1. Diabetes and Coronary Artery Disease
By Jean Molinary, DO

2. Screening for Diabetes in Adults
ADA: Risk based, or starting at the age of 45, then every 3 years if normal

3. Diabetes is Target-oriented:

4. Macrovascular complications: higher with DM

5. Remember Why We Treat
Glucose control has greatest impact on Microvascular disease= PREVENTING MISERY
 Macrovascular impact of glucose control takes longer, is only modest, but is real; Other approaches are more potent = PREVENTING DEATH
Tailoring regimens to reduce CV disease is the next frontier in diabetes management

6. What outcomes do we really care about in diabetes?
SURROGATE (INTERMEDIATE) OUTCOMES:
- HbA1c lowering
- failure of monotherapy to lower glucose levels
CLINICALLY IMPORTANT OUTCOMES:
- Macrovascular: MI, stroke, CV death
- Microvascular: renal disease, neuropathy, retinopathy
- adverse events

8. Outcome: Macrovascular (CV) events
Since 2008, the FDA has required evidence demonstrating the CV safety for newly approved glucose-lowering medications (CV outcome trials).
A large number of CV outcome trials have now been conducted demonstrating CV non-inferiority and/or superiority of newer glucose lowering medications (e.g. DPP- 4’s, SGLT-2’s, GLP-1RA’s).
Primary outcome: 3-point MACE (CV death, MI, stroke)
CV effects appear to be independent of effects on HbA1c.

11. Big Change #1: Choose based on Cardiac and Renal status

12. Mechanisms of Cardio-renal Benefit: SGLT-2 Inhibitors vs GLP-1 Receptor Agonists

13. GLP-1 RA vs. SGLT-2 Inhibitor - Positives
• GLP-1 – RA • Greater A1c reduction • Greater weight loss • No hypoglycemia • Probably more anti- atherogenic potential • Indicated for all levels of GFR (except for exenatide) • Can be once weekly
• SGLT-2 inhibitor • Oral • No hypoglycemia • Better for heart failure • Probably better for CKD • Lower cost • Not depend upon Beta-cell function

14. GLP-1 RA vs. SGLT-2 Inhibitor - Negatives
• Injection
• Nausea
• Higher cost
• Lesser efficacy with lower 𝛽𝛽- cell reserve
SGLT-2 inhibitor
Less A1c lowering
Genital mycotic infections
Volume depletion
DKA
Less effective at low GFR

15. GLP-1 RA: Safety Warnings
Acute Kidney Injury
Pancreatitis
Medullary Cancer of the Thyroid
Gallbladder conditions (Liraglutide)
Retinopathy (Semaglutide)

16. GLP-1 agonists common cautions and concerns
Not so Real
• Thyroid cancer
Medullary TC: An increased incidence of C-cell neoplasia in rodents, however, no established mechanism in humans and no increased incidence of nodular disease or any form of thyroid cancer
• Hypotension
Systolic blood pressure fell by 3.6mm Hg in the liraglutide 1.8mg group compared with 0.7mm Hg in the glimepiride group; clinically harmful low BP not described, not seen in practice
• Pancreatic Cancer
Multiple metananalyses or prospectively followed subjects show NO increased risk across all agents
Real
• GI intolerance
- Very common with exenatide, semaglutide, liraglutide
• Gallstone disease - Liraglutide
• Pancreatitis – Low risk
- In Practice, often Gallstone mediated
-  FDA has previously warned of an increased (post-marketing) risk of acute pancreatitis among users of exenatide, but this risk appears low and not clearly related to taking the drug
-  Liraglutide and semaglutide: elevated amylase and lipase activity, without symptoms of acute pancreatitis.

17. Thyroid Cancer Events in GLP-1 RA CVOT

18. Time to Confirmed pancreatitis: LEADER

19. SGLT-2 Inhibitor: Safety Warnings
Acute Kidney Injury • Volume Depletion
Hyperkalemia
UTI’s
Genital Infections/Fournier’s gangrene
Diabetic Ketoacidosis
Amputations (canagliflozin, ertugliflozin)

20. Fournier’s Gangrene with SGLT-2 inhibitors
Most commonly due to genital or anorectal abscess, pressure sores, chronic catheterization
Impairment in microcirculation or immunosuppression
Comorbid conditions usually present:
Diabetes
Hypertension
Obesity
Congestive heart failure
Smoking
Immunosuppression
Peripheral vascular disease
Alcohol abuse
Suspect when pain out of proportion to physical findings

21. How to Handle DKA Associated with Use of SGLT2 Inhibitors
If a diabetic individual develops DKA during SGLT2 inhibitor therapy, do not restart it, as there have been several reports of recurrent of DKA with continuous SGLT2 inhibitor therapy
SGLT2 inhibitor therapy should be also stopped during acute illness and at least 48 h before any planned procedure, so that a catabolic state is not aggravated and the risk of DKA is minimized.
Carefully consider alternative antihyperglycemic therapies

22. Minimizing Amputation Risks with SGLT-2 Inhibitors
Canagliflozin (SGLT-2 inhibitors) should be used with caution in individuals at risk for amputations, such as those with advanced PVD, severe peripheral neuropathy or prior history of lower-limb amputation or foot ulceration.
Minimize risk for volume depletion
Discontinue SGLT-2 inhibitors in the presence of active foot ulcer, infection.

23. Tips and Tricks: SGLT2 inhibitors
Choose the right patient who can afford it
With heart disease
With heart failure
With CKD
Circumcised men without urinary hesitancy/frequency
Women without serious tinea
Educate
Hold for fasting
Hold for procedures

24. WHAT ABOUT OLDER MEDS?
Define the effects of metformin, sulfonylureas and thiazolidinedione on cardiovascular risk.

25. Metformin Metformin available since 1995.
Mechanism: reduce hepatic glucose output. May also increase
insulin sensitivity.
Dosing: slow titration, with meals, 2000 mg/day maximal effective dose.
A1c lowering: 1-2%
Pros: weight loss, no hypoglycemia, efficacy, metabolic improvements, outcome measurements, history of use. Possible cancer prevention effect
Cons: GI side-effects, renal insufficiency and lactic acidosis.

26. What should come after metformin?
What is your practice?

27. Sulfonylureas Available since 1954.
Names: Glipizide, Glyburide, Glimeperide
Mechanism: bind to SU receptor, stimulates insulin secretion = the insulin squeeze
Dosing: prior to meals, glucose-lowering effect plateaus around 1⁄2 max dose.
A1c lowering: 1-2%
Pros: long history of use, cost, efficacy, daily dosing, outcomes measurements.
Cons: weight gain, hypoglycemia, (CV effects, beta- cell decline?), caution with renal and liver dysfunction.

28. Do Sus increase CV mortality?
Recent meta-regression analysis of 19 RCTs with SUs as comparator
Sulfonylureas were associated with an increased risk of cardiovascular events and mortality in 5 of the 6 studies found to have low design bias (relative risks 1.16– 1.55)
In patients with ASCVD, it is wise to avoid agents that are known to act on the myocardial ATP sensitive potassium channel
Glyburide should be avoided
3rd generation glimepiride has not been found to have myocardial activity and do not appear to impair “ischemic preconditioning”
Glipizide – no human studies showing specific potential harm •
More reassurance from glimepiride?
A recent large CVOT comparing DPP4 inhibitor linagliptin to glimepiride did not show a difference (CAROLINA) in MACE; linagliptin vs. placebo also did not show a difference (CARMELINA)

29. Tips and Tricks: Sulfonylurea
Do not use glyburide
Long acting; cardiovascular concerns
Start with glimepiride
Consider using premeal shorter acting (glipizide) as a “next step” after failure, may have more potency
Don’t titrate beyond the max effective dose
If control is poor after 10 years, not working, replace!

30. Thiazolidinediones Available since 1997
Pioglitazone is the TZD mostly available
New Data
Lowers progression to cirrhosis in Nonalcoholic Steatohepatitis (Cusi, 2016)
Lowers risk of stroke (Kernan, 2016)
Prevents progression from prediabetes to diabetes (Kernan, 2016)

31. TZDs are affordable and effective but should I use them?
Rosiglitazone
Meta-analysis1 of all available randomized trials
MI risk increased 43% (p=0.03) - CV death risk increased 64%
(p=0.06)
Risk of CV death was double the comparator (p=0.02)
MI risk confirmed with longer- term meta-analysis2
Pioglitazone
• Meta-analysis3 of 19 trials
The primary outcome (death, non- fatal MI, non-fatal stroke) was 18% LESS common with pioglitazone (p=0.005)
Pioglitazone: 4.4% - Control: 5.7%

32. Thiazolidinediones IRIS study
                       
The TZD, pioglitazone,’d fatal/non-fatal stroke & MI by 24% (and 52%progression to DM) in 3895 insulin resistant patients with stroke or TIA.
(Supports MACE results from PROactive study.)

33. TZD Side Effects Heart Failure
Rates of HF are substantially increased with both rosiglitazone and pioglitazone (relative increase %, absolute increase 1-2%)1,2
FDA issued a black box warning about this risk for both TZDs

34. Glitazones side effects
Fractures
Glitazones cause an increased risk of fracture in women • PROactive: 5.1% (pio) v. 2.5% (placebo) • ADOPT: 9.3% (rosi) v. 3.5% (glyburide) v. 5.1% (metformin)
Hypoglycemia
Glitazones do not appear to increase risk of hypoglycemia; more limited data for other agents although risk theoretically low
Bladder cancer
debate about whether pioglitazone promotes or causes bladder cancer
dose response
FDA withdrew warnings about the use of pioglitazone being associated with an increased risk of bladder cancer.

35. Tips and Tricks: TZDs Select the right patient: Fatty liver
TIA, stroke history
MI history, normal EF, unable to take SGLT2i

36. Bottom Line: When to avoid a class

37. Approach to Hyperglycemia
Endocrine Society: Patients ≥ 65 years old with diabetes should have their outpatient regimen “designed specifically to minimize hypoglycemia”
Relaxing glycemic targets for older patients with high burden of comorbidities and limited life expectancy may be appropriate, yet goals that minimize hyperglycemia are indicated for all patients

38. Is hypoglycemia risk reduction worth the price tag?
Answer: Sometimes, mostly in older adults and those with ASCVD

39. Mild symptomatic hypoglycemia is not associated with serious clinical effects.
Severe hypoglycemia is serious, particularly in the elderly
People > 80 years old, 25% of hospital admissions related to diabetes were due to severe hypoglycemia. Falls increase with lower A1c in those on insulin
Almost 50% presented with loss of consciousness.
Approximately 5% were associated with stroke, myocardial infarction, TIAs, or death
Severe hypoglycemia is associated with increase mortality, and the more frequent the events, the higher the risk of death
Observed in both Inpatient and outpatient settings
Increased risk of death is 10x higher in the year after a severe event than in subsequent years (VADT)
Hypoglycemia limits the ability achieve and maintain glycemic control

40. Glycemic Targets

41. Glycemic Targets
Note targets set to be achievable without significant hypoglycemia
Included a lower-limit to HbA1c given data suggesting higher
hypoglycemia and mortality risk at lower HbA1c levels, especially
with insulin
Does not mean to a higher HbA1c means safety from hypoglycemia!

42. Why focus on Hypoglycemia?
Increase risk for: falls, fractures, arrhythmias
Bi-directional association with cognitive decline
In analysis of the ADVANCE trial: severe hypoglycemia nearly doubles adjusted risk for micro- and macro- vascular events

43. GLP-1 Receptor Agonists
Low risk of hypoglycemia
+CV benefit (recent CVOT ~50% over age 65)
Careful with weight loss and appetite suppression in elderly population
Weekly dosing may be easier for care givers, help adhere to the treatment plan
Increased risk of pancreatitis has not been clearly established
GLP-1 agonists may be beneficial for cognition?

44. Reducing Risk for Adverse Reactions with GLP-1 Receptor Agonists
Avoid Volume Depletion/Nausea and Vomiting
Start low and go slow – consider even slower titration than recommended or use medication with lowest risk for nausea (Exenatide QW)
Advise about risk for nausea and vomiting, with recommendation to seek early medical attention if severe
Advise to serve smaller serving sizes and to eat more slowly – stop when no longer hungry

45. SGLT2 inhibitors Low risk for hypoglycemia, can promote weight loss
Likely class effect on reducing CV events, CHF and CKD progression
Risks include polyuria/dizziness, dehydration, genital mycotic infections, DKA
Canagliflozin: lower bone density at total hip (but not other sites), increased risk of limb fracture (but not spine); amputations?
No signal that side effects are worse in elderly compared to phase 3 studies

46. Reducing Risk for Adverse Reactions with SGLT-2 Inhibitors
Volume Depletion
Assess BP – if at goal, consider reducing doses of other antihypertensives, especially diuretics
Advise consumption of additional 500 ml of water daily
Genital Mycotic Infections
Consider risk-benefit in those with history of recurrent GMI or incontinence
Advise on careful genital hygiene
Consider use of barrier creams/ointments
DKA
Avoid in patients with Type 1 diabetes
Advise patients about symptoms
Discontinue prior to planned procedures
Early intervention with fluid, carbs and insulin in symptomatic patients
Amputations
Avoid volume depletion
Delay using in presence of ulcer or extremity infection, until healed
Advise patient to discontinue in presence of ulcer, lower extremity infection

47. Summary
The long-term benefits of SGLT-2 inhibitors and GLP-1 receptor agonists (over and beyond glycemic control and weight) outweigh the serious risks that have been described in clinical trials
Reduction in 3-point MACE
Reduction in hospitalization for heart failure (SGLT-2 inhibitors) • Reduction in risk for progression of diabetic kidney disease
Counselling patients of the relative risks of and how to minimize serious adverse events is important to help patients make informed decisions.