Module 2 Flashcards
main complications of diabetes:
microvascular disease
macrovascular disease
Microvascular Disease
nervous system—causing neuropathy
eyes—causing retinopathy (both non-proliferative and proliferative)
kidneys—causing nephropathy
Retinopathy
Diabetes is the leading cause of blindness
35% of people with diabetes had
7% had proliferative diabetes retinopathy
7% had diabetic macular oedema
10% vision-threatening stages
Modifiable Risk Factors for T2DM
hyperglycemia
hypertension
dyslipidemia
Macrovascular Complications
heart disease, stroke and peripheral arterial disease.
Atherosclerotic cardiovascular disease (ASCVD)—defined as
coronary heart disease (CHD), cerebrovascular disease, or peripheral arterial disease presumed to be of atherosclerotic origin—is the leading cause of morbidity and mortality for individuals with diabetes.
younger onset TDM compared to older age onset
increase in microvascular and macrovascular complications
more rapid progression
worse prognosis
What should women with diabetes (either type 1 or 2) do to reduce the risks to their unborn child during pregnancy?
should have excellent glycaemic control - an HbA1c level of <6.5% (48 mmol/mol),reduce the risk of congenital anomalies
pregnancy should be avoided at HbA1c >10% (86mmol/mol).
take folic acid 5mg daily starting pre-conception and continue until 12 weeks gestation
low-dose aspirin from the end of the first trimester to delivery to reduce the risk of pre-eclampsia.
What are the congenital abnormalities that can occur?
diabetic embryopathy : anencephaly, microcephaly, congenital heart disease, and caudal regression
directly proportional to elevations in A1c during the first 10 weeks of pregnancy
What complications can arise with gestational diabetes?
Gestational diabetes, develops in the third trimester
risk of macrosomia and birth complications.
Is there a risk to the child after they are born?
increased risk of type 2 diabetes and obesity for the child later in life.
How Do We Treat Diabetes?
life styles changes, weight loss and increased activity
glycemic control
the management of hypertension and dyslipidemia
good nutrition
Goals of Medical Nutritional Therapy
1] Promote and support healthful eating patterns, including a variety of foods, in appropriate portions, to:
Improve individualised HbA1c, BP and cholesterol levels
Achieve and maintain body weight goals
Delay or prevent complications
2] Address individual nutrition needs based on personal and cultural preferences. Consider:
Health literacy and numeracy
Access to food choices
Willingness to make behavioural changes and barriers to change
3]Encourage people to maintain the pleasure of eating
Provide positive messages about food choices
Limit food choices only where indicated by evidence
4]Provide the person with diabetes with practical tools for day-to-day meal planning
Diabetes Remission
some groups with T2DM have demonstrated a return to normal glycaemia following weight loss.
What is the DiRECT study?
Who participated?
What are some implications of the study?
What were the findings of the study?
The Diabetes Remission Clinical Trial (DiRECT)
primary care led weight management programme aiming to help people with T2DM of less than 6 years’ duration to lose 10-15kg.
306 people aged 20-65 with T2DM and BMI 27-45kg/m2
intervention group received liquid meal replacement [The Counterweight Plus very low calorie liquid meal]supplements providing 825-853 kcal/day for 12 to 20 weeks with a weight loss goal of 15kg before food was gradually reintroduced
Diabetes and blood pressure drugs were stopped
Remission was achieved in around 50% of participants
Decreases in liver and pancreas fat were identified on scanning
thought to have contributed to improved beta cell function and glycaemic control
Older People and Anorexia
lower energy needs,suffer from lack of appetite, altered taste and smell, and difficulties with chewing and eating,impact on their willingness and ability to eat.
result in anorexia with or without micro nutrient deficiencies.
intentional and un-intentional weight loss risk to bone density and the potential of micro nutrient deficiency
Older People and Obesity
Changes in muscle mass and strength in the elderly (sarcopenia)
BMI is not a good predictor of adiposity.
Chronic Care Model (CCM)
multi-faceted approach
improving the skills of health care professions
working in teams
strategies to educate and support patients
health information systems (including local registers)
decision support mechanisms
CCM Element
Self-management support =Empower and prepare patients to manage their health and health care
Delivery system—a multi-disciplinary team= Assure the delivery of effective, efficient clinical care and self-management support
Decision support= Promote clinical care that is consistent with scientific evidence and patient preferences
Clinical information systems=Organize patient and population data to facilitate efficient and effective care
Health care organization=Create a culture, organization and mechanisms that promote safe, high quality care.
Community resources=Help patients access needed services in the community.
Team Members of Diabetic Care
Doctors and nurses Dietitian Administrator Health educator Pharmacist Podiatrist Mental Health Worker
Care Coordinator
Form a pro-active working relationship Carry out a person centered assessment Provide a central, continuous point of contact act as the key advocate Assist the patient Demonstrate local knowledge Carry out care planning Hold people to account
Different Modes of Care
Delivering Care
Structured Education Programs
why UKPDS was a landmark clinical trial?
involved people who were newly diagnosed and without complications.
treat early
Metformin
Gluconeogenesis is the process by which glucose is generated from non-carbohydrate precursors.
Metformin acts to inhibit this process in the liver,
through inhibition of the mitochondrial respiratory chain complex 1 and activation of AMP-activated protein kinase.
increases the peripheral utilization of glucose in the tissues
decreases absorption from the gastrointestinal tract
cheap to use and does not cause hypoglycemia.
a long-term reduction in risk of microvascular complications, myocardial infarction and overall mortality.
‘start low, go slow’ titration
Gut symptoms not tolerated, changing to a slow-release version of the drug or possibly by decreasing the dose.
can be used in pregnancy for either pre-existing or gestational diabetes.
Long-term metformin result in vitamin B12 -deficiency - test and supplement in those with anaemia or neuropathy.
Sulfonylureas
closing ATP-sensitive potassium channels in the beta-cell of the pancreas.
initiates a chain of events - results in insulin release.
meglitinides
stimulate the release of insulin from the pancreatic beta cells by binding to ATP sensitive potassium channels.
Thiazolidinediones
binding to peroxisome proliferator-activated receptors (PPARs) changing the transcription of genes
influence lipid and carbohydrate metabolism.
first drug[troglitazone] launched in 1997 withdrawn after cases of hepatotoxicity and liver failure.
Pioglitazone is the only drug still available
alpha glucosidases inhibitor
delays the digestion and absorption of starch and sucrose by inhibiting intestinal alpha glucosidases.
GLP1 receptor agonists
also called incretin mimetics
help to lower blood sugar levels after a meal.
given by daily or weekly injection,
oral versions are in late stage development.
Dipeptidyl peptidase 4 (DPP-4) inhibitor
DPP-4) is an enzyme = cleave the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), thus inactivating them
results in increased blood concentration of these incretins
augment the glucose-dependent insulin and glucagon responses
reducing blood sugar.
Sodium-glucose co-transporter-2 inhibitor [SGLT2] inhibitor
Sodium-glucose co-transporter-2 is a sodium dependent glucose transport protein
inhibition causes less glucose to be reabsorbed from the urine
decreasing blood sugar levels.
What is the most serious potential complication of metformin use?
What co-morbidities or other medical events make it more likely?
Lactic acidosis
mortality rate of around 50% ,less than 10 cases per 100,000 patient years of use.
Triggers for lactic acidosis include: Triggers dehydration and sepsi
metformin should be stopped during acute illness where tissue hypoperfusion or dehydration are likely to occur (e.g. myocardial infarction or gastroenteritis).
stopped for two days before having a general anesthetic
three days after the use of iodine containing contrast media.
should not be used at all if -
creatinine is over 1.70 mg/dL (150 µmol/L)
eGFR less than 30 mL/min/1.73 m2
reviewed when the creatinine reaches 1.47 mg/dL (130 µmol/L)
eGFR falls below 45 mL/min/1.73 m2.
eGFR falls to between 30 and 45 mL/min/1.73 m2,dose is reduced by half to maximum 1g daily
two different types of Metformin that can be administered.
Metformin standard release
500mg with breakfast
Increase to twice daily
then three times daily at one week intervals for a normal maintenance dose of 2g per day
usually 1g twice daily, although 850mg three times daily can be used
Adhere to the 3g daily maximum limit
Metformin prolonged release (or modified release)
500mg with evening meal
Gradually increase dose every 10–15 days for a normal maintenance dose of 2g per day
Adhere to the 2g once daily maximum dose limit
Different HbA1c Targets
1]patients without significant hypoglycemia or other adverse effects, newly diagnosed, treated only with lifestyle change or metformin, have a long life expectancy and no significant cardiovascular disease.
2]Most adults who aren’t pregnant should achieve this HbA1c target.
3]Patients with a history of symptomatic hypoglycemia, limited life expectancy, advanced micro- or macro-vascular complications or extensive co-morbidities. Long-standing diabetics who have always struggled to maintain control despite education and appropriate management might also fit into this group.
1]6.5% (48 mmol/mol)
2]7% (53 mmol/mol)
3] 8% ( 64mmol/mol)
which therapies would you discuss as follow-on to metformin?
DPP4-I [weight neutral]
SGLT2-I[promote weight loss]
GLP1 rA[costly]
priority is to avoid further weight gain and ideally to lose weight.
consider an SGLT2 inhibitor before a GLP-1 RA if the eGFR is above the threshold for initiation of this class of drugs (currently eGFR 60 mL/min/1.73 m2)
Sulfonylureas
Examples?
MOA?
Guideline Recommendition?
gliclazide, glimepiride, glibenclamide (glyburide)
only works if there are functioning beta cells
closing ATP-sensitive potassium channels in the beta-cell of the pancreas. This initiates a chain of events which results in insulin release
cheap
most common side effect is hypoglycaemia
recommending gliclazide as a specific drug
in terms of hypoglycaemia risk, gliclazide is a safer option than glibenclamide (glyburide)
used with care in patients with renal impairment.
neutral with atherosclerotic cardiovascular disease and heart failure.
three different types of sulfonylureas
Gliclazide immediate release
- 40-80mg daily with breakfast
- give in divided doses when dose is above 160mg daily
- 320mg daily maximum limit
Gliclazide slow release
- 30mg daily with breakfast
- 120mg daily maximum limit
- 30mg modified release gliclazide = 80mg standard release
Glimepiride
- start with 1mg daily
- increase at 1-2 week intervals by 1mg to usual dose of 4mg daily
- 6mg maximum dose
- little additional benefit above 4mg
Thiazolidinediones
Examples?
MOA?
why controversial?
pioglitazone, rosiglitazone
binding to peroxisome proliferator-activated receptors (PPARs) and changing the transcription of genes that influence lipid and carbohydrate metabolism
actions at PPAR gamma 1 and 2 (found mainly in adipose tissue) improve the insulin sensitivity of the peripheral tissues
action at PPAR alpha affects lipid metabolism
overall effect = increase glucose uptake and use in peripheral tissues and decrease gluconeogenesis in the liver reducing insulin resistance
troglitazone(1997): hepatotoxicity and liver failure.
rosiglitazone(1999): withdrawn from UK in 2010
increased risk of heart failure
Pioglitazone benefit for atherosclerotic CVD provided they do not have a history of heart failure.
Thiazolidinediones Risk
eye- Worsening of macular oedema
heart- increased risk for patients with heart failure when it is combined with insulin.
lungs- very small increase in pneumonia with pioglitazone
bladder-small increased risk of bladder cancer
should not be used in patients with a history of bladder cancer or uninvestigated macroscopic hematuria,those who have risk factors for bladder cancer
bones- increased risk of fractures.Postmenopausal women are most at risk.
Thiazolidinediones—Dose Information
pioglitazone
15–30 mg once daily (15mg if elderly)
45mg daily maximum limit
Alpha Glucosidase Inhibitors Examples? MOA? Side effects? Guideline Recommendition?
acarbose and miglitol
delays the digestion and absorption of starch and sucrose by inhibiting intestinal alpha glucosidases.
Low risk for hypoglycaemia, decreased postprandial glucose rises, cardiovascular safety and low cost
carbohydrates remain in the intestine, causing side effects : flatulence and diarrhea
relatively modest effect on HbA1c
taken three times a day (with each meal)
Polysaccharides
polysaccharides will not help to reverse the hypoglycaemia in the event of a hypoglycaemic episode absorption will be blocked by the drug
only glucose tablets (monosaccharaide )are used to treat hypoglycaemia in patients taking alpha glucosidase inhibitors.
Alpha Glucosidase Inhibitors – Dose Information
acarbose
50mg daily
Increase to 50mg three times a day for 6–8 weeks, to 100mg three times a day
200mg, three times a day, daily maximum limit
modest reduction in HbA1c
GI A/E
3 times daily
not widely use
Meglitinides Examples? MOA? Side effects? Guideline Recommendition?
nateglinide and repaglinide.
stimulate the release of insulin from the pancreatic beta cells by binding to ATP sensitive potassium channels.
their affinity to the binding site is lower and they dissociate from it more quickly than sulfonylureas
much quicker acting than the sulfonylureas
Normal action is within 15–30 minutes.
taken immediately before a meal,
titrated towards the number of meals missed.
cause hypoglycaemia and weight gain
relatively cheap, reduce post prandial glucose increases and are safe when used cautiously in renal disease.
Meglitinides – Dose Information
Repaglinide
0.5mg within 30 minutes of a main meal or 1mg if changing from another oral antidiabetic drug
Adjust at intervals of 1–2 weeks
16mg daily maximum limit
Nateglinide
60mg three times a day, taken within 30 minutes of a main meal
180mg, three times a day, maximum limit
not use widely
useful for irregular eating pattern
GLP-1 Receptor Agonists (GLP-1 RAs)
Incretin Mimetics
1]What is GLP-1?
2]How long does the normal incretin response last?
3]What are examples of GLP-1 RA drugs?
4]How do they work?
5What are the advantages of this treatment?
6]Expense and side effects?
7]What do the guidelines recommend?
1]Glucagon-like peptide 1,one of the main incretin hormones
increases glucose dependent insulin secretion and decreases glucagon secretion
slows gastric emptying
increases satiety
2]response lasts for 2–3 hours after a meal is eaten.
3]exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide
4]GLP-1 is inactivated by dipeptidyl peptidase 4 (DPP-4),any synthetic GLP-1 RAs need to be resistant to this inactivation
molecular manipulation,addition of extra fatty acids.
extra C-16 fatty acid makes liraglutide resistant to DPP-4,gives it a longer half-life.
5]decreased weight,reduced glucose,proven CVD benefits (liraglutide, semaglutide, dulaglutide).
6]Costs are high,education on how to inject is required.
Acute pancreatitis may occur
Gastrointestinal side effects are common
Worsening of pre-existing retinopathy
7] recommends GLP-1 RAs as the first injectable instead of insulin in carefully selected patients:
- ASCVD (or very high risk of ASCVD)
- Chronic kidney disease and albuminuria
- need to minimise hypoglycaemia
- need to minimise weight gain or promote weight loss
People who have had diabetes for several years and who are taking medications, have markedly reduced____.
incretin responses
The lack of release of GLP-1 in response to food is a contributor to ____
hyperglycemia
Drug Information __GLP-1 Receptor Agonists (GLP-1 RAs)
semaglutide, dulaglutide and extended release exenatide
-given weekly
liraglutide, lixisenatide,
- given daily
shorter acting drugs more impact on post prandial glucose
These are all injectable apart from oral semaglutide
Oral semaglutide
- must be administered daily
- first thing in the morning on an empty stomach a small sip of water
- wait at least 30 minutes before taking any other medication,food or drink.
GLP-1 RAs—Dose Information
Exenatide
-5 micrograms twice daily—take at least six hours apart and within one hour of a main meal
-Allow one month and then double dose if needed
-10 micrograms, twice daily, maximum limit
Exenatide modified release
-2mg once weekly—no need to escalate the dose
Liraglutide
-0.6mg daily
-Allow at least one week and then increase to 1.2mg daily
-1.8mg daily maximum limit
Lixisenatide
-10 micrograms once daily—take within one hour of the first meal of the day or the evening meal
-Allow at least two weeks and then double the dose
-20 micrograms once daily maximum limit
Semaglutide
-Starting dose 0.25 mg weekly, increasing after 4 weeks to 0.5 mg weekly and after at least 4 weeks if required to maximum dose 1 mg weekly
Dulaglutide
-Starting dose is 0.75 mg weekly in monotherapy and can be considered in those who are frail for example those ≥ 75 years.
-For add on therapy use 1.5 mg weekly.
-If further glycemic control required, the dose can be increased to 3mg after at least 4 weeks and to 4.5mg after a further 4 weeks .
When starting GLP-1 RAs, no change is needed to doses of metformin, pioglitazone or SGLT2 inhibitors, but doses of sulfonylureas and insulins should be reduced initially and can be titrated if needed.
DPP4-I must be stopped when GLP-1 RA are started
DPP-4 Inhibitors Examples? How long do effect last? How do they work? What are additional advantages? Treatment Risks?
sitagliptin, vildagliptin, linagliptin, alogliptin, saxagliptin
have long half-lives
given once daily
85% inhibition 24 hours later,effectively restores circulating GLP-1 to the levels of a non-diabetic patient.
cleave the incretin hormones glucagon-like peptide-1 (GLP-1),glucose-dependent insulinotropic peptide (GIP),inactivating them
results in increased blood concentration of these incretins,augment the glucose-dependent insulin and glucagon responses,reducing blood sugar
DPP-4 inhibitors can preserve beta cell mass and function
neutral with ASVD
saxagliptin and possibly alogliptin increase the risk of hospitalisation for heart failure.
inhibiting other peptidases in this group, such as DPP-8 and 9 can cause renal and skin toxicity
Common side effects: gastrointestinal disturbances, nasopharyngitis. Pancreatitis is a rare but severe
DPP-4 inhibitors + sulphonylureas = increased risk of hypoglycaemia due to the sulfonylurea.
all drug are safe in renal disease except linagliptin are excreted renally. excreted in bile
DPP-4 Inhibitors—Dose Information
flat dose structure so the dose should not be increased.
Sitagliptin
-100mg once daily
Saxagliptin
-5mg once daily
Linagliptin
-5mg once daily
Vildagliptin
- 50mg twice daily (once in combination with a sulfonylurea)
- should not be used in hepatic impairment or if ALT or AST is > 3x normal.
Alogliptin
-25mg once daily
SGLT-2 Inhibitors
1]Examples?
2]How do they work?
3]What are additional advantages?
4]Drug Side Effects?
1]Sodium-glucose co-transporter-2 is a sodium dependent glucose transport protein.
dapagliflozin, canagliflozin, empagliflozin, ertugliflozin
2]cause less glucose to be reabsorbed from the urine, decreasing blood sugar levels
glucose-lowering mode of action requires normal glomerular-tubular function in the kidneys,the effect is reduced in renal impairment.
dapagliflozin and empagliflozin should not be initiated if the eGFR is less than 60 ml/min/1.73m2.
can continue until the eGFR is consistently < 45 ml/min/1.73m2 and then must be stopped.
lower doses of canagliflozin and empagliflozin should be used when the eGFR is between 45 and 60 ml/min/1.73m2.
renal protective effects in the CREDENCE trial, canagliflozin
For treatment of diabetic kidney disease
add on to ACE-inhibitors or ARBs
a dose of 100 mg canagliflozin once daily
3]action independent of the actions of insulin.
less risk of hypoglycemia
less over-stimulation of the pancreatic beta cells
causing weight loss
small reduction in blood pressure.
4] bladder: increased risk of urinary tract infection,vulvovaginitis in women,balanoposthitis in men –due to the increased amount of glucose in the urine encouraging fungal and bacterial growth.
Bone: increased risk of fracture with canagliflozin,
increased risk of amputation with the previous amputation seen with ertugliflozin
increased risk of diabetic ketoacidosis (DKA) without significant hyperglycemia
SGLT-2 Inhibitors– Dose Information
Dapagliflozin
- 10mg once daily—no increase is needed
- 10mg once daily maximum limit
Canagliflozin
- 100mg once daily—taken before breakfast
- Increase if initial dose is tolerated, additional glucose lowering is required and eGFR is >60ml/min/1.73m2
- 300mg once daily maximum limit
- 100mg can now be initiated down to an eGFR of 45 ml/min/1.73m2 and to an eGFR of 30 in those with high levels of albuminuria (ACR >300mg/g, approximately 30mg/mmol)
- Do not initiate if eGFR <30ml/min/1.73m2 but can be continued if already started until dialysis or transplantation.
Empagliflozin
- 10mg once daily
- Increase if initial dose is tolerated, additional glucose lowering is required and eGFR is >60ml/min/1.73m2
- 25mg once daily maximum limit
Ertugliflozin
- Starting dose 5mg once daily
- In patients tolerating this, the dose can be increased to 15 mg once daily if required
Case scenario
50-year-old,concerned about weight gain,need to urinate all the time,had a couple of urinary tract infections in the last six months,several episodes of fungal balanitis treated with clotrimazole cream
currently taking metformin 1g twice a day,never misses a dose
not had any cardiovascular complications and no retinopathy.
BMI: 33.2 kg/m2 (gain of 3kg in six months)
HbA1c: 7.9% (63 mmol/mol)
BP: 144/92 mmHg
eGFR: 64 mL/ minute/1.73 m2
his medication needs to be increased.
Which?
Dulaglutide 1.5mg weekly
After at least 4 weeks the dose can be increased to 3mg weekly and to 4.5mg weekly after an additional 4 weeks.
use of SGLT2i or GLP-1 where it is important to avoid further weight gain and aim to achieve weight loss.
recommend other non-insulin agents if metformin alone hasn’t worked, rather than going straight to insulin tends to increase body weight.
