1. Diabetes and Cardiovascular Disease (CVD): Managing Patients with
High Risk and Co-Morbid
Conditions

2. Acknowledgements
We acknowledge the work of Cindy Lamendola, MSN, ANP, FPCNA, FAHA, in the development of this presentation.
Disclosures: Eiger BioPharmaceuticals – Research Grant
Presenter - Practice Point

3. Presenter
Speaker
Disclosures

4. Objectives
Summarize the treatment recommendations for patients with diabetes to reduce their risk of cardiovascular disease.
Describe the relationship between acute coronary syndrome (ACS) and hyperglycemia in patients with diabetes mellitus.
Describe how using shared decision-making with a complex patient can increase the rate of treatment adherence
Read objectives:
Since majority of people have type 2 DM this talk will focus on patients w type 2 DM

5. Prevalence of Diabetes
29.1 million people or 9.3% of the U.S. population have diabetes. (Majority are type 2)
1.25 million have type 1 diabetes
Diagnosed: 21.0 million people
Undiagnosed: 8.1 million people (27.8% of people with diabetes are undiagnosed).
Prevalence in Seniors: 25.9%, or 11.8 million people age >65 have diabetes (diagnosed and undiagnosed).
Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, Atlanta, GA: U.S. Department of Health and Human Services; 2014.
National Diabetes Information Clearinghouse. National Diabetes Statistics, Available at:
According to NHANES data from 1988 to 1994 compared with 2005 to 2010, the prevalence of DM increased from
8.4% to 12.1%. This increase was most pronounced among≥65 years of age (increase in prevalence from 18.6%
to 28.5%).22 -Mozaffarian D, et. al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360.

6. Diabetes and Cardiovascular Disease (CVD)
CVD is the leading cause of morbidity & mortality for those with diabetes and the largest contributor to the direct and indirect costs of diabetes.
At least 68% of people with diabetes >65 years of age die of some form of heart disease; and 16% die of stroke.
Common conditions coexisting with type 2 diabetes e.g hypertension, and dyslipidemia are clear risk factors for ASCVD.
Cardiovascular disease is the major cause of morbidity and mortality for individuals with diabetes, and the largest contributor to the direct and indirect costs of diabetes
The common conditions coexisting with type 2 diabetes, such as hypertension and dyslipidemia, are clear risk factors for atherosclerotic cardiovascular disease, and diabetes itself confers independent risk
Common conditions coexisting with type 2 diabetes are clear risk factors for ASCVD.
Diabetes confers independent risk for ASCVD
Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing of slowing CVD in people with diabetes. Large benefits are seen when multiple risk factors are addressed globally.
Finally, the Association recommends systematic assessment at least annually of all people with diabetes for cardiovascular risk factors, including dyslipidemia, hypertension, smoking, family history of premature coronary disease, and the presence of albuminuria. Abnormal risk factors should be treated.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and
risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71. Mozaffarian D, et. al. on behalf of the
American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—
2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360

7. Diabetes and Cardiovascular Disease (CVD)
Diabetes itself confers independent risk CVD ~ 2x higher risk then in people without diabetes.
Systematically assess all patients with diabetes for CV risk factors and control these risk factors to prevent/slow CVD in people with diabetes.
Diabetes confers independent risk for ASCVD
Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing of slowing CVD in people with diabetes. Large benefits are seen when multiple risk factors are addressed globally.
Finally, the Association recommends systematic assessment at least annually of all people with diabetes for cardiovascular risk factors, including dyslipidemia, hypertension, smoking, family history of premature coronary disease, and the presence of albuminuria. Abnormal risk factors should be treated.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and
risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71. Mozaffarian D, et. al. on behalf of the
American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—
2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360

8. Age-adjusted* percentage of people aged 20 years or older with diagnosed diabetes, by race/ethnicity, United States, 2010–2012
Speaker Notes: Briefly review slide with noted populations at highest risks for diabetes
*Based on the 2000 U.S. standard population.
Source: 2010–2012 National Health Interview Survey and
2012 Indian Health Service’s National Patient Information Reporting System.

9. Relationship Between Insulin Resistance, Diabetes, Cardiovascular Risk Factors, and CVD Consequences of Insulin Resistance and Hyperinsulinemia
Insulin Resistance
Genetic Influences
Environmental
Influences
Physical Activity
Weight
Hyperinsulinemia
Glucose intolerance  type 2 diabetes
Dyslipidemia - ↑TG ↓HDL
Small dense LDL & remnant lipoproteins
HTN - ↑ sodium retention &* SNS activity
Endothelial dysfunction - ↑MNC*, ↑CAM*
Prothrombotic state - ↑plasminogen
activator inhibitor ↑fibrinogen levels
Increase in inflammatory markers -
HS-CRP, WBC
Speaker Notes:
This algorithm is a brief overview of the metabolic consequences of insulin resistance and hyperinsulinemia. This is for a review with focus on CV risk factors resulting from Insulin resistance and hypeinsulinemia.  
This slide represents the proposed role of insulin resistance and compensatory hyperinsulinemia, and the consequences associated with insulin resistance. 
Insulin resistance is influenced 50% by genetics and 50% by environmental factors, for example, increased weight and decreased physical activity.
Metabolic abnormalities associated with insulin resistance are:
-  Glucose intolerance - Ranging from impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes.
 -  Dyslipidemia - High TG and low HDL, small dense LDL, postprandial lipemia and remnant lipoproteins (very atherogenic particles).
 -  Hypertension -The mechanism may be influenced by increased sodium retention and sympathetic nervous system (SNS) activity. Only about 50% of people with hypertension are insulin resistant.
 -  Endothelial dysfunction - Increases in both mononuclear cell binding and cellular adhesion molecules (CAM). 
 - Prothrombotic state - Increases in plasminogen activator inhibitor (PAI -1), and in fibrinogen levels (less ability to lyse clots and produce more clots).
- Inflammatory markers – increase in high sensitivity-C reactive protein (HS-CRP), white blood cells.
These metabolic abnormalities associated with hyperinsulinemia and insulin resistance put a person at increased risk for CVD as well as type 2 diabetes
Reference: Reaven   . Endocrinol Metab Clin N A  . 2004;33:283.
*Mononuclear cells
*Cellular adhesion molecules
*Sympathetic nervous
system
Increased Risk for CVD
Reaven G. Endocrinol Metab Clin N Am ;33:283

10. Case Study Lilly F.
PT ID: 46-yr-old Black woman, executive secretary (worried - job security)
CC: She is concerned about her health; weight has increased and physical activity decreased
PMH: Pre-hypertension, pre DM – hasn’t been seen in ~ 2 yrs
Lifestyle Hx: Tobacco use: 20 pack/years - quit 20 years ago; alcohol intake: rare; physical activity: walks 30 min/week
FH: Mother: diabetes; father: HTN; sibs: A&W
Current medication: None
Physical Examination
Height: 5’ 5”
Wt: 162 lbs
BMI: 27 kg/m2
BP: 142/95 mmHg
HR:78 BPM
Speaker Notes:
Lilly now has type 2 DM as well as uncontrolled CV risk factors putting her at risk for CVD.
Prevention for CVD early on is extremely important and early treatment for DM and CVD risk factors has been found to reduce morbidity and mortality. 
As in previous slides Lilly has most likely been insulin resistant for many years with increasing risk factors for CVD.
Laboratory Results
TC: 220 mg/dl
TG: 340 md/dl
HDL: 44 mg/dl
LDL: 108 mg/dl
Non-HDL: 176 mg/dl
Fasting Glucose 150 mg/dL (previously 115)
Serum Cr: 0.7 mg/dl
ALT: 20 U/L
TSH – WNL
GFR: 83 mL/min
Albuminuria WNL

11. CVD Risk Factor Control in People with Diabetes
Up to 48.7% of individuals with self-reported DM do not meet goals for:
Glycemic control
Blood pressure or
Lipid goals
Only 14.3% meet all 3 targets and did not smoke.
Data from National Health and Nutrition Examination Survey (NHANES) and Behavioral Risk Factor Surveillance System (BRFSS),
Note: We as health care providers must do better to help our patients to achieve glycemic and CV RF to prevent micro and macrovascular disease.
Mozaffarian D, et. al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360

12. Should Lilly have ASCVD Calculated?
In primary prevention of CVD some treatment recommendations are based on ASCVD risk score.
Gender: Female, Age: 46 years, Race: African American
Total Cholesterol: 220 mg/dL
HDL-Cholesterol: 44 mg/dL
Systolic Blood Pressure: 142 mm Hg
Diabetes: Yes
Smoker: No
10 Year ASCVD Risk: 7.3% calculated risk vs 0.6 % risk w optimal risk factors **
Lifetime ASCVD Risk: 39% calculated risk vs 8% risk with optimal risk factors**
ACC/AHA guideline on the assessment of cardiovascular risk: a report of the
American College of Cardiology/American Heart Association Task Force on
Practice Guidelines. Circulation. 2014;129(suppl 2):S49-S73.
Please read this: Intended for use if there is not ASCVD and the LDL-cholesterol is <190 mg/dL
**Optimal risk factors include: Total cholesterol of 170 mg/dL, HDL-cholesterol of 50 mg/dL, Systolic BP of 110 mm Hg, Not taking medications for hypertension, Not a diabetic, Not a smoker
We will discuss this further as we review guidelines recommendations for aspirin and lipids
ACC/AHA slightly different than ADA for statin intensity
The ASCVD Risk Calculator –enables health care providers and patients to estimate 10-year and lifetime risks for atherosclerotic cardiovascular disease (ASCVD), defined as coronary death or nonfatal myocardial infarction, or fatal or nonfatal stroke, based on the Pooled Cohort Equations and the work of Lloyd-Jones, et al., respectively. The information required to estimate ASCVD risk includes age, sex, race, total cholesterol, HDL cholesterol, systolic blood pressure, blood pressure lowering medication use, diabetes status, and smoking status. Estimates of 10-year risk for ASCVD are based on data from multiple community-based populations and are applicable to African-American and non-Hispanic white men and women 40 through 79 years of age. For other ethnic groups, we recommend use of the equations for non-Hispanic whites, though these estimates may underestimate the risk for persons from some race/ethnic groups, especially American Indians, some Asian Americans (e.g., of south Asian ancestry), and some Hispanics (e.g., Puerto Ricans), and may overestimate the risk for others, including some Asian Americans (e.g., of east Asian ancestry) and some Hispanics (e.g., Mexican Americans). Estimates of lifetime risk for ASCVD are provided for adults 20 through 59 years of age and are shown as the lifetime risk for ASCVD for a 50-year old without ASCVD who has the risk factor values entered into the spreadsheet. The estimates of lifetime risk are most directly applicable to non-Hispanic whites. We recommend the use of these values for other race/ethnic groups, though as mentioned above, these estimates may represent under- and overestimates for persons of various ethnic groups. Because the primary use of these lifetime risk estimates is to facilitate the very important discussion regarding risk reduction through lifestyle change, the imprecision introduced is small enough to justify proceeding with lifestyle change counseling informed by these results.

13. ADA Clinical Practice Recommendations Evidence of Grading System
A: Clear evidence from adequately powered, well conducted, generalizable RTC’s, including evidence from a multicenter trial or meta-analysis that incorporated quality ratings in the analysis; Compelling non experimental evidence;
Supportive evidence from adequately –powered, well conducted RTC’s
B: Supportive evidence from well-conducted cohort studies;
Supportive evidence from a well- conducted case-control study
Here is the Association’s evidence grading system in use for these clinical practice recommendations, used to clarify and codify the evidence that forms the basis for each of the recommendations in the 2016 Standards of Medical Care in Diabetes.
The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E. As we proceed through this presentation you’ll see these grades next to each of the recommendations listed.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

14. Clinical Practice Recommendations –Evidence of Grading System
C: Supportive evidence from poorly controlled or uncontrolled studies or evidence from observational studies with high potential for bias
Evidence from case series or case reports
Conflicting evidence with the weight of evidence supporting the recommendation
E: Expert Consensus or clinical experience
Here is the Association’s evidence grading system in use for these clinical practice recommendations, used to clarify and codify the evidence that forms the basis for each of the recommendations in the 2016 Standards of Medical Care in Diabetes.
The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E. As we proceed through this presentation you’ll see these grades next to each of the recommendations listed.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

15. ADA Lifestyle Goals Diet: Individualize Medical Nutrition Therapy
Promote healthful eating patterns, eating a variety of nutrient-dense
foods in appropriate portion sizes, reduce saturated fat, avoid trans
fat to improve overall health and to:
Attain individualized glycemic, blood pressure, and lipid goals
Delay or prevent complications of diabetes
Base Nutrition needs on personal & cultural preferences,
Health literacy & numeracy, access to healthful foods, willingness
and ability to make behavioral changes & barriers to change.
Weight Loss: Modest weight loss achievable with a target of 5-7% of total body weight by the combination of lifestyle modification and the reduction of energy intake.
Achieve and maintain body weight goals
Bases for all diabetes treatment begins with lifestyle changes
Figuring out what to eat can be the most challenging part of daily self-management for people with diabetes. The Association has long held that there is no “one size fits all” approach to medical nutrition therapy, and lays out four goals for MNT for adults with diabetes:
1. We want to promote and support healthful eating patterns, emphasizing a variety of nutrient-dense foods in appropriate portion sizes, in order to improve overall health and specifically to:
Achieve and maintain body weight goals
Attain individualized glycemic, blood pressure, and lipid goals
Delay or prevent complications of diabetes
To address individual nutrition needs based on personal and cultural preferences, health literacy and numeracy, access to healthful foods, willingness and ability to make behavioral changes, and barriers to change.
As far as energy balance, overweight or obese adults with type 2 diabetes benefit from modest weight loss with a weight loss target of 5-7% of total body weight
American Diabetes Association Standards of Medical Care in Diabetes. Strategies for
improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1):S6-S12
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print

16. ADA Lifestyle Goals
Exercise: At least 150 min/wk of moderate-intensity aerobic activity over at least 3 days/week with no more than 2 consecutive days without exercise. (A)
All individuals, including those with diabetes, should reduce sedentary time, particularly by breaking up extended amounts of time (>90 min) spent sitting. (B)
Perform resistance training at least twice weekly. (A)
(If no contraindications)
Smoking: Advise all patients not to use cigarettes, other tobacco products, or e-cigarettes. (A)
Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care. (B)
Recommendations for physical activity for people with diabetes1 are summarized on this slide
Adults with diabetes should be advised to perform at least 150 min/week of moderate-intensity aerobic physical activity (with “moderate” defined as 50–70% of maximum heart rate), spread over at least 3 days/week with no more than 2 consecutive days without exercise. [
All individuals, including those with diabetes, should be encouraged to reduce sedentary time, particularly by breaking up extended amounts of time (>90 min) spent sitting.
And finally, in the absence of contraindications, adults with type 2 diabetes should be encouraged to perform resistance training at least twice per week.
The Association offers two key recommendations in the areas of tobacco and e-cigarettes. First, do advise all patients not to use cigarettes, other tobacco products, or e-cigarettes. This last one – e-cigarettes– is hard, but there just are no rigorous studies demonstrating that e-cigarettes are a healthier alternative to smoking or that e-cigarettes can facilitate smoking cessation. More extensive research of their short- and long-term effects is needed to determine their safety and their cardiopulmonary effects in comparison with smoking and standard approaches to smoking cessation so the Association recommends against their use.
And secondly, do include smoking cessation counseling and other forms of treatment as a routine component of diabetes care.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

17. ABC’s of ADA Guidelines
A1c (HbA1c)
Antiplatelet
Blood Pressure
Cholesterol (lipids)
HbA1c (Hemoglobin A1c)
American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2016; 39 (Suppl. 1): S39-S46

18. Individualization is key: Avoidance of hypoglycemia
Glycemic Targets
HbA1c < 7.0% (mean PG  mg/dl [ mmol/l])
Plasma Glucose (PG) mg/dl ( mmol/l)
Post-prandial PG <180 mg/dl (10.0 mmol/l)
Post –Prandial is 1-2 h after beginning a meal
Individualization is key:
Tighter targets ( %) - younger, healthier
Looser targets ( %) - older, shorter life expectancey, comorbidities, severe hypoglycemia, multiple medications with poor glycemic control
Avoidance of hypoglycemia
Consider less stringent goals: Hx of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and long standing
diabetes with difficulty reaching goal despite multiple Rxs
There is evidence for a cardiovascular benefit of intensive glycemic control after long-term follow-up of study cohorts treated early in the course of both type 1 and type 2 diabetes. For example in the Diabetes Control & Complications Trial (DCCT) there was a trend toward lower risk of CVD events with intensive control. In the 9-year post-DCCT follow-up of the Epidemiology of Diabetes Interventions and Complications (EDIC) cohort, participants previously randomized to the intensive arm had a significant 57% reduction in the risk of nonfatal myocardial infarction (MI), stroke, or CVD death compared with those previously in the standard arm.
The benefit of intensive glycemic control in this type 1 diabetic cohort has been shown to persist for several decades and to be associated with a modest reduction in all-cause mortality
The ACCORD, ADVANCE, and VADT suggested no significant reduction in CVD outcomes with intensive glycemic control in participants followed for 3.5−5.6 years who had more advanced type 2 diabetes than UKPDS participants. There was also an increase in hypoglycemia
Details of these studies are reviewed extensively in the Association’s position statement on intensive glycemic control and the prevention of cardiovascular events, which you can download for free from care.diabetesjournals.org.
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets.
Diabetes Care 2016; 39 (Suppl. 1): S39-S46 Association Standards of Medical Care in Diabetes

19. Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials
Study
Microvasc
CVD
Mortality
UKPDS  
DCCT / EDIC*
ACCORD 
ADVANCE
VADT
This slide presents an overview of the microvascular, macrovascular and mortality outcomes from large T1DM and T2DM randomized clinical trials that have focused on the relationship between glycemic control and complications. From these, it is clear, that more intensive glycemic control in both T1DM and T2DM prevents or delays microvascular complications, specifically retinopathy and albuminuria.
In contrast the data concerning glucose control and macrovascular complications are more complex. In the context of relatively short clinical trials, more intensive glucose control has an overall neutral effect on cardiovascular events.
In longer term follow-up investigations, however, a statistically significant beneficial effect eventually emerged in both the DCCT (Type 1) and the UKPDS (Type 2.)
DCCT and UKPDS long-term follow up – A1C<7% in the years soon after diagnosis of DM  long term reduction in risk of macrovascular disease.
The benefit of intensive glycemic control in this type 1 diabetic cohort has been shown to persist for several decades and to be associated with a modest reduction in all-cause mortality
10 years of FUP of UKPDS cohort (Holman et al, NEJM 359, 2008):
- MI reductions 15% with SU or insulin (p=0.01), 33% with metformin as initial therapy
- All cause mortality 13 and 27%.
Notably, however, in ACCORD, an increase in mortality was observed in those patients assigned to the most intensive glucose-lowering therapy. This has raised concerns that overly aggressive glycemic targets in older patients at high cardiovascular risk may be problematic. So, HbA1c targets should be individualized to the patient and disease state.
The ACCORD, ADVANCE, and VADT suggested no significant reduction in CVD outcomes with intensive glycemic control in participants followed for 3.5−5.6 years who had more advanced type 2 diabetes than UKPDS participants.
Details of these studies are reviewed extensively in the Association’s position statement on intensive glycemic control and the prevention of cardiovascular events, which you can download for free from care.diabetesjournals.org.
Initial Trial
Long Term Follow-up
* in T1DM
Kendall DM, Bergenstal RM. © International Diabetes Center 2009; Used with permission NDEI
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.
Holman RR et al. N Engl J Med. 2008;359: DCCT Research Group. N Engl J Med 1993;329;977.
Nathan DM et al. N Engl J Med. 2005;353: Gerstein HC et al. N Engl J Med. 2008;358:2545.
Patel A et al. N Engl J Med 2008;358: Duckworth W et al. N Engl J Med 2009;360:129. (erratum:
Moritz T. N Engl J Med 2009;361:1024)

20. Used with permission NDEI
Type 2 Diabetes Therapy and Cardiovascular Events: Comparing VADT With Other Trials
Why no significant benefit for CVD with intense glucose lowereing? 1. Other CVD Risk Factors were treated
2. All studies had lower rates of CVD in the Standard Care Arm then originally predicted
3. Many had established CVD
Subset analysis suggest significant benefit of intensive glycemic control on CVD in those with shorter duration of DM, lower A1c and/or absence of known CVD
Another interesting finding was in a subset analysis of the three trials there was a significant benefit of
intensive glucose lowering in those people with a shorter duration of diabetes, a lower A1c at the beginning of the study and/or absence of known CVD. These findings were also seen in the follow-up of the DCCT and UKPDS trials, where people with new diabetes were studied. 8
Type 2 Diabetes Therapy and Cardiovascular Events: Comparing VADT With
Other Trials
In the Veterans Affairs Diabetes Trial (VADT), Duckworth and colleagues compared the effects of intensive and standard glucose control on cardiovascular events.
A total of 1,791 military veterans (mean age, 60.4 years) who had a suboptimal response to antihyperglycemic therapy were randomized to receive intensive (n=899) or standard (n=892) glucose control
The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in A1C compared with the standard-therapy group.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) studies assessed different populations with different approaches but reached similar conclusions as did VADT.
The mean age of subjects in ACCORD was 62 years, and the duration of diabetes was 10 years, with 35% of subjects receiving insulin at baseline.
The mean age of subjects in ADVANCE was 66 years, and the duration of diabetes was slightly shorter (8 years), with 1.5% of subjects receiving insulin at baseline.
In VADT, 52% of subjects received insulin, with the remainder receiving a maximal dose of an oral agent; diabetes had been diagnosed a mean of 11.5 years earlier.
Baseline A1C levels were 7.2% in ADVANCE, 8.1% in ACCORD, and 9.4% in VADT.
After intensive therapy, A1C levels were 6.4% in ADVANCE and ACCORD, and 6.9% in VADT; following standard therapy, levels were 7.0%, 7.5%, and 8.4%, respectively.
Across all three studies, hypoglycemia and weight gain were greater in the intensive-therapy cohorts.
Duckworth W, Abraira C, Moritz T, et al; for VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(12):
Used with permission NDEI

21. Benefit of Intense Glucose Lowering
Real benefit of glycemic lowering on CVD in type 2, even if proven, is modest compared with and incremental to treatment of other CVD risk factors.
Subset analysis of the three trials: A possible significant benefit of intensive glycemic control on CVD might be seen in: those with a shorter duration of DM; lower A1c; and/or absence of known CVD.
These findings were also seen in the follow-up of the DCCT and UKPDS trials, where people with new diabetes were studied.
Please see page 68 of ADA 2016 guidelines for detailed information on the following trials re blood pressure lowering.
Subset analysis suggest significant benefit of intensive glycemic control on CVD in those with shorter duration of DM, lower A1c and/or absence of known CVD
Another interesting finding was in a subset analysis of the three trials there was a significant benefit of
intensive glucose lowering in those people with a shorter duration of diabetes, a lower A1c at the beginning of the study and/or absence of known CVD. These findings were also seen in the follow-up of the DCCT and UKPDS trials, where people with new diabetes were studied. 8
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2016; 39 (Suppl. 1): S39-S46 Association Standards of Medical Care in Diabetes

22. ADA Recommendations for Pharmacological Therapy For Type 2 Diabetes
Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacological agent for type 2 diabetes. (A)
Consider initiating insulin therapy(with or without additional agents) in patients with newly diagnosed type 2 diabetes and markedly symptomatic and/or elevated blood glucose levels or A1C. (E)
If non insulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target over 3 months, then add a second oral agent, a glucagon-like peptide1 receptor agonist, or basal insulin. (A)
American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2016; 39 (Suppl. 1): S39-S46 Association Standards of Medical Care in Diabetes
These are the current recommended pharmacotherapy guidelines for Since then new studies have emerged (discussed later) that show CVD and renal disease benefit so stayed tuned for ADA 2017 recommendations

23. ADA Recommendations for Antiplatelet Agents
Anti-platelet agents, aspirin
Consider aspirin therapy mg/day (C)
As a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%)
Includes most men or women with diabetes age ≥50 years who have at least one additional major risk factor, including:
Family history of premature ASCVD
Hypertension
Smoking
Dyslipidemia
Albuminuria
Speaker Notes: Aspirin recommendations are no longer simple for primary prevention
This is one of the reasons we calculated Lilly’s ASCVD risk score – we will discuss what recommendation was made later.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

24. ADA Recommendations for Antiplatelet Agents
Aspirin is not recommended for ASCVD prevention in adults with diabetes at low ASCVD risk, since potential adverse effects from bleeding likely offset potential benefits
Low risk: 10-year CVD risk < 5%, such as in men or women with diabetes aged < 50 years and with no major additional ASCVD risk factors
In Patients with diabetes < 50 years of age with multiple other risk factors (e.g., 10 year risk 5-10%, clinical judgement is required (E)
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

25. ADA Recommendations for Antiplatelet Agents
Aspirin therapy mg/day as secondary prevention in those with diabetes and a history of ASCVD (A)
For patients w/ASCVD & aspirin allergy, clopidogrel 75 mg/day should be used (B)
Dual antiplatelet therapy is reasonable for up to a year after acute coronary syndrome (B)
Speaker Notes: Note ASCVD can include – stroke or vascular disease besides CAD
ASCVD Atherosclerotic Cardiovascular Disease
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

26. Lilly and Aspirin Should Lilly be started on aspirin?
She is 46 yrs old. Her ASCVD risk is 7.3% but has multiple CVD Risk Factors.
1. As a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%)
Includes most men or women with diabetes age ≥50 years who have at least one additional major risk factor, including:
Family history of premature ASCVD- No
Hypertension - Yes
Smoking - No
Dyslipidemia- Yes
Albuminuria- No
Speaker Notes:
Could ask for a show of hands – or just point out this is a good time to utilize shared decision making process to review benefits and risk and ask for her thoughts, concerns and barriers she may have about taking aspirin

27. Lilly and Aspirin Should Lilly be started on aspirin?
She is 46 yrs old. Her ASCVD risk is 7.3% but has multiple CVD Risk Factors.
2. In Patients with diabetes < 50 years of age with multiple other risk factors (e.g., 10 year risk 5-10%, clinical judgement is required (E)
Patient Centered Care and shared decision making process should be used to make a decision using scientific data and review of benefits and potential side effects
Speaker Notes:
Could ask for a show of hands – or just point out this is a good time to utilize shared decision making process to review benefits and risk and ask for her thoughts, concerns and barriers she may have about taking aspirin

28. A Patient Centered Approach
“...providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions.”
Gauge patient’s preferred level of involvement.
Explore, where possible, therapeutic choices. Consider using decision aids.
Shared Decision Making – a collaborative process between patient and clinician, using best available evidence and taking into account the patient’s preferences and values
Final decisions regarding lifestyle choices ultimately lie with the patient.
ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015
Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596
There is increasing emphasis on ‘patient-centeredness’ in chronic disease management. This is of particular importance in those conditions, like diabetes, that necessitate patient involvement in lifestyle changes and multiple mediations
Patient Centered Care has been described by the Institute of Medicine as “providing care that is respectful of and responsive to individual patient preferences, needs, and values – ensuring that patient values guide all clinical decisions.” Shared decision making (SDM) is a key component of patient-centered care.
EASD - European Association for the Study of Diabetes

29. ADA Recent Blood Pressure Studies
Is lower better?
Action to Control Cardiovascular Risk in Diabetes (ACCORD)
Does Systolic Blood Pressure < 120 mm/Hg provide better cardiovascular protection than mm/Hg? The blood pressure goal was reached (119/64) but there was no CVD benefit. Answer: No
Action in Diabetes and Vascular Disease (Advance)
Answer: Yes
This study showed a significant reduction in the risk of the primary composite end point (major macrovascular or microvascular event) and significant reductions in the risk of death from any cause and of death from cardiovascular causes with a blood pressure of 136/73 mm Hg in the treated group.
Speaker Notes: Please see page 68 of ADA 2016 guidelines for detailed information on the following trials re blood pressure lowering.
ACCORD, ADVANCE, SPRINT (sprint Trial reviewed in notes of slide)
Given the epidemiological relationship between lower blood pressure and better long-term clinical outcomes, two landmark trials, Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action iniabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation–Blood Pressure (ADVANCE-BP), examined the benefit of tighter blood pressure control in patients with type 2 diabetes.
The ACCORD trial examined whether a lower SBP of <120 mmHg in patients with type 2 diabetes at high risk for ASCVD provided greater cardiovascular protection than an SBP of 130–140 mmHg. The study did not find a benefit in primary end point (nonfatal MI, nonfatal stroke, and cardiovascular death) comparing intensive blood pressure treatment (goal < 120 mmHg, average blood pressure achieved 119/64 mmHg on 3.4 medications) with standard treatment (average blood pressure achieved 143/70 mmHg on 2.1 medications). In ACCORD, there was no benefit of aggressive blood pressure lowering, despite the extra cost and efforts.
In ADVANCE, the active blood pressure intervention arm (a single-pill, fixed-dose combination of perindopriland indapamide) showed a significant reduction in the risk of the primary composite end point (major macrovascular or microvascular event) and significant reductions in the risk of death from any cause and of death from cardiovascular causes. The baseline blood pressure among the study subjects was145/81 mmHg. Compared with the placebo group, the patients treated with a single-pill, fixed-dose combination of perindopril and indapamide experienced an average reduction of 5.6mmHg in SBP and 2.2 mmHg in DBP. The final blood pressure in the treated group was 136/73 mmHg, not quite the intensive or tight control achieved in ACCORD.
Recently published 6-year follow-up of the ADVANCE–Post-Trial ObservationalStudy (ADVANCE-ON) reported that the reductions in the risk of death from any cause and of death from cardiovascular causes in the intervention group were attenuated, but remained significant (12).

30. ADA Recommendations for Hypertension
Treat to a blood pressure goal of
<140/< 90 mmHg. (A)
BP Targets <130/<80 mmHg, may be appropriate for certain individuals, i.e younger patients, those with albuminuria and/or other CVD RD if it can be achieved without undue treatment burden. (C/B)
People with diabetes and hypertension should be treated to a systolic blood pressure goal of <140 mmHg. There is strong evidence that systolic BP greater than 140 is harmful, and suggests clinicians should promptly initiate and titrate therapy in an ongoing fashion to achieve and maintain SBP <140 mmHg in most patients; (Note Lilly’s BP is > 140 ) Lilly also has dyslipidemia – but to get to a goal of <130/<80 might take 2 meds – another talking pt in shared decision making to try a med + lifestyle
We’ll talk about your older adult patients shortly;
Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden. Similarly, strong evidence from randomized clinical trials supports diastolic blood pressure targets less than 90.
Lower diastolic targets, such as <80 mmHg, may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden.
These targets are in harmonization with a recent publication by the Eighth Joint National Committee that recommended, for individuals over 18 years of age with diabetes, a DBP threshold of <90 mmHg and SBP <140 mmHg.
Reason for C/B evidence in <130/<80 evidence is C for less than 130 and B for < 80
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

31. ADA Recommendations: Hypertension Treatment in Older Adults
In older adults, pharmacological therapy to achieve treatment goals of <130/70 are not recommended. (B)
Lifestyle intervention including: (B)
Weight loss if overweight
DASH-style diet including reduced sodium, increased potassium
Moderation of alcohol intake
Increased physical activity
In older adults pharmacological therapy to reach goals of less than 130/70 is not recommended. Treating to less than SBP less than 130 has not been shown to improve cardiovascular outcomes and treating to DBP less than 70 has been associated with higher mortality in this population.
Lifestyle therapy for elevated blood pressure consists of weight loss if overweight, DASH-style dietary pattern including reducing sodium and increasing potassium intake, moderation of alcohol intake, and increased physical activity
In the SPRINT Trial they did not include patients with diabetes because there were ongoing trials looking at lowering blood pressure and impact of CVD and they did not show benefit :
The Systolic Blood Pressure Intervention Trial, or SPRINT, included more than 9,300 people with high blood pressure who were age 50 and older and had at least one other risk factor for heart disease and stroke. The patients were followed for a median of more than three years, much shorter than expected because investigators stopped the trial early after seeing the striking results.
Using medications to lower systolic blood pressure to around 120 reduced the risk of having or dying from a heart attack, stroke or heart failure by a quarter, compared with lowering it to the commonly recommended target of less than 140. During the study, 243 patients in the intensive treatment group had a so-called event versus 319 patients in the standard treatment group.
Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

32. ADA Recommendations for Hypertension
Pharmacological therapy for patients with diabetes and HTN includes:
Either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB). (B)
If one class is not tolerated, substitute the other. (C)
Multiple drug therapy (two or more agents at maximal doses) generally required to achieve BP targets. (B)
If using ACE inhibitors, ARBs, or diuretics, monitor serum creatinine / eGFR & potassium levels. (E)
Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71
Read Slide:
Date from older research trials on benefits of ACE/ARB’s – see ADA guidelines CVD risk reduction

33. Recommendations for Lilly and HTN Treatment
She may have had untreated HTN for several years.
She has not been successful with lifestyle changes due to life stressors.
Treatment Recommendation:
ACE or, if not tolerated, ARB.
Do you think she will need more than one drug?
This might be a good time to bring up choices.
Lifestyle goals in addition to one medication.
We will discuss Aspirin choice later
As stated earlier just to get to < 140/90 mm Hg will take one medication and possible 2 but we can emphasize importance of lifestyle and benefit on reducing HTN and also offer support
(Dietitian referral, CDE referral, educational materials and close follow up)

34. We need to make a plan together
She now has type 2 DM & CVD risk factors that need treatment. I need to ask what she is thinking – there will be many changes
We need to make a plan together
How did this happen? I wonder if I really have diabetes or am just nervous. I’m really scared – but not sure I want start taking medications
When discussing any treatments – shared decision making is always part of the process
Important to know your patient and ask questions:
What are you thinking – concerns, barriers - etc
What are your needs
Help to determine/understand barriers to change

35. A Patient Centered Approach
In a shared decision-making approach, clinician and patient:
Act as partners, mutually exchanging information and deliberating on options, to reach a consensus on the therapeutic course of action.
Evidence supports the effectiveness of this approach.
Engaging patients in health care decisions may enhance adherence to therapy.
Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) DIABETES CARE, VOLUME 35, JUNE 2012-

36. ADA Statin Treatment Recommendations
Age
Risk Factors
Statin Intensity*
<40 years
None
ASCVD risk factor(s)**
Moderate or high
ASCVD
High
40–75 years
Moderate
ASCVD risk factors
ACS & LDL >50 who can’t tolerate high dose statin
Moderate + ezetimibe
>75 years
Here is a summary of recommendations for statin treatment in people with diabetes. All of these recommendations are in addition to lifestyle therapy, as indicated by the asterisk by Recommended Statin Intensity.
For your patients less than 40 years old without ASCVD risk factors, no statins are recommended. If they do have risk factors-- which, as indicated by the double asterisk there, include LDL ≥100 mg/dL (2.6 mmol/L), high blood pressure, smoking, overweight or obesity, and family history of premature ASCVD–moderate or high dose statin therapy is recommended. For patients with overt ASCVD, a high dose is recommended.
For your patients aged with no risk factors, moderate dose statin therapy is recommended in addition to lifestyle. For patients in this age group with ASCVD risk factors, a high dose is recommended, and for your patients with acute coronary syndrome and LDL over 50 who can’t tolerate high dose statin therapy, a moderate dose plus ezetimibe is recommended (along with lifestyle intervention). *** AHA/ACC guidelines vary slightly suggesting moderate
And finally, for your patients over 75 years old with no risk factors, a moderate dose is recommended. With ASCVD risk factors, a moderate or high dose, and with overt ASCVD, a high dose along with that lifestyle therapy. And again for your patients in this age group with acute coronary syndrome and LDL over 50 who can’t tolerate high dose statin therapy, moderate dose plus ezetimibe is recommended.
[SLIDE]
*In addition to lifestyle therapy.
**ASCVD risk factors include LDL cholesterol ≥100 mg/dL (2.6 mmol/L), high blood pressure, smoking, overweight and obesity, and family history of premature ASCVD.
In addition to lifestyle therapy. ** ASCVD risk factors include LDL cholesterol ≥100 mg/dL (2.6 mmol/L), high blood pressure, smoking, overweight and obesity, and family history of premature ASCVD.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

37. Statin Treatment ACC/AHA guidelines Differ slightly from ADA Using ASCVD risk score
Primary Prevention in Individuals with Diabetes and LDL-C 70–189 mg/dL :
Moderate-intensity statin therapy should be initiated or continued for adults 40–75 years of age with diabetes. (A, Strong)
High-intensity statin therapy is reasonable for adults 40–75 years of age with diabetes with a ≥7.5% estimated 10-year ASCVD risk‖ unless contraindicated. (E-Expert Opinion)
In adults with diabetes, who are <40 years of age or >75 years of age, or with LDL <70 mg/dL it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects and drug–drug interactions and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy. (E-Expert Opinion)
Please read this: Intended for use if there is not ASCVD and the LDL-cholesterol is <190 mg/dL
**Optimal risk factors include: Total cholesterol of 170 mg/dL, HDL-cholesterol of 50 mg/dL, Systolic BP of 110 mm Hg, Not taking medications for hypertension, Not a diabetic, Not a smoker
On the basis of this large and consistent body of evidence,4 major statin benefit groups were identified for whom the
ASCVD risk reduction clearly outweighs the risk of adverse events based on a strong body of evidence.
These are : 1) secondary prevention in individuals with clinical ASCVD, 2)primary prevention in individuals with primary elevations of LDL-C ≥190 mg/dL, 3) primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL, and 4) primary prevention in individual without diabetes
and with estimated 10-year ASCVD risk ≥7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL.
For the primary prevention of ASCVD in individuals with diabetes (diabetes mellitus type 1 and type 2), estimated 10-year ASCVD risk can also be used to guide the intensity of statin therapy (This taken from info below)
ASCVD Additional information: Moderate evidence supports the use of statins for primary prevention in individuals with 5% to <7.5% 10-year ASCVD risk, 40 to75 years of age with LDL-C 70 to 189 mg/dL. Selected individuals with <5% 10-year ASCVD risk, or <40 or >75 years of age may also benefit from statin therapy. Clinicians and patients should engage in a discussion of the potential for ASCVD risk-reduction benefits, adverse effects, drug–drug interactions, and consider patient preferences for treatment.
This discussion also provides the opportunity to re-emphasize healthy-lifestyle habits and address other risk factors.
Clinical ASCVD is defined by the inclusion criteria for the secondary-prevention statin RCTs (acute coronary syndromes,a history of MI, stable or unstable angina, coronary
or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic
origin). For primary prevention in individuals without clinical ASCVD or diabetes who have an LDL-C 70 to 189 mg/dL, the estimated absolute 10-year risk of
ASCVD (defined as nonfatal MI, CHD death, or nonfatal and fatal stroke) should be used to guide the initiation of statin
therapy. The 10-year ASCVD risk should be estimated with the Pooled Cohort Equations (Section 4.7).
For the primary prevention of ASCVD in individuals with diabetes (diabetes mellitus type 1 and type 2), estimated 10-year ASCVD risk can also be used to guide the intensity of statin therapy.
A Report of the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic
Cardiovascular Risk in Adults (Circulation. 2014;129[suppl 2]:S1-S45)
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic
Cardiovascular Risk in Adults (Circulation. 2014;129[suppl 2]:S1-S45)

38. High- and Moderate-Intensity Statin Therapy*
High Intensity
Statin Therapy
Lowers LDL by ≥50%
Atorvastatin mg
Rosuvastatin mg
Moderate-Intensity
Statin Therapy
Lowers LDL by 30-50%
Atorvastatin mg
Rosuvastatin 5-10 mg
Simvastatin mg
Pravastatin mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Pitavastatin 2-4 mg
Here’s a quick summary of recommended statin dosing for high and moderate intensity therapy. Note that these are all based on once-daily dosing.
* * Once-daily dosingg
American Diabetes Association Standards of Medical Care in Diabetes.
Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71 38

39. ADA Recommendation: Lipid Treatment
Intensity of statin may need to be adjusted based on tolerability, LDL-C levels. (E)
Ezetimibe + moderate intensity statin therapy provides add’l CV benefit over moderate intensity statin therapy alone; consider for patients with a recent acute coronary syndrome w/ LDL ≥ 50mg/dL or in patients who can’t tolerate high-intensity statin therapy. (A)
Intensify lifestyle therapy & optimize glycemic control for patients with:
Triglyceride levels >150 mg/dL (1.7 mmol/L) and/or HDL cholesterol <40 mg/dL (1.0 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women. (C)
For patients with fasting triglyceride levels ≥ 500 mg/dL (5.7 mmol/L), evaluate for secondary causes and consider medical therapy to reduce the risk of pancreatitis. (C)
In clinical practice, providers may need to adjust intensity of statin therapy based on individual patient response to medication (e.g., side effects, tolerability, LDL cholesterol levels).
The addition of ezetimibe to moderate intensity statin therapy has been shown to provide additional cardiovascular benefit compared to moderate intensity statin therapy alone, and may be considered for patients with a recent acute coronary syndrome with an LDL cholesterol ≥ 50mg/dL or in those patients who cannot tolerate high-intensity statin therapy Combination therapy (statin/fibrate) has not shown to improve ASCVD outcomes and is generally not recommended. However, therapy with statin and fenofibrate may be considered for men with both triglyceride level ≥204 mg/dL and HDL cholesterol level ≤34 mg/dL
Combination therapy (statin/niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone and may increase the risk of stroke and is not generally recommended.
Statin therapy is contraindicated in pregnancy.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

40. ADA Recommendation: Lipid Treatment
Combination therapy (statin/fibrate) doesn’t improve ASCVD outcomes and is generally not recommended. (A)
Consider therapy with statin and fenofibrate for men with both TG ≥204 mg/dL (2.3 mmol/L) and HDL ≤34 mg/dL (0.9 mmol/L). (B)
Combination therapy (statin/niacin) hasn’t demonstrated additional CV benefit over statins alone, may raise risk of stroke & is not generally recommended. (A)
Statin therapy is contraindicated in pregnancy (B)
Standards of Medical Care in Diabetes. Cardiovascular disease and risk management.
Diabetes Care 2016; 39 (Suppl. 1): S60-S71
Combination therapy (statin/fibrate) has not shown to improve ASCVD outcomes and is generally not recommended. However, therapy with statin and fenofibrate may be considered for men with both triglyceride level ≥204 mg/dL and HDL cholesterol level ≤34 mg/dL
Combination therapy (statin/niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone and may increase the risk of stroke and is not generally recommended.
Statin therapy is contraindicated in pregnancy.
Note to Speaker: AHA guidelines are not specific to men re tg reduction

41. ADA/AHA Recommendation Lipid Treatment: Lilly and Statin Dose
By both guidelines Lilly would qualify for a statin.
ADA – Recommended dose would be High
AHA – Since Lilly’s ASCVD risk score is 7.3%. (recommendation is moderate dose) realistically little difference between 7.3 % and 7.5% so she could qualify for a high dose per AHA guidelines.
But this could be a talking point in helping to make the treatment decision together.
Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71
Although goals are slightly different it allows for evidenced based message and discussion to look at mod dose.  Also her LDL is not that high and she can would probably have good results on moderate dose.
AHA differs slightly but in essence Lilly’s ASCVD 10 yr risk status is 7.4%  and in AHA risk cut is set at 7.5% So both pretty much agree on high dose
Moderate-intensity statin therapy should be initiated or continued for adults 40–75 years of age with diabetes. (A Strong)
High-intensity statin therapy is reasonable for adults 40–75 years of age with diabetes with a ≥7.5% estimated 10-year ASCVD risk‖ unless contraindicated. E (Expert Opinion)
In adults with diabetes, who are <40 years of age or >75 years of age, or with LDL <70 mg/dL it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects and drug–drug interactions and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy. E (Expert Opinion)

42. Improving CV Risk Factors in People with DM
Hypertension: Blood pressure control reduces the risk of CVD
among people with diabetes by 33% to 50%
Dyslipidemia - Improved control of LDL cholesterol can reduce
cardiovascular complications by 20% to 50%.
Physical Activity/Weight loss – Nurses Health Study: 74% CVD,
82% CHD, & 91% diabetes in women could be prevented by five
lifestyle behaviors: 1) not smoking, 2) regular physical activity,
3) healthy weight, 4) eating healthier food, 5) moderate alcohol intake.
Speaker Notes: When we talk about taking medications or lifestyle changes to reduce CVD it is important to let them know there is scientific evidence that it works.
Heart and Stroke Facts Centers for Disease Control and Prevention.. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Reimer R CJDM 2002;26: Bassuk and Manson, AJL2008;VA-HIT: a randomized controlled trial Mar 28; 285(12):

43. DM Medications and Impact on CVD: What’s new?
Metformin
Reduction in CVD
Reduction in all cause mortality
Caution: In renal disease or severe HF
Thiazolidinedione (TZD)- Pioglitazone
Decrease in CVD, insulin sensitizer, reduced HTN, improved triglycerides
Caution: Can increase weight (dose dependent) and cause edema
Contraindicated in Class III/IV heart failure or symptomatic HF
Glucagon-like peptide 1 (GLP-1) agonists
Weight Loss
Liraglutide (Victoza® )
Decrease CVD (LEADER)
Caution: Cannot be used in people at risk for pancreatitis
This slide is meant for a brief review of whats new in DM meds and CVD outcomes
Metformn: 10 years of FUP of UKPDS cohort (Holman et al, NEJM 359, 2008):
- MI reductions 15% with Sulfonylurea or insulin (p=0.01), 33% with metformin as initial therapy
- All cause mortality 13 and 27%.
Accumulating observational data suggest that metformin may be safely continued down to glomerular filtration rate (GFR) of 45 mL/min/1.73m2 or even
30 mL/min/1.73 m2 (19). If metformin is used in the lower GFR range, the dose should be reduced and patients should be advised to stop the medication for nausea,
vomiting, and dehydration. ADA Guidelines 2016 Diabetes Care
Thiazolidinedione TZD Pioglitazone (Actos) : IRIS=Insulin Resistance Intervention after Stroke IRIS Pioglitazone Lowers Risk for Stroke and TIA Vs Placebo Kernan WN, Viscoli CM, Furie KL, et al; for the IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374( ). In IRIS, pioglitazone lowered the risk for stroke and TIA compared with placebo among subjects with insulin resistance who had a recent ischemic stroke or TIA.
Pioglitazone also decreases CVD events, triglycerides and blood pressure
Glucagon-like peptide 1 (GLP-1) agonists –Liraglutide (Victoza): Trial•LEADER assessed the long-term effects of the GLP-1 receptor agonist, liraglutide, on cardiovascular outcomes in high-risk patients with type 2 diabetes. A total of 9,340 patients receiving standard care for type 2 diabetes were assigned 1:1 to liraglutide 1.8 mg/d (or max tolerated dose; n=4,668) or placebo (n=4,672).
•The primary composite endpoint was first occurrence of death from CV causes, nonfatal (including silent) MI, or nonfatal stroke over a median of 3.8 years.
Marso SP, Daniels GH, Brown-Frandsen K, et al; for the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med DOI: /NEJMoa
RESULTS: The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.
CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
SGLT2 Inhibitors Sodium–Glucose Cotransporter 2 Inhibitors :
EMPA-REG (Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), NEJM 2015
Associated with lower CVD event rate and mortality in patients with CVD (EMPA-REGOUTCOME) N=7010, DM2 + established CVD, 3.1 years
EMPA-REG OUTCOME was a cardiovascular safety study of the SGLT2 inhibitor, empagliflozin. Initial results demonstrated that empagliflozin reduced cardiovascular mortality by 38% and all-cause mortality by 32% relative to placebo.1
Results: 1) nonfatal MI, HR (0.87) decreased slightly but not significantly (P=0.22) 2) stroke, HR (1.24) increased slightly but not significantly (P=0.22)
3) CV death, HR (0.62) decreased significantly by 38% (P=0.001)
Treatment with empagliflozin produced a 39% lower risk for incident or worsening nephropathy relative to placebo. The rate of the endpoint occurred among 525/4,124 patients (12.7%) taking empagliflozin compared with 388/2,061 patients (18.8%) taking placebo (HR=0.61; P<0.001).
•Wanner C, Inzucchi SI, Lachin JM, et al; for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med DOI: NEJMoa
Dipeptidyl peptidase 4 (DPP-4) inhibitors
SAVOR (Saxagliptin (Onglyza) Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) NEJM 2013 – vs placebo, T2DM + high CV risk, n=16,492, median follow up 2.1 years, composite of CV death and non-fatal MI or stroke
No difference, increase in HF hospitalizations in Saxa group
EXAMINE (Cardiovascular Outcomes Study of Alogliptin (Nesina) in Patients with T2DM and ACS), NEJM, 2013 vs placebo, T2DM + recent MI/UA, n=5380, composite of CV death and non-fatal MI or stroke, 1.5 years
No difference, no increased risk of HF
TECOS (Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (Januvia) NEJM 2015, same + hospitalization for UA, n=14.671, 3 years
Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

44. DM Medications and Impact on CVD: What’s new?
Sodium–Glucose Cotransporter 2 -SGLT2 Inhibitors
Modest weight loss
Blood pressure reduction
Empaglflozen (Jardiance®)
Decrease in CVD (EMPA-REG OUTCOME)
Decrease in kidney disease
Caution: dose adjustment in people with kidney disease
Dipeptidyl peptidase 4 (DPP-4) inhibitors: Saxagliptin (Onglyza), Alogliptin (Nesina), Sitagliptin (Januvia)
Three trials looking at CVD outcomes – each study showed no difference in CVD outcomes to comparative grp.
Saxaglipitin study had increase in HF admissions
This slide is meant for a brief review of whats new in DM meds and CVD outcomes
Metformn: 10 years of FUP of UKPDS cohort (Holman et al, NEJM 359, 2008):
- MI reductions 15% with Sulfonylurea or insulin (p=0.01), 33% with metformin as initial therapy
- All cause mortality 13 and 27%.
Accumulating observational data suggest that metformin may be safely continued down to glomerular filtration rate (GFR) of 45 mL/min/1.73m2 or even
30 mL/min/1.73 m2 (19). If metformin is used in the lower GFR range, the dose should be reduced and patients should be advised to stop the medication for nausea,
vomiting, and dehydration. ADA Guidelines 2016 Diabetes Care
Thiazolidinedione TZD Pioglitazone (Actos) : IRIS=Insulin Resistance Intervention after Stroke IRIS Pioglitazone Lowers Risk for Stroke and TIA Vs Placebo Kernan WN, Viscoli CM, Furie KL, et al; for the IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374( ). In IRIS, pioglitazone lowered the risk for stroke and TIA compared with placebo among subjects with insulin resistance who had a recent ischemic stroke or TIA.
Pioglitazone also decreases CVD events, triglycerides and blood pressure
Glucagon-like peptide 1 (GLP-1) agonists –Liraglutide (Victoza): Trial•LEADER assessed the long-term effects of the GLP-1 receptor agonist, liraglutide, on cardiovascular outcomes in high-risk patients with type 2 diabetes. A total of 9,340 patients receiving standard care for type 2 diabetes were assigned 1:1 to liraglutide 1.8 mg/d (or max tolerated dose; n=4,668) or placebo (n=4,672).
•The primary composite endpoint was first occurrence of death from CV causes, nonfatal (including silent) MI, or nonfatal stroke over a median of 3.8 years.
Marso SP, Daniels GH, Brown-Frandsen K, et al; for the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med DOI: /NEJMoa
RESULTS: The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.
CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo
SGLT2 Inhibitors Sodium–Glucose Cotransporter 2 Inhibitors :
EMPA-REG (Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), NEJM 2015
Associated with lower CVD event rate and mortality in patients with CVD (EMPA-REGOUTCOME) N=7010, DM2 + established CVD, 3.1 years
EMPA-REG OUTCOME was a cardiovascular safety study of the SGLT2 inhibitor, empagliflozin. Initial results demonstrated that empagliflozin reduced cardiovascular mortality by 38% and all-cause mortality by 32% relative to placebo.1
Results: 1) nonfatal MI, HR (0.87) decreased slightly but not significantly (P=0.22) 2) stroke, HR (1.24) increased slightly but not significantly (P=0.22)
3) CV death, HR (0.62) decreased significantly by 38% (P=0.001)
Treatment with empagliflozin produced a 39% lower risk for incident or worsening nephropathy relative to placebo. The rate of the endpoint occurred among 525/4,124 patients (12.7%) taking empagliflozin compared with 388/2,061 patients (18.8%) taking placebo (HR=0.61; P<0.001).
•Wanner C, Inzucchi SI, Lachin JM, et al; for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med DOI: NEJMoa
Dipeptidyl peptidase 4 (DPP-4) inhibitors
SAVOR (Saxagliptin (Onglyza) Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) NEJM 2013 – vs placebo, T2DM + high CV risk, n=16,492, median follow up 2.1 years, composite of CV death and non-fatal MI or stroke
No difference, increase in HF hospitalizations in Saxa group
EXAMINE (Cardiovascular Outcomes Study of Alogliptin (Nesina) in Patients with T2DM and ACS), NEJM, 2013 vs placebo, T2DM + recent MI/UA, n=5380, composite of CV death and non-fatal MI or stroke, 1.5 years
No difference, no increased risk of HF
TECOS (Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (Januvia) NEJM 2015, same + hospitalization for UA, n=14.671, 3 years
Standards of Medical Care in Diabetes. Cardiovascular disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

45. Lilly’s Treatment Decisions
Lilly wanted to take a anti diabetic medication as she has seen the problems her mom has had with uncontrolled T2 DM.
Metformin is the best first line treatment. It also has CVD benefits and is weight neutral.
If she needs a second medication a GLP-1 agonist would be a good choice as helps with weight loss. New data regarding liraglutide and CVD benefits would also make this a good second medication choice.
She agreed to start the ACE inhibitor for her HTN and engage in lifestyle changes to help benefit
BP reduction.
Results of treatment decision were made as a team
after a discussion about her understanding, concerns barrier to meet goals - and scientific evidence.
She potentially could have financial problems if she loses her job - all things to consider

46. Lilly’s Treatment Decisions
Goals were agreed upon for weight loss and physical activity and she was referred to the CDE and dietitian for further education.
We were going to see if there was a YMCA program for people with diabetes and if not encourage her to exercise with a friend to help with adherence.
She initially wanted to evaluate benefits of lifestyle changes before starting a statin. After discussion regarding scientific evidence she said she would think about taking a moderate dose statin and let us know her decision in the 1 month follow up. She decided not to take aspirin at this time.
She was to see the CDE in one month and RTC in 3 months with f/u lab work.
Patent centered care in working together to help empower her may help with compliance to lifestyle changers and medication
Hopefully she will agree to the statin (even mod dose) and eventually aspirin.
Also close follow up helps with adherence to the plan
Talking Pt – I didn’t mention on slides:  The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices recommends influenza and pneumococcal vaccines for all individuals with diabetes (

47. Hyperglycemia and Acute Coronary Syndrome: AHA Scientific Statement
Hyperglycemia is associated with markedly increased mortality rates in patients hospitalized with acute coronary syndromes (ACS) (with and without diabetes).
Important unanswered question: Is elevated glucose a direct mediator of adverse outcomes in ACS patients or just a marker of greater disease severity?
Many theories but no definitive understanding of pathophysiology.
Paucity of trials but some suggestion w persistent elevated glucose lowering improved short and long outcomes.
Speaker Notes: Fortunately Lilly did not have an MI/ACS but there is increasing concern but many unanswered questions in hyperglycemia in ACS setting.
Executive Summary for your information
Hyperglycemia and Acute Coronary Syndrome
A Scientific Statement From the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism
Prakash Deedwania, MD, FAHA, Chair; Mikhail Kosiborod, MD; Eugene Barrett, MD, PhD; Antonio Ceriello, MD; William Isley, MD; Theodore Mazzone, MD, FAHA; Philip Raskin, MD, FAHA
Abstract—Hyperglycemia is common and associated with markedly increased mortality rates in patients hospitalized with acute coronary syndromes (ACS). Despite the fact that several studies have documented this association, hyperglycemia remains underappreciated as a risk factor, and it is frequently untreated in ACS patients. This is in large part due to limitations of prior studies, and the remaining critical gaps in our understanding of the relationship between hyperglycemia and poor outcomes. The main objective of the present statement is to summarize the current state of
knowledge regarding the association between elevated glucose and patient outcomes in ACS and to outline the most important knowledge gaps in this field. These gaps include the need to specifically define hyperglycemia, develop optimal ways of measuring and tracking glucose values during ACS hospitalization, and better understand the physiological mechanisms responsible for poor outcomes associated with hyperglycemia. The most important issue, however, is whether elevated glucose is a direct mediator of adverse outcomes in ACS patients or just a marker of greater disease severity. Given the marked increase in short- and long-term mortality associated with hyperglycemia,
there is an urgent need for definitive large randomized trials to determine whether treatment strategies aimed at glucose control will improve patient outcomes and to define specific glucose treatment targets. Although firm guidelines will need to await completion of these clinical trials, the present statement also provides consensus recommendations for hyperglycemia management in patients with ACS on the basis of the available data. (Circulation. 2008;117: )
Elevated glucose is common in ACS patients and is a powerful predictor of adverse outcomes.1–25 Yet, despite growing body of knowledge about the prognostic importance of elevated glucose in ACS patients and some evidence of improved outcomes from tight glucose control in other critically ill populations, clinicians currently have limited guidance regarding the evaluation and management of hyperglycemia in the ACS setting. The lack of specific direction in regard to glucose management in ACS patients stems from methodological limitations of prior studies and the lack of convincing data from randomized trials to establish the benefit of tight glucose control in this patient population. Because of these limitations, multiple critical knowledge gaps currently exist in our understanding of the relationship between elevated glucose and adverse outcomes in ACS patients.
Prakash Deedwania, MD, i. e., Circulation. 2008;117:

48. Hyperglycemia and Acute Coronary Syndrome: AHA Statement Summary
Glucose level should be a part of the initial laboratory
evaluation in all patients with suspected or confirmed ACS (A)
2. In Patients with ACS admitted to ICU monitor glucose levels (B)
3. It is reasonable to consider intensive glucose control in patients with significant hyperglycemia (plasma glucose >180 mg/dL), regardless of prior diabetes history (B)
4. Until further data are available, approximation of normoglycemia appears to be a reasonable goal (suggested range for plasma glucose 90 to 140 mg/dL), as long as hypoglycemia is avoided. (C)
Prakash Deedwania, MD, i. e., Circulation. 2008;117:
Speaker Note:
Read from slide –Recommendations from Committee – these from they are similar to 2016 ADA hospitalized patients with hyperglycemia.
Some potential thoughts about pathophysiology: hyperglycemia ACS and poor outcomes
Decrease in collateral circulation
2 Kersten and colleagues have shown decreased collateral circulation and increased infarct size in the setting of severe hyperglycemia.
3. Studies in animals have shown that acute hyperglycemia abolishes ischemic preconditioning and promotes apoptosis.
4. Hyperglycemia is also associated with elevated systolic and diastolic blood pressures and QT prolongation, changes that were alleviated with hyperglycemia correction.
5. Microvascular dysfunction,
6. Prothrombotic state (see next slide)

49. Hyperglycemia and Acute Coronary Syndrome: AHA Statement Summary
Intravenous infusion of insulin, is the most effective method
of controlling glucose in patients hospitalized in ICU. Avoid
hypoglycemia, shown to have an adverse prognostic impact. (B)
6. Institute treatment as soon as feasible. (C)
7. Maintain plasma glucose in patients in <180 mg/dL with subcutaneous insulin regimens. (C)
8. Evaluate ACS patients with hyperglycemia but no prior history of diabetes (preferably before hospital discharge (B)
9. Make a plan for optimal outpatient glucose control in patients with established diabetes, newly diagnosed diabetes, or evidence of insulin resistance prior to discharge. (C)
Prakash Deedwania, MD, i. e., Circulation. 2008;117:
Speaker notes – read from slide
Other possible pathophysiology possibilities
Higher glucose levels in patients with ACS have also been associated with higher free fatty acid concentrations, insulin
resistance, and impaired myocardial glucose utilization, thus increasing the consumption of oxygen and potentially worsening
ischemia. Higher free fatty acid concentrations have been linked to increased incidence of malignant ventricular
arrhythmias. Finally, hyperglycemia has been linked to an impaired immune response.57 Figure 3 summarizes the
detrimental effects of glucose on cardiovascular and other organ systems

50. Used with permission NDEI.
Steno-2: Effect of Multifactorial Intervention on Various CV Events in Type 2 Diabetes
Older trial but shows the CVD benefits of lifestyle and Risk Factor reduction in patients w type 2 DM
In the Steno-2 study, 160 patients with type 2 diabetes and persistent microalbuminuria were randomized to receive either intensive therapy (n=80) or conventional therapy (n=80). Intensive therapy consisted of multiple drug combinations and behavior modification. Patients were observed for a total mean period of 13.3 years (mean treatment period, 7.8 years; mean observational follow-up period, 5.5 years).
This figure shows the number of events for each component of the composite endpoint. During the 13.3-year study period, there were 51 events among 25 patients in the intensive-therapy group and 158 events among 48 patients in the conventional-therapy group. The mean number of major cardiovascular events was 0.6 with intensive therapy and 2.0 with conventional therapy.
The number of events in each category was greater for conventional therapy than for intensive therapy.
There was an absolute risk reduction for death from any cause of 20% among patients who received intensive therapy versus those who received conventional therapy.
In at-risk patients with type 2 diabetes, earlier intensive intervention with multiple drug combinations and behavior modification provided sustained carryover benefits with regard to rates of death from any cause.
Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:
20% Absolute Risk Reduction - dying from any event
13% Absolute Risk Reduction death from CV causes
29 % Absolute Risk Reduction of CV events
Decrease in RR of nephropathy
Decrease in RR of autonomic neuropathy
57% ↓ in RR of progression in retinopathy
Statins and Antihypertensives had biggest effect
Early Intervention compared to late intervention may be explanation
No diff in grps of major hypoglycemia or medication side Gaede P et.al, NEJM 358;6 Feb 7, 2008. .
Used with permission NDEI.

51. Patient Centered Care: Summary
Use a patient-centered communication style that incorporates patient preferences, assesses literacy and numeracy, and addresses cultural barriers to care. (B)
Treatment decisions should be timely and based on evidence- based guidelines that are tailored to patient preferences, prognoses, and comorbidities. (B)
If goals not met – review adherence, identify barriers to treatment, fears of medications, cultural issues , financial burden especially with multiple medications, consider different treatment, define explicit goals .
Encourage Family and Social support.
Refer to Cardiac Rehabilitation.
American Diabetes Association Standards of Medical Care in Diabetes. Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12

52. Summary
Patients with diabetes represent a challenging population with an increased risk for CVD, multiple CV risk factors, co-morbid conditions and multiple medications.
Health care providers need to be knowledgeable
about scientific evidence and National Guidelines for CVD risk reduction.
All health care professionals, irrespective of clinical setting, need to be involved in:
Identification and assessment of CVD risk factors
Initiating treatment of CVD risk factors
Incorporating both lifestyle interventions and pharmacotherapy to get patients to goal.

53. THANK YOU!
QUESTIONS?

54. Discussion Questions
Do the diabetic patients in your setting understand their risks regarding heart disease?
What is the biggest barrier your patients encounter when it comes to making lifestyle change?
Are you aware of PCNA tools such as the Heart Healthy Toolbox to help patients engage in lifestyle change?