ENDO - Diabetes management and therapeutics Flashcards
describe currently available oral hypoglycaemic agents used in Type 2 Diabetes and the rationale for drug use
- Metformin (First line. CI in renal impairment)
- Sulphonylureas (Second line. used if HbA1c is above target on metformin. Risk of hypos - CI in some professionals)
- α-Glucosidase inhibitors
- Thiazolidinediones (E.g. Glitazone. Third line if SU CI. no hypos but weight gain)
- DPP4 inhibitors (Third line if SU CI. induces weight loss)
- GLP-1 analogues (Third line if SU CI.induces weight loss)
- SGLT2 inhibitors (will be available in Australia late 2013)
explain the indications of specific oral hypoglycaemic agents
(Step down every time HbA1c is above target)
1. Starting with metformin at diagnosis as first line.
- SU
- DPP4 inhibitor if SU CI
- GLP1 analogue if SU CI & significantly overweight - Triple therapy
- metformin + SU + DPP4i
- metformin + DPP4i + SU
- metformin + GLP1 + SU - Add daily insulin (basal or premix). DPP4i or GLP1 are usually ceased when insulin is added!
- metformin + SU + insulin - Multiple insulin doses (SA + LA)
describe the major insulins and insulin regimens used to treat both type 1 and type 2 diabetes.
Short acting: aspart, glulisine, lispro
- Onset 10-20 minutes
- Peak, 1-3 hrs
- Duration 3.5-4.5 hrs
Long acting: detemir, glargine
- Onset: 2-4 hrs
- Peak: 8-10 hrs detemir, variable for glargine
- Duration: 14-16 hrs detemir 16-24 hrs for glargine
T1D:
Use short acting insulin just before meals with carbs calculation & use long acting at night before bed for a basal line to mimic the physiological insulin levels.
T2D:
- Glargine (LA) before bed at initiation
- Mixtard 30/70 at dinner (once a day) or Mixtard 30/70 BD at breakfast & dinner
- concurrent use of Metformin BD (breakfast & dinner) + Gliclazide MR at breakfast if daily insulin at dinner
What is the evidence base for diet and lifestyle modifications in the management of diabetes?
- intensive glycaemic control reduces compilcations in type 1 diabetes
- early glycaemic control reduces CVD many years later; “legacy effect
- Aim for very good control early in the course of diabetes
- An individual’s HbA1c target must be balanced against the risk of hypoglycaemia
What are the aims of blood glucose management in diabetes?
- Relieve Symptoms
- Prevent or delay long term complications
- Avoid adverse effects of treatment (hypoglycaemia)
- Assist psychological adjustment and improve QOL
What is the balance between strict glycaemic control and hypoglycaemia?
- EARLY intensive glycaemic control reduces mortality and complications (C.f. Tight control LATE in type 2 diabetes offers little benefit for CV complications)
- HbA1c
What level of HbA1C reduces microvascular Cx irrespective of duration of disease?
less than or equal to 7.0%
How can you prevent a hypo by a dietary factor or a pharmagolocial factor? (e.g. hypo pre-lunch)
Switching to lower GI foods (whole grain bread, low GI cereal, porridge, baked beans, etc) -> slower carbohydrate absorption and higher pre-lunch glucose.
A mid-morning snack may be helpful
Changing to more frequent insulin administration is the optimal solution.
E.g. Novorapid (insulin aspart): 6, 6, 8. Lantus (Glargine): 14 before bed.
What are the principals of insulin therapy in T1D?
•Rapid acting analogues generally favoured for most patients
•Long acting analogues are best for basal insulin
•“Basal bolus” regimen preferred:
- Rapid acting insulin analogue with meals (bolus).
- Long acting insulin once or twice a day to provide background (basal) insulin level (which T1D lacks).
•Some patients will be suitable for continuous insulin infusion via a portable pump.
Ideally, basal insulin and mealtime short-acting insulin should be used to mimic normal insulin production and control post-prandial hyperglycaemia
When would you typically inject short acting & long acting insulin?
Short acting insulin just before meals (do carb calculation)
Long acting at night after dinner, which lasts throughout the day
What is a major contributor to HbA1C especially at lower HbA1c levels?
Post prandial glucose
Describe rapid acting insulin.
- examples
- onset
- peak
- duration
aspart, glulisine, lispro
- Onset 10-20 minutes
- Peak, 1-3 hrs
- Duration 3.5-4.5 hrs
Describe long acting insulin.
- examples
- onset
- peak
- duration
Insulin detemir (Levemir)
•Onset of action: 2 hours
•Peak action: 8-10 hours
•Duration of action: 14-16 hours
Insulin glargine (LANTUS)
•Onset of action: 2-4 hours
•Peak action: variable 8-16 hours
•Duration of action: 21-24 hours
True “peakless” insulins are currently in development
What are the principals of T2D therapy?
- Weight loss (80% + overweight)
- Exercise
•Oral anti-diabetic agents:
- Monotherapy
- Dual oral therapy
- Triple oral therapy (sometimes used)
- Insulin
•Manage CV risk factors: lipids, hypertension, smoking, etc.
What are types of oral anti-diabetic agents commonly used in T2D?
- Metformin (CI in renal impairment) - first line. Except in renal function. Reduce dose if eGFR less than 40, and cease if less than 30.
- Sulphonylureas (risk of hypos. e.g. Gliclazide).
- α-Glucosidase inhibitors
- Thiazolidinediones (e.g. glitazone)
- DPP4 inhibitors (induces weight loss)
- GLP-1 analogues (induces weight loss)
- SGLT2 inhibitors (will be available in Australia late 2013)
What are the principals of drug therapy in T2D?
Choice of drug depends on the individual
•Renal impairment: caution with metformin
•Hypoglycaemia a danger: avoid SU and insulin (if possible)
•Overweight: GLP1 and DPP4i an advantage, avoid glitazone
•Long duration of diabetes: β cell function likely to be reduced - insulin often required
Describe metformin as a treatment for T2D
- Metformin is first line in most patients
- Inhibits hepatic glucose production
(+): No weight gain; no major hypoglycaemia!!
(-): GI intolerance is main SE (nausea, diarrhoea) – minimised by using slow release form (XR)
•C/I in renal failure: risk of lactic acidosis. Reduce dose if eGFR
Describe sulphonylurea as a treatment for T2D
E.g. Gliclazide (c.f. Glitazone), glipizide, glibenclamide, glimepiride
- Stimulate B cell insulin release
- Usually 2nd line in type 2 diabetes
(-): weight gain, hypoglycaemia (gliclazide less than others) - C/I or use with caution in pilots, professional drivers, etc.
- Rapidly effective – start with a low dose
- Added if HbA1C is above target on maximal tolerated metformin (up to 2000mg)
- Gliclazide is the SU of choice: backed by good trial evidence. Has same efficacy but less hypoglycaemia than comparable SU’s
What should you use if HbA1C is above target on metformin and SU is contraindicated? Discuss +s and -s of DPP4 inhibitors, GLP-1 agonists, Glitazone (pioglitazone)
You could use DPP4-inhibitors, GLP1 agonists or glitazone.
- DPP4 I – efficacy fair, no hypo’s, no weight gain
- GLP-1 – efficacy good, no hypo’s, WEIGHT LOSS but requires injection
- Glitazone (pioglitazone) – efficacy good, no hypo’s but WEIGHT GAIN, fluid retention, bone loss etc.
Describe managements at initiation of insulin in T2D
- Most patients are insulin resistant and large insulin doses may be required
- Metformin is usually continued
- Sulphonylureas (SU) are continued if once daily insulin is started.
Insulin:
•Once daily: Pre-mixed insulin pre-dinner or glargine at bed time and continue oral agents
•Twice daily: BD pre-mixed insulin and continue metformin
Describe Alpha-Glucosidase inhibitors (Acarbose) as an oral-hypoglycaemic agent
- mechanism
- (+)
- (-)
•Inhibits gut alpha glucosidase , the enzyme that breaks down starches and disaccarides
(+): No weight gain or hypoglycaemia
(-): flatulence (poor tolerance). Must be used with first mouthfuls of food to be effective
Describe thiazolidinediones (oral-hypoglycaemic agent)
(glitazones) pioglitazone, rosiglitazone
- Stimulate ppar gamma and REVERSE insulin resistance
- Effects additive to metformin and S/U (and insulin)
(+): no hypoglycaemia
(-): weight gain, fluid retention and CCF, bone fractures, possible bladder cancer risk (Pio), increase CV events (Rosi – now rarely used)
Describe GLP-1 analogues (oral-hypoglycaemic agent)
Exenatide, liraglutide
- Improve pancreatic islet glucose SENSING and insulin release
- Slow gastric emptying and improve satiety leading to weight loss in most patients
- Used mainly in obese patients with diabetes
(+): weight loss
(-): nausea, vomiting, pancreatitis? (no long-term data), Hypoglycaemia – rare if used alone
•Given as s/c injection before meal ( liraglutide daily; exenatide BD)
Describe DPP-4 inhibitors (oral-hypoglycaemic agent)
Sitagliptin, vildagliptin, saxagliptin, linagliptin
•Prolong GLP-1 action, leading to improved ß-cell sensing: INCREASE INSULIN SECRETION, decrease glucagon secretion
- Commonly used second line after metformin if sulphonylureas are C/I
- Several are available in combination with metformin
(+): no hypos if used alone
(-): occ nausea, hypersensitvity (no long term data)
Describe SGLT2 inhibitors (oral-hypoglycaemic agent)
Gliflozins, Dapagliflozin
• (make you pee sugar) Promote glycosuria, thus lowering blood glucose
(+): mild weight loss, no hypo if used alone
(-): Candida genital infections
•Long term effects unknown (new drug – no post marketing information)
Describe regular insulin (not SA or LA).
- examples
- onset
- peak
- duration
Actrapid
Humulin R
- Onset of action: 30 minutes
- Peak action: 2-4 hours
- Duration of action: 5-8 hours
Used for IV injections & infusions when SA analogues have no advantage in IV use + cost more
Describe medium-acting insulin (not SA or LA).
- examples
- onset
- peak
- duration
NPH (neutral protamine Hagedoorn)
- Onset of action: 2 hours
- Peak action: 6-10 hours
- Duration of action: 12-16 hours
This is a cloudy insulin
Used in “pre-mixes”
Describe pre-mixed insulin
- examples
- onset
- peak
- duration
A mixture of regular (Mixtard) or short acting analogue (Novomix, Humalog mix) with NPH insulin (medium acting)
- Onset of action: 10 minutes
- Double peak action: 1-3 hours and 6-10 hours
- Duration of action: 12-16 hours
- Frequently used BD in type 2 diabetes
explain the mechanisms of action of oral hypoglycaemic agents
- Metformin
- SU
- Alpha-Glucosidase inhibitors (Acarbose)
- Thiazolidinediones
- GLP-1 analogues
- DPP4 inhibitors
- SGLT2 inhibitors
- Metformin (biguanide class): Inhibits hepatic glucose production
- SU: Stimulate B cell insulin release
- Alpha-Glucosidase inhibitors (Acarbose): Inhibits gut alpha glucosidase (the enzyme that breaks down starches and disaccarides)
- Thiazolidinediones: Stimulate ppar gamma and reverse insulin resistance. But weight gain
- GLP-1 analogues: Improve pancreatic islet glucose sensing and insulin release. Slow gastric emptying and improve satiety leading to weight loss in most patients
- DPP4 inhibitors: Prolong GLP-1 action, leading to improved ß-cell sensing: increase insulin secretion, decrease glucagon secretion
- SGLT2 inhibitors: Promote glycosuria, thus lowering blood glucose
What oral hypoglycaemic agents can cause hypoglycaemia? What else should you avoid in risk of hypoglycaemia?
Sulphonylureas (Gliclazide)
Insulin
What does DCCT (diabetes controlled complications trial) show?
Intensive glycaemic control reduces complications in type 1 diabetes over 6.5 years; retinopathy > neuropathy > nephropathy
What does DCCT/EDIC (diabetes study) show?
Early glycaemic control reduces CVD many years later in type 1 DM: “(metabolic) legacy effect”. 57% risk reduction in non fatal MI, stroke or CVD death.
But also legacy effect in T2D.
Intensity of glycaemic control for most benefit
Strict control early on (HbA1C less than 7.0) -> relax later on (Late tight control does little benefit in T2D)
HbA1C target is different for different conditions & criteria.
Which oral hypoglycaemics are still continued on insulin?
Metformin
Sulphonylurea is also continued only on daily insulin (long acting; not short acting)
Difference between Novomix & Mixtard
They are both combination insulins with short acting & medium acting.
Novomix has novorapid as its short acting insulin, which has a faster onset of 10-20 minutes compared to Mixtard which has Actrapid as its short acting insulin, which has a slower onset of 20-30 minutes.
Hence Novomix is taken with the meal, Mixtard is taken before the meal.
Novomix is more commonly used now due to less complications of delayed meal & causing hypoglycaemia etc
