Pharmacology of DM- 1 & 2 Flashcards
What are the foundations of managing diabetes?
FOR ALL:
- Appropriate lifestyle modification
- Multifactorial risk reduction to prevent and treat macrovascular complications
- HTN
- Dyslipidemia
- Body fat
- Prevent and treat microvascular complications
Glycemic control:
- For type 1: insulin ONLY; must always be “on board”
- For type 2: oral agents, insulin, combinations
What are the (3) main lifestyle modifications that should be made in managing diabetes?
- Diet
- Exercise
- Weight control
What are the general principals of a diabetic diet (Type I and II)?
Type I
- Under 60% carbs; keep carb proportions low (best for weight control)
- 30-35% fat: stick to healthy fats
- Limit salt and alcohol
Type II
- Same principles except may also want to limit total calories (reduction in energy intake to lower body weight in the obese)
What are the benefits of exercise on diabetes?
- Mechanism
- Guidelines
- Increases insulin sensitivity
- CV benefits
- 20 min/day, HR 120/min, DAILY (brisk walk)
- Acute effect and fades quickly, so need to do everyday
What are the benefits of weight loss on diabetes?
- Promotes insulin sensitivity (independent of exercise)
- Beneficial effect is proportional to central fat lost (deep visceral fat is what contributes to insulin sensitivity; liposuction of subcutaneous fat has no effect)
- Even loss of 3-5lb changes fasting glucose! (although may not have huge CV effect)
- CV benefits
- IBW: but ANY degree helps
- LookAHEAD: NIH trial that got 5% sustained body weight loss with CV effect being end result studied… not very encouraging results. No difference (can’t compete with statin effect) BUT big change in glycemic control. Actually optimistic outcome (?)
What was found in DCCT/EDIC and follow up trials?
- HbA1C
- CV effects
- Glycemic control
- Microvascular effects
Dealing with Type I diabetics!
- HbA1C difference at close of study (better in intensive vs. conventional group)
- No change in CV effects at closeout (but only because it took longer for manifestations to come about)
- Intensive insulin therapy reduced the risk of cardiovascular complications in type 1 diabetes
- No difference in glycemic control in trial follow up, BUT intensive therapy reduced the incidence of retinopathy and microabluminuria in type I diabetes
What was the population of the UKPDS study?
Type II diabetics
What was found in the UKPDS study?
- End point glycemic control
- Endpoints
- Follow up
Glycemic control
- Intensive therapy group had big drop in HbA1C down to normal level (under 6.5%); conventional group had tiny drop
- Initial HbA1C drop was not sustainable; both groups rose in parallel, but intensive group still lower. HbA1C remained below initial levels for 6 yrs
Endpoints
- Microvascular complications greatly reduced for intensive group (retinopathy, microalbuminemia reduced 20-30%)
- Macrovascular complications did not achieve statistical significance
Follow-up
- Glycemic levels converged
- Sustained benefits for intensive group, including CV effects (decrease in MI rates many years later)
Not quite as impressive improvements as type I study, but glycemic control is tremendously important, even if unsustained
Why, despite continuing therapy, was it that glycemic control/HbA1C was unsustainable in UKPDS study?
Thought to be due to progressive beta cell loss
- Inexorable increase in glycemia due to increasing lessening of insulin secretion
What are targets for glycemic control in Type II diabetes (organs and the problem)
- Drugs for each
Gut
- a-GSI
- Diet
- Incretins
Liver (increased glucose production)
- BG
- Insulin
Pancreas (impaired insulin secretion)
- SU
- Meglitinides
- Incretins
Kidneys (glycosuria)
- SGLT2 inhibitors
Muscle and Fat (receptor/post-recep defect and insulin resistance)
- TXD
- BG
- Insulin
- Exercise
What are oral antihyperglycemic classes?
- Secretagogue
- Biguanide
- a-Glucosidase inhibitor
- Glitazone (TZD)
- Incretins
- SGLT2 inhibitors
What are secretagogue drugs?
- Sulfonylureas
- Repaglinide
- Nateglinide
What are biguanide drugs?
- Metformin
What are a-Glucosidase inhibitors?
- Acarbose
- Miglitol
What are Glitazone (TZD) drugs?
- Pioglitazone
- Rosiglitazone
What are incretins?
GLP-1 agonists:
- Exenatide
- Liraglutide
Dipeptidyl peptidase inhibitors:
- “Glipitins”
What are SGLT2 inhibitors?
- Dapagliflozin
- Canagliflozin
What is the mechanism of insulin secretagogues?
- Efficacy depends on what
- Power comparison
- Dosing
- Side effects
- Main risk
- Mechanism = basal and/or prostprandial insulin secretion
- Efficacy depends on functioning B cells
- Power of sulfonylureas > Nateg/Repag in terms of A1C decrease (0.5-1%)
Dosing:
- Sulfonylureas: 1-2x/day
- Repaglinide/nateglinide: 3-4x/day with meals
Side effects:
- Weight gain
- SIADH
Main risk = hypoglycemia
How does Metformin (MOA of French Lilac) work?
- Mechanism?
Metformin -> LKB-1 -> phosphorylation/activation of AMPK
- Decreased ACC activity (effects below)
- Decreased SREBP-1 expression/activity and thus less gene expression of FAS
- Less hepatic FA, VLDL synthesis, increased FA oxidation
- Less hepatic steatosis, increased liver insulin sensitivity
- Decreased hepatic glucose production
- Increased muscle glucose uptake
Describe the action profiles of insulin/analogs
- Regular
- NPH
- Ultralente
- Aspart
- Lispro
- Glargine
- Aspart and Lipro have fastest increase and most peaked insulin serum levels (4-6 hr peak)
- Regular (6-8 hr peak)
- NPH (12-20 hr peak)
- Ultralente (18-24 peak)
- Glargine (24 hr peak)
What treatment/combo are best for mimicing physiologic insulin release?
- Glargine to maintain fasting levels of insulin
- Lispro or Aspart 3x/day with meals
What are the usual sites of insulin administration? Results?
- Upper arms
- Thighs
- Lower abdomen
- Buttocks
May result in insulin-induced lipoatrophy nad lipohypertrophy
