This document discusses diabetes management and cardiovascular outcomes. It recommends screening adults for diabetes starting at age 45. It notes that glucose control has the greatest impact on microvascular disease while macrovascular benefits are more modest. Newer medications like GLP-1 agonists and SGLT-2 inhibitors have shown cardiovascular benefits independent of HbA1c lowering. The document provides guidance on balancing risks and benefits of different medication classes for diabetes treatment.
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?
CLINICALLY IMPORTANT
OUTCOMES:
- Macrovascular: MI, stroke, CV
death
- Microvascular: renal disease,
neuropathy, retinopathy
- adverse events
SURROGATE (INTERMEDIATE)
OUTCOMES:
- HbA1c lowering
- failure of monotherapy to lower
glucose levels
7.
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.
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
GLP-1 – RA
• 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
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.
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
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.
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
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)
• Available since 1997
• Pioglitazone is the TZD mostly available
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 50-100%, 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
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
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.
