T2DM- Presentation and complications Flashcards
True or False?
Over 25% of the patients with diabetes in the UK do not know they have it
True
Type 2 diabetes has an insidious onset
• T : True • F : False
True
What is meant by an insidious onset
Compared to type 1 diabetes that always presents acutely with ketosis, type 2 diabetes patients spend months to years not knowing they have diabetes at all: insidious.
Patients don’t often know that they have T2DM- slowly rising glucose
T1DM- will present more acutely with acidosis and hyperglycaemia.
What are the symptoms of a slowly rising blood glucose in T2DM
– Tiredness, lethargy
– Polyuria and polydipsia
– Often drink Lucozade (or coke) because of thirst
– Glucose SLOWLY rises further
– With other co-morbidities it become difficult to drink enough
– Osmotic diuresis causes loss of water and a rise in sodium
– EVENTUALLY the glucose is VERY high, as is the sodium
Hyperosmolar and rising Na+ because of polyuria.
Water leaves the brain- can result in confusion
Blood is like treacle- increasing risk of strokes
How do we calculate osmolality
Osmolality = cations + anions + glucose + urea
Na + K Cl + bicarb
= 2(cations) + glucose + urea
= 2(Na + K ) + glucose + urea Glucose rises to 90mM
Na rises to 160mM Osmolality=430mM
Normal osmolality=296
Neutral charge of body is why we just double the cations by 2 (a lot more anions to measure)
Describe the issue with the insidious onset of T2DM
- Patients may have type 2 diabetes for many months or years before they know they have diabetes
- They have hyperglycaemia but no acidosis
- Intermittent polyuria and polydipsia
- Assumed to be “prostate trouble” or “water work infections”
- Half of patients with diabetes do NOT know they have it.
Describe the consequences of the insidious onset of T2DM
- Months to years of hyperglycaemia
- Slow damage to the endothelium
- Micro and Macrovascular damage
- If the patients ignore the polyuria, the first time they present might be with a complication …
What are the microvascular complications
Microvascular – Aetiology: Glycosylation of basement membrane proteins -> “leaky” capillaries – Retinopathy – Nephropathy – Neuropathy
What are the macrovascular complications
– Aetiology: Dyslipidaemia, hypertension, hypercholesterolaemia – IHD – CVA – Peripheral gangrene
Old infarcts will be white
What’s important to remember about the treatment of HHS in older patients
Can’t suddenly normalise their numbers- they don’t cope well with a. rapid ‘flux’ of fluid from different compartments.
What are the bigger vessels in retinopathy
Veins
What can be seen in background diabetic retinopathy
- Hard exudates (cholesterol) • Microaneurysms (“dots”)
* Blot haemorrhages
What treatment should we use for background diabetic retinopathy
Improve blood glucose control
Purpose of regular screening
What can be seen in pre-proliferative retinopathy
Cotton wool spots- these are due to ischaemia
Why is ischaemia in the eye a problem
Ischaemia — hypoxia — (same as intermittent claudication in legs)- will stimulate new vessel growth (proliferative stage)
these vessels are thin-walled- bleed easily (probably also hypertensive)- blood in vitreous is bad- blindness
We aim to stop it getting to the proliferative stage
How do we manage diabetic retinopathy
Background:
–improve control of blood glucose
–warn patient that warning signs are present
- Pre-proliferative (cotton wool spot) • Suggests general ischaemia
- If left alone, new vessels WILL grow
- Needs: Pan retinal photocoagulation
• Proliferative (visible new vessels)
• Also needs:
–Pan retinal photocoagulation
Where on the eye is pan-retinal photocoagulation performed
Periphery- can lose up to 1/3rd of the peripheral vision without noticing- same cannot be said for the macula!
Aim to protect macula- can still see normally without periphery- other parts of periphery help you detect motion
• Is there real evidence that good glucose control prevents complications?
YES
UKPDS study (1977-1997) Cumulative risk reduction of 25% with intensive vs conventional Reduction in any diabetes related end-point (12%) Micro-vascular complications (25%) Retinopathy progression (21%) Micro-albuminiaria (34%) MI (16%) Diabetes-related death (10%) All-cause related death (6%)\
• But only after about 15 years in NEWLY
diagnosed type 2 diabetes
Describe the follow up from 1998 to 2008
- Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control.
- In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies.
- What happened to glucose control?\
- The glucose control became the same as the control group (they gave up trying).
- What happened to the patients mortality when they stopped having “good control”?\
Mortality stayed better
Describe the legacy effect of intensive blood glucose control
- With more than 66,000 person-years of follow up, this large post-trial study showed that benefits of an intensive strategy to control blood glucose levels in patients with type 2 diabetes were sustained for up to 10 years after the cessation of randomized interventions.
- Benefits persisted despite the early loss of within-trial differences in glycated hemoglobin levels between the intensive-therapy group and the conventional- therapy group — a so-called legacy effect.
- The trial showed the extended effects of improved glycemic control in patients with newly diagnosed type 2 diabetes, some of whom were followed for up to 30 years.
Summarise the UKPDS
• 20 years intervention (1977 to 1997)
• Tight control takes a long time to prevent heart attacks. Heart attacks occur after many years or poor control. NEW ONSET DIABETES in 1977
• 10 years further follow up (1997 to 2007)
• Legacy effect of benefit even after the study is
over
• Good control now prevents heart disease in the future
Describe the ACCORD` study
- Sponsored, so need shorter study, so chose patients who already had vascular disease with diabetes (ie high risk of a soon event)
- Accord: United States and Canada.
- Type 2 diabetes mellitus and a glycated haemoglobin level of 7.5% or more over age of 40 and had cardiovascular disease
Aimed for a HbA1c (<6%)- chose patients who already has IHD and poor heart function
What did the ACCORD study (and other similar studies) show
- Accord: found good control INCREASED mortality • Advance
- DCCT
- UKPDS
This is despite reducing mortality from primary outcomes (MI and stroke)
Why did the mortality rate increase in the ACCORD study
DCCT: type 1 diabetes, good control improves outcome
• UKPDS: New type 2 diabetes put onto good control
• Low mortality in both groups for 15 years, but then good control improved outcome, LEGACY EFFECT
• ACCORD: take older people who had poor control for a long time, and suddenly massively tighten control (A1c=6%): they already had coronary artery disease, so increased unexpected death
Sudden death: already had damaged heart from IHD, intensive therapy increased hypoglycaemic episodes- heart can’t suddenly compensate- VF on top of M.I-death.
What is the take-home message regarding blood glucose control
- Early on, when you have no complications, tight control is very important.
- When you have had many years of diabetes and atheroma, suddenly improving control can be dangerous
- In elderly, be less aggressive
Summarise the management of hyperglycaemia
- Diet and exercise
- Biguanide (Metformin)
- Sulphonylureas (eg gliclazide)
- Insulin sensitisers : thiozolidinediones such as rosiglitazone or pioglitazone
- Insulin itself (there are several new insulin analogues now available)
- Incretins (GLP-1 analogues)
- Gliptins (Dipeptidyl peptidase 4 inhibitors).
Rosiglitazone no longer used (associated with increased death in ACCORD study)
What are incretins
Peptide that stimulate insulin release
broken down by dipeptidyl peptidase 4 inhibitors
Summarise insulin use in T2DM
- Insulin is an excellent treatment, even for patients who are not dependent on it (NIDDM)
- Patients need a long acting (depot) insulin, such as insulin Zinc suspension
- Together with a short acting insulin such as normal soluble insulin with each meal
- Traditionally “Insulatard” (SLOW) and “Actrapid” (FAST)
What is the problem with soluble natural insulin
Problem: when soluble natural insulin is given subcutaneously, it forms a hexamer under the skin
• This delays release :
• “Inject 30 mins before meals
A+B chains clump together
Describe some insulin analagoues
- Lispro switch of
- B28 (Pro)/B29 (Lys)
- Aspart
- (Pro 28) to Asp (28)
- These analogues are very rapid acting and mean that patients can inject and eat
Describe short acting insulin analogues
- Gives patients a licence to inject immediately before meals
- (many were doing this with the old insulins anyway).
- Profile more closely mimics insulin profile of insulin following a meal.
- Twice the cost of soluble insulin
Describe long acting insulin analogues
• Different alterations in the molecule to try and attain a plateau like concentration over time.
Summarise long acting insulin analogues
• Different alterations in the molecule to try and attain a plateau like concentration over time.
Describe insulin glargine (Lantus)
- A long acting insulin that seems to give the least variation in plasma insulin levels for 24 h after injection.
- Previous long acting insulins were Zn suspensions of insulin. Efficacy slowly waned over 24 h.
• A21 (Asn to Gly) • B31, B32 Arg
What are the benefits of insulin Glargine
- Main advance is that this once daily insulin injection improves quality of life as there lower risk of hypoglycaemia.
- Gives background concentration of insulin.
- Normal pancreas makes continuous secretion of insulin.
Describe insulin Detemir
- 14 carbon fatty acid chain attached to B29.
- Delayed onset 7h
- Can be used as part of basal bolus.
What are the advantages of insulin
- Can give best control of HbA1c when combined with diet and exercise.
- No side effects (compared to : )
- metformin (diarrhoea)
- SU (occasional reactions)
- thiazolidinediones (rare hepatic, ?osteoporosis)
Compare C-peptide levels in T2DM to T1DM
T2DM- raised
T1DM- none
What are the disadvantages of insulin
- If you drive HGV, cannot work
- (exenatide exempt)
- Hypoglycaemia common with good control (less heart attacks)
- Weight gain
- Increased insulin as a consequence (vicious cycle)
- Huge doses required in patients with type 2 diabetes
Why do we get weight Gain in insulin
- If glycosuria stops, many calories saved.
- Increased appetite
- Improved well being
- Set point of body weight (hypothalamic) that we discussed yesterday.
- Poor control enables one to lose weight.
Summarise GLP-1 analogues
- GLP-1 is secreted from the gut, and signals the pancreas to make even more insulin.
- It also has a direct effect on appetite and gastric emptying
- Exanatide (Exendin 4) 1996 in animals.
Describe the role of incretins in glycaemic control
Ingestion of food
Release of incretins (GLP-1 and GIP) from G.I tract
Beta cells of pancreas:
Increased insulin release— increased peripheral glucose uptake
Alpha cells of pancreas (GLP-1 only):
Decreased glucagon
Decreased glucagon and increased insulin decrease HGO and thus improve glycaemic control.
Describe some other effects of GLP-1
- Reduces gastric emptying
- Increases hypothalamic satiety.
- (directly on hypothalamic GLP-1 receptors).
- Animal studies showed this in 1996.
Increase satiety
Describe the different incretins used as drugs
GLP-1: endogenous
• Exendin 4 from Gila monster venom: similar in structure to GLP-1 but has longer half life
• Exenatide: synthetic version of exendin 4.
• Increases hypothalamic satiety (1996)
Describe why considering incretins is important
- Exenatide: this is an injection
- Gliptins: vildagliptin and sitagliptin
- (DPP4 inhibitors)
- Will these drugs improve glucose control without the usual weight gain?
YES
Exanatide
• Liraglutide (Victoza or Saxenda) • Semaglutide
Despite being protein- oral forms ow exist- globular capsule that prevents degradation in the stomach.
They reduce risk of all primary outcomes vs placebo and help you to lose weight.
What is important to remember about incretins
- Exercise for weight reduction must not be forgotton
- Exenatide
- Gliptins: vildagliptin and sitagliptin
- Both seem effective strategies in weight reduction in type 2 DM
Describe renal glucose handling in the nephron of a healthy individual
- Plasma glucose concentration: 5–5.5 mmol/L
- Plasma filtered: 180 L/day
- Glucose filtered: 160–180 g/day
- Glucose reabsorbed: 160–180 g/day
- Glucose excreted: Minimal
SGLT2- 90%
SGLT1-10%
PCT
SGLT2 inhibitors prevent glucose reabsorption and therefore increase glycosuria.
Describe the side effects of SGLT2 inhibitors
- Safety evaluated in >6,000 people with type 2 diabetes who received canagliflozin in nine double-blind, controlled phase 3 clinical studies
- Primary assessment of safety and tolerability was conducted in a pooled analysis (N=2,313) of four 26-week placebo-controlled clinical studies
- In this analysis, reactions classed as very common (≥10%) or common (≥1%) included:
Very common • Hypoglycaemia when used in combination with insulin or sulphonylurea • Vulvovaginal candidiasis (thrush)
Common • Constipation, thirst, nausea • Polyuria (increased urine volume) or pollakiuria (increased urine frequency) • Urinary tract infection • Balanitis or balanoposthitis • Dyslipidaemia • Increased haematocrit
• How long will it take them to prevent death? SGLT2i
6 months
Describe the lessons learned from the EMPA-REG outcome on SGLT2 inhibitors
Outcome: 3-point MACE (major adverse cardiovascular events)
Cohort- adults with T2DM and established CVD
HbA1C (7-10)
Reduced HbA1c, SBP, DBP, weight, waist circumference and HR
Reduced all outcomes (1% per year)
eGFR decreases initially but then stabilises (renal protective effect)- reduced new onset macroalbuminaria, doubling of serum creatinine
Summarise what we make of SGLT2 inhibitors overall
Trial critique
• Relative risk reduction ~14% overall.
• Substantial effect on CV mortality (30% reduction)
• Absolute reductions in CV mortality 1% pa
• NNT is 100 = £48,000 to prevent one death
• Additional benefits on renal function and heart failure
May increase risk of DKA in T2DM patients
