Events by Baseline CAC Score[15]

    • The RACED substudy of VADT reflects results of the end of the randomized trial
    • The substudy used coronary artery calcium (CAC) measured by computed tomography (CT), which correlated with atherogenic burden in coronary arteries
    • Patients with CAC <100 had substantially fewer events than patients with scores >100

  • Slide 12.

    Slide 12.

    (Enlarge Slide)
  • Atherosclerosis Timeline[16]

    • Endothelial dysfunction has the greatest impact on the development of atherosclerosis before atherogenesis occurs
    • The UKPDS study enrolled patients before they had developed atherosclerosis
    • The ACCORD, VADT, and ADVANCE studies started when patients already had significant fibrous plaque; glycemic control will not have much impact at that point
    • Early intervention can make a different over a decade or more of life
    • In later intervention, reducing risk by reducing HbA1c is less important than considering other atherogenic risk factors

  • Slide 13.

    Slide 13.

    (Enlarge Slide)
  • Mechanisms by Which Diabetes Leads to CHD[17]

    • Hypertension can lead to coronary heart disease (CHD)
    • Infection can lead to increased inflammation
    • The impact of hyperglycemia on advanced glycosylated end products and oxidative stress leads to atherosclerosis
    • Increased inflammation, insulin resistance, hypertension, endothelial dysfunction, dyslipidemia, and prothrombotic state are related to visceral adiposity
    • Atherosclerosis is subclinical until symptoms/and or an event occur

  • Slide 14.

    Slide 14.

    (Enlarge Slide)
  • Overview of CV Outcome Studies With Antidiabetic Agents[18]

  • Slide 15.

    Slide 15.

    (Enlarge Slide)
  • Evolution of the FDA CV Safety Requirements and CV Safety Concerns[19-22]

    • Development of muraglitazar, a dual-α/γ agonist, was discontinued because of an increased risk of death, major CV events, CHF, and renal insufficiency in studies
    • In 2007, a meta-analysis of studies of rosiglitazone suggested an increased CV risk
      • Withdrawn from major markets
      • Prescription restrictions in United States

  • Slide 16.

    Slide 16.

    (Enlarge Slide)
  • FDA Postmarketing CVOT Requirements[23]

    • Companies marketing antidiabetic agents must provide data showing no increased CV risk
    • Postmarketing CV outcome trials with a placebo comparator are required for agents with a hazard ratio (HR) between 1.3 and 1.8
    • Agents with an HR >1.8 are not approvable

  • Slide 17.

    Slide 17.

    (Enlarge Slide)
  • The Rate of Dying From CVD Has Dropped Dramatically in Diabetes[24]

    • A dramatic reduction in the risk of dying from CVD events occurred between 1998 and 2004
    • This risk has fallen from a 2.4-fold higher risk in 1998 to a 2.0-fold higher risk in 2004

  • Slide 18.

    Slide 18.

    (Enlarge Slide)
  • Number (in Millions) of Persons With Diabetes Aged ≥35 With Self-Reported Heart Disease or Stroke[25]

    • The increased number of patients with diabetes who report CVD or stroke over the last decade is due to the increased number of patients with diabetes

  • Slide 19.

    Slide 19.

    (Enlarge Slide)
  • Metabolic Components of Diabetes: ADA Treatment Recommendations [12,26-28]

    • Multifactorial treatment of CV risk factors, especially cholesterol, is important

  • Slide 20.

    Slide 20.

    (Enlarge Slide)
  • Examining the Data Across T2D Treatment: Older Agents

  • Slide 22.

    Slide 22.

    (Enlarge Slide)
  • UKPDS Study: Fatal or Nonfatal MI, Sudden Death[27,29]

    • In the UKPDS study, intensive blood glucose lowering just missed statistical significance in lowering risk for nonfatal MI or sudden death
    • Only 342 overweight individuals in the metformin group had statistically significant reductions in adverse events

  • Slide 23.

    Slide 23.

    (Enlarge Slide)
  • UKPDS Study: Metformin[29]

    • In the UKPDS study, metformin showed more beneficial effect than sulfonylureas or insulin for
      • Any diabetes endpoint
      • All-cause mortality
      • Stroke
    • A UKPDS substudy of sulfonylurea monotherapy vs sulfonylurea + metformin showed an increased risk of diabetes-related death in the sulfonylurea + metformin group, probably a statistical fluke
    • Metformin may be first-line pharmacotherapy for patients who are overweight and have diabetes

  • Slide 24.

    Slide 24.

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  • 10-Year Follow-Up of UKPDS: Mean HbA1c and Body Weight[30]

    • Patients were followed observationally
    • In the intervention group, HbA1c was hard to sustain in usual care
    • Conventional group saw reduction in HbA1c
    • For most of the 10-year follow-up, HbA1c and weight were similar in the metformin and sulfonylurea-insulin groups

  • Slide 25.

    Slide 25.

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  • 10-Year Follow-Up of UKPDS: HR for Prespecified Aggregate Clinical Outcomes[30]

    • For any diabetes endpoint in the 10-year follow-up of the UKPDS study
      • Both intensive treatment groups did better
      • Benefits were statistically significant in both groups after study
    • For MI
      • The sulfonylurea-insulin group missed statistical significance for HR
      • Benefits were statistically significant in metformin group

  • Slide 26.

    Slide 26.

    (Enlarge Slide)
  • 10-Year Follow-Up of UKPDS: HR for Prespecified Aggregate Clinical Outcomes (cont)[30]

    • Reductions in microvascular disease through the follow-up period
      • Remained statistically significant in the sulfonylurea-insulin group
      • Were not statistically significant in the metformin group, probably a function of small numbers in that study
    • Reductions in death from any cause
      • Were statistically significant in the sulfonylurea-insulin group
      • Remained statistically significant in the metformin group

  • Slide 27.

    Slide 27.

    (Enlarge Slide)
  • UKPDS: Effect of Earlier Glucose Control[27,30]

    • Any diabetes-related endpoint, microvascular disease, MI, and all-cause mortality all improved in the intensive treatment group
    • Through most of follow-up period, the intensive treatment group had similar HbA1c levels as the conventional group
    • "Legacy effect" of early better control was carried long-term

  • Slide 28.

    Slide 28.

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  • Metformin Use Among Patients With T2D and Atherothrombosis[31]

    • Patients were followed for 2 years to assess the effects of metformin use on mortality
    • All-cause mortality was 25% lower among patients who used metformin
    • Metformin may decrease mortality when used as secondary prevention

  • Slide 29.

    Slide 29.

    (Enlarge Slide)
  • Comparative Effectiveness of Sulfonylurea or Metformin Monotherapy on CV Events in T2D[32]

    • The effects of sulfonylureas and metformin on CV outcomes in patients with T2D were examined in a study of data from linked VA and Medicare databases
    • The metformin group had a lower incidence of CV events than the sulfonylurea group

  • Slide 30.

    Slide 30.

    (Enlarge Slide)
  • Sulfonylureas and CV Risk[33]

    • The CV safety of sulfonylureas was examined in a meta-analysis
    • The incidence of major adverse cardiovascular events (MACE, 29 trials) was equivalent in the sulfonylurea and comparator groups
    • CV mortality (37 trials) was higher for sulfonylureas vs comparators

  • Slide 31.

    Slide 31.

    (Enlarge Slide)
  • Metformin + Sulfonylurea Combination Therapy Is Associated With Increased Mortality Risks[34]

    • A meta-analysis of 9 trials was conducted
    • Metformin plus sulfonylurea increased the relative risk of a composite endpoint of
      • CV hospitalization/mortality
      • Fatal/nonfatal events
    • Effect was irrespective of reference group (diet, metformin, or sulfonylurea monotherapy)
    • Meta-analyses and database analyses are lower level of evidence than prospective randomized controlled trials (RCTs)

  • Slide 32.

    Slide 32.

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  • Ongoing CAROLINA® Trial[35]

    • The ongoing CAROLINA® trial is examining linagliptin (a dipeptidyl-peptidase-4 [DPP-4] inhibitor) vs a sulfonylurea
    • More than 6000 patients have been enrolled
    • Results are expected in September 2018

  • Slide 33.

    Slide 33.

    (Enlarge Slide)
  • PROspective Actos Clinical Trial in Macrovascular Events Study Design[36]

  • Slide 34.

    Slide 34.

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  • PROactive Primary Endpoint[36]

    • A 10% nonsignificant reduction in the primary endpoint was seen with pioglitazone
    • HbA1c was lower in the pioglitazone group

  • Slide 35.

    Slide 35.

    (Enlarge Slide)
  • PROactive Prioritized Secondary Endpoint: Composite of All-Cause Mortality, Nonfatal MI, and Stroke[36]

    • A 16% reduction in the secondary endpoint was statistically significant

  • Slide 36.

    Slide 36.

    (Enlarge Slide)
  • PROactive: Pioglitazone (Pio) Reduces "Hard" Coronary Heart Disease Endpoints[37]

    • In a post hoc analysis of data from PROactive on patients with previous MI, the effects of pioglitazone on recurrent MI were examined
    • Occurrence of fatal or nonfatal MI (excluding silent MI) was reduced by 28% with pioglitazone
    • Occurrence of ACS was reduced by 37%

  • Slide 37.

    Slide 37.

    (Enlarge Slide)
  • PROactive: Time to Fatal/Nonfatal Stroke in Patients With Previous Stroke[38]

    • In a post hoc analysis, a 47% reduction in time to fatal/nonfatal stroke was seen among patients in the pioglitazone group with previous stroke
    • No difference was observed among patients without a previous stroke

  • Slide 38.

    Slide 38.

    (Enlarge Slide)
  • PROactive: HF Hospitalization and Mortality[36]

    • The significant increase in risk of hospitalization for HF seen in the PROactive study is sometimes seen with thiazolidinediones (TZDs)
    • No statistically significant increase in risk of fatal HF was observed

  • Slide 40.

    Slide 40.

    (Enlarge Slide)
  • Rosiglitazone Evaluated for CV Outcomes in Oral Agent Combination Therapy for T2D (RECORD): Time to CV Death or CV Hospitalization[39]

    • No increase in CV death or CV hospitalization was observed in the RECORD study

  • Slide 42.

    Slide 42.

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  • RECORD: Deaths and Hospitalization From CV Causes[39]

    • The randomized RECORD study provides a stronger level of evidence than the 2007 meta-analysis
    • No statistically significant increase was found in the relative risk for CV death, all-cause death, MI, or stroke between the rosiglitazone and active control groups
    • An increased risk of HF was observed in the rosiglitazone group

  • Slide 43.

    Slide 43.

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  • BARI 2D: Rosiglitazone and Mortality and CV Endpoints[40]

    • A reduction in the risk of stroke with rosiglitazone treatment was seen in the BARI 2D study

  • Slide 44.

    Slide 44.

    (Enlarge Slide)
  • IRIS Trial: Post-Stroke EFS of Pio in Patients With Insulin Resistance[41]

    • The IRIS trial enrolled patients who had prior stroke and insulin resistance but no diabetes
    • Pioglitazone reduced stroke or MI by 24% vs placebo
    • A reduction in patients progressing from insulin resistance to actual T2D was observed

  • Slide 45.

    Slide 45.

    (Enlarge Slide)
  • STOP-NIDDM Trial: Acarbose Prevents T2D and CV Events in Patients With Impaired Glucose Tolerance[42]

    • α-glucosidase inhibitors are not commonly used in the United States
    • In the STOP-NIDDM study, a 50% reduction in CV events was observed in patients receiving acarbose
    • Postprandial hyperglycemic was not measured, only presumed
    • Methodological issues in this study include a potential statistical fluke

  • Slide 46.

    Slide 46.

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  • Acarbose CV Evaluation

    • Examining whether acarbose reduces future events and/or progression of diabetes in patients with impaired glucose tolerance who have already had CV events
    • Trial is nearing conclusion

  • Slide 47.

    Slide 47.

    (Enlarge Slide)
  • The ORIGIN Trial

    • Insulin was the first antihyperglycemic agent

  • Slide 48.

    Slide 48.

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  • ORIGIN: MI, Stroke, or Death From CV Causes[43]

    • No difference in CV outcomes was found between standard care and insulin glargine treatment
    • The ORIGIN trial met the FDA safety standard, although it was not part of the CV outcomes trials

  • Slide 50.

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  • ORIGIN: HbA1c and Other Outcomes[43]

    • Early initiation of treatment resulted in low HbA1c at end of 7 years in both groups
    • The insulin group had more severe cases of hypoglycemia, but the number of events was low
    • Weight gain with insulin was statistically significant but not huge

  • Slide 51.

    Slide 51.

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  • ORIGIN: Cancer and New T2D[43]

    • No increased risk of cancer was seen in the ORIGIN study

  • Slide 52.

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  • Ochsner Medical Center New Orleans, LA

  • Slide 55.

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  • Examining the Data Across T2D Treatment: Modern Agents

  • Slide 56.

    Slide 56.

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  • DPP-4-I: Alogliptin, Linagliptin, Saxagliptin, Sitagliptin[44]

    • Food is absorbed from the intestine
    • Glucagon-like peptide-1 (GLP-1) stimulates insulin secretions and suppresses glucagon secretion
    • Hypogluconemia is a significant component of T2D
    • Blocking GLP-1 leads to a 2-fold increase in native GLP-1 in the blood stream

  • Slide 57.

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  • SAVOR, EXAMINE, and TECOS: Key Results

    • In the SAVOR study (saxagliptin vs placebo), a surprisingly higher incidence of hospitalization for HF was seen in the saxagliptin group[45]
    • The EXAMINE study (alogliptin vs placebo) had a short median follow-up[46]
    • In the TECOS study (sitagliptin vs placebo), no signal for HF was observed[48]

  • Slide 60.

    Slide 60.

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  • SAVOR-TIMI: Risk of HHF With Saxagliptin vs Placebo[49]

    • People with an estimated glomerular filtration rate (eGFR) ≤60 had higher risk of hospitalization for HF (HHF)
    • People with a history of HF had a higher risk of HHF

  • Slide 61.

    Slide 61.

    (Enlarge Slide)
  • FDA Drug Safety Communication DPP-4-I, April 5, 2016[51]

  • Slide 63.

    Slide 63.

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  • SGLT2 Inhibitors: Canagliflozin, Dapaglifozin, Empagliflozin [53-55]

    • Glucose is reabsorbed in the proximal convoluted tubule of the kidney after filtration
    • Leveraging this mechanism leads to glycosuria
      • Reduction in plasma glucose
      • Reduction in HbA1c
      • Osmotic diuresis
      • Caloric loss
      • Weight reduction

  • Slide 65.

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  • EMPA-REG: Study Design[56]

    • Patients were randomized 2:1 to empagliflozin or placebo

  • Slide 67.

    Slide 67.

    (Enlarge Slide)
  • EMPA-REG: Baseline Characteristics -- T2D[56]

    • Patients were at high risk for CV events

  • Slide 68.

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    (Enlarge Slide)
  • EMPA-REG: Primary Outcome 3-Point MACE[56]

    • First time an antihyperglycemic agent demonstrated reduction in CV risk

  • Slide 70.

    Slide 70.

    (Enlarge Slide)
  • EMPA-REG: CV Death, MI, and Stroke[56]

    • The HR for the primary outcome of death from CV causes, nonfatal MI, or nonfatal stroke was 0.86, and was highly statistically significant
    • Rates of nonfatal MI did not significantly differ between groups
    • Rates of nonfatal stroke favored placebo, but the difference was not statistically significant

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  • EMPA-REG: Hospitalization for HF[56]

    • A 35% reduction in hospitalization for HF was observed in the EMPA-REG study

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  • Empagliflozin to Be Studied for the Treatment of People With Chronic HF[57]

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  • GLP-1 RAs: Albiglutide, Dulaglutide, Exenatide (BID, QW), Liraglutide, Lixisenatide,* Semaglutide*[61]

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  • CV Effects of GLP-1 Receptor Activation[62]

    • GLP-1 receptor activation produces a pharmacologic level of GLP-1 in the bloodstream
    • DPP-4 inhibition offers physiologic doubling, but a pharmacologic level is needed for weight reduction

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  • ELIXA Study Design[63]

    • The ELIXA study enrolled an "extraordinarily sick group of people"
    • Lixisenatide is a short-acting once-GLP-1 receptor agonist (RA)

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  • ELIXA: Key Study Population and Baseline Characteristics[63]

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  • ELIXA: ITT Analysis[63]

    • Lixisenatide met criteria for noninferiority but not superiority to placebo

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  • ELIXA: Mean HbA1c Level, According to Study Visit[63]

    • A difference of−0.27 percentage points (95% CI, −0.31 to −0.22 in mean HbA1c was maintained throughout the trial in the lixisenatide group

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  • LEADER: Baseline Characteristics[64]

    • HbA1c was higher than in other outcomes trials

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  • LEADER: What We Know So Far, Topline Results

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  • FREEDOM-CVO Trial: A Study to Evaluate CV Outcomes in Patients With T2D Treated With ITCA 650[65]

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  • Practical Implications: What Does It Mean for My Practice and Patients

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  • Polling Question: What Would You Add Next? Audience Response

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  • Polling Question: What Would You Add Next? Audience Response

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  • Question From the Audience: Does the panel think SGLT2 inhibitors should be distinguished as the second-line class after metformin based on CV outcomes trial data?

    • Dr Anderson
      • The CV outcome trial benefit is in a unique group of individuals
      • The GLP-1 RA class has good benefits in terms of weight reduction, nonglycemic benefits, and probably better efficacy
    • Dr Jabour
      • We do not know how the EMPA-REG findings apply to younger patients without CVD
      • LEADER is positive, ELIXA is neutral. We do not yet know the best second-line agent
    • Dr Wysham
      • I would choose empagliflozin for a patient with heart disease

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  • Question From the Audience: How have the CV outcome trials affected guidelines so far, and how do you think they will impact them in the future?

    • Dr Blonde
      • After metformin, therapy should be individualized, and the order should be GLP-1 RA first and SGLT2 inhibitor second
      • Canadian guidelines changed the order for people with CVD. Patients similar to the patients in the EMPA-REG trials should receive an SGLT2 inhibitor with proven benefit in reducing CV events

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  • Question From the Audience: What does the panel think CAROLINA® results may do to guidelines? Particularly since it is a study of a DPP-4 inhibitor vs a sulfonylurea?

    • Dr Blonde
      • The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) list 6 choices, including sulfonylureas, to add to metformin, and the choice is individualized
      • The American College of Endocrinology (ACE) algorithm emphasizes treatments with low risk for hypoglycemia
      • CAROLINA® is not likely to affect the guidelines
    • Dr. Anderson
      • Most sulfonylurea use is done reluctantly for reasons of cost
      • Hopefully better agents will be made available for patients

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  • Question From the Audience: Today, Dr Ele Ferrannini presented in an oral session, and concurrently published in Diabetes Care, the hypothesis that β-hydroxbutyrate is taken up by the heart and oxidized in preference to fatty acids, and contributed to the effects seen with empagliflozin in EMPA-REG....what is the panel's thought?

    • Dr Blonde
      • Both are related to fuel energetics potentially having a role
      • It makes the heart more efficient at making ATP with lower oxygen demands
    • It is compelling for the kidney as well as the heart

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  • Large Non-Insulin CV Outcomes Trials in T2D

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