t2d treatment intensification 2 Flashcards
FDA Guidance for Industry Evaluating Cardiovascular Risk in New Antidiabetic
Therapies to Treat Type 2 Diabetes
when is it: Approvable; no need for postmarketing study Approvable; need for postmarketing study Not approvable
Superiority, non-inferior (less than 1 for hazard ratio)
non-inferiorily, hazard ratio more than 1
inferior or underpowered (wide CI)
Study design placebo controlled to show their drug is no worse than placebo in increasing risk of CV utcome
mace outcomes
3, 4, 5
3-P MACE = CV Death, nonfatal MI, nonfatal Stroke
4-P MACE = 3-P MACE + Unstable Angina hospitalization
5-P MACE = 4-P MACE + Heart failure hospitalization
– Cardiovascular-related death – Nonfatal myocardial infarction – Nonfatal stroke – Hospitalization for unstable angina – Hospitalization for heart failure
common features of CVOT
Inclusion criteria selected to identify patients at high risk of cardiovascular outcomes
– Prior cardiovascular event or documented atherosclerotic disease (
If you had primary event, you are at risk of secondary)
– Multiple cardiovascular risk factors
• Placebo controlled trial
• Background glucose lowering therapy allowed at clinician’s discretion according to local guidelines
2 drugs vs 3 drugs
Slight diff in glucose levels
Is it a drug effect or diff in bg levels
• Non-inferiority design
results of studies done with MACE Outcomes
gliptinbs, glutides, gliflozins
(dpp-4, glp, sglt) safe for MACE outcomes
These drugs are safe
Leader study was first to show liraglutide lowers risk of CV events
renal outcomes
SGLT2 showed renal benefit and less heart failure signal
amputation signal from canvas
canvas showed favoured placebo, credence and others did not show difference
Cohort and case control studies to see if signal is there
Usually Start if above 60
Credence started b/w 30-60
- Less likely to develop or progress CKD
Start early
Other Safety Signals
DPP4 inhibitors – Pancreatitis • GLP1 receptor agonists – Retinopathy (SUSTAIN 6 [semaglutide]) • SGLT2 inhibitors – Genitourinary infection (mycotic and bacterial) – Diabetic ketoacidosis • Health Canada Warning: clinical trial and post-market cases of DKA have been reported. A number of cases have been atypical with blood glucose <13.9 mmol/L. Assess for DKA if non-specific symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, anorexia, excessive thirst, and unusual fatigue or sleepiness occur, regardless of blood glucose level. – Fracture • Thiazolidinediones – Heart failure • Health Canada Warning: can cause or exacerbate fluid retention and heart failure. Not recommended in patients with a history of ischemic heart disease. – Macular edema – Distal fractures in women
Sulfonylureas and Adverse Cardiovascular Effects
~36 studies examining the risk of cardiovascular events in patients using sulfonylureas
– 3 randomized controlled trials (UGDP, UKPDS, Hong et al)
– 29 cohort studies
– 4 case-control studies
• Overall impression…
– It looks like sulfonylureas are associated with an increased risk of adverse cardiovascular events
– If you are going to use one, perhaps gliclazide has the lowest risk among sulfonylureas
Incrreased risk
DPP4 just as good or worse as sulfonylurea
Use glicazide
Risk of MI is much lower
Cardiovascular Mortality – 14 Studies
Relative to glyburide, significantly lower using gliclazide
chlorpropamide the hgihest
CAROLINA trials
what did it show?
Patients: type 2 diabetes (median 6.3 years) at high risk for cardiovascular disease
• Intervention: linagliptin
• Control: glimepiride
• Outcome: 3-point MACE (cardiovascular death, nonfatal myocardial infarction,
nonfatal stroke)
NO DIFF B/W DPP OR SULFONYLUREA for 3 point MACE event
As safe as DPP4
what did CAROLINA show for hypoglycemia?
Sulfonylurea promotes bg release
Risk of hypoglycemic events much HIGHER than dpp
Insulin may be used at any time in the course of type 2 diabetes [Grade
D, Consensus] In people not achieving glycemic targets on existing noninsulin antihyperglycemic medication(s), the addition of an _____________should be considered over__________, if lower risk of hypoglycemia and/or
weight gain are priorities [Grade B, Level 2]
once daily basal insulin regimen
premixed insulin or bolus only regimens
In adults with type 2 diabetes treated with basal insulin therapy, if lower risk of hypoglycemia is a priority [over cost]:
a) Long-acting insulin analogues (________) should be considered over NPH insulin to reduce the
risk of nocturnal and symptomatic hypoglycemia [Grade A, Level 1A]
b) _________may be considered over insulin glargine U-100 to reduce overall and nocturnal hypoglycemia [Grade B, Level 2 for patients with ≥1 risk factor for hypoglycemia, Grade C, Level 3 for others and severe hypoglycemia in patients at high CV risk [Grade C, Level 3]
c)_________ may be considered over insulin glargine U-100
to reduce overall and nocturnal hypoglycemia [Grade C, Level 3]
insulin glargine U-100, glargine U-300, detemir, degludec
Insulin degludec
Insulin glargine U-300
insulin regimen
24 hours of action, once a day
Degludec –> ultra long, once a week
Check morning sugars
Increase dose if needed
1 dose of bolus for largest meal of the day
Close to hypoglycemia, can back off
If bolus on top of basal dose, need to stop sulfonylurea (much higher risk)
- When bolus insulin is added to antihyperglycemic agents,____________ may be used instead of __________ insulin to improve glycemic control [Grade B, Level 2]
rapid acting analogues
short aciting
