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DPD > T2DM- Presentation and complications > Flashcards

T2DM- Presentation and complications Flashcards

1
Q

True or False?

Over 25% of the patients with diabetes in the UK do not know they have it

A

True

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2
Q

Type 2 diabetes has an insidious onset

• T : True • F : False

A

True

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3
Q

What is meant by an insidious onset

A

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.

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4
Q

What are the symptoms of a slowly rising blood glucose in T2DM

A

– 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

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5
Q

How do we calculate osmolality

A

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)

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6
Q

Describe the issue with the insidious onset of T2DM

A
  • 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.
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7
Q

Describe the consequences of the insidious onset of T2DM

A
  • 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 …
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8
Q

What are the microvascular complications

A 
Microvascular
– Aetiology: Glycosylation of basement
membrane proteins -> “leaky” capillaries
– Retinopathy
– Nephropathy
– Neuropathy
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9
Q

What are the macrovascular complications

A 
– Aetiology: Dyslipidaemia, hypertension,
hypercholesterolaemia
– IHD
– CVA
– Peripheral gangrene

Old infarcts will be white

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10
Q

What’s important to remember about the treatment of HHS in older patients

A

Can’t suddenly normalise their numbers- they don’t cope well with a. rapid ‘flux’ of fluid from different compartments.

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11
Q

What are the bigger vessels in retinopathy

A

Veins

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12
Q

What can be seen in background diabetic retinopathy

A
  • Hard exudates (cholesterol) • Microaneurysms (“dots”)

* Blot haemorrhages

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13
Q

What treatment should we use for background diabetic retinopathy

A

Improve blood glucose control

Purpose of regular screening

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14
Q

What can be seen in pre-proliferative retinopathy

A

Cotton wool spots- these are due to ischaemia

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15
Q

Why is ischaemia in the eye a problem

A

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

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16
Q

How do we manage diabetic retinopathy

A

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

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17
Q

Where on the eye is pan-retinal photocoagulation performed

A

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

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18
Q

• Is there real evidence that good glucose control prevents complications?

A

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

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19
Q

Describe the follow up from 1998 to 2008

A
  • 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

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20
Q

Describe the legacy effect of intensive blood glucose control

A
  • 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.
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21
Q

Summarise the UKPDS

A

• 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

22
Q

Describe the ACCORD` study

A
  • 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

23
Q

What did the ACCORD study (and other similar studies) show

A
  • Accord: found good control INCREASED mortality • Advance
  • DCCT
  • UKPDS

This is despite reducing mortality from primary outcomes (MI and stroke)

24
Q

Why did the mortality rate increase in the ACCORD study

A

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.

25
Q

What is the take-home message regarding blood glucose control

A
  • 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
26
Q

Summarise the management of hyperglycaemia

A
  • 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)

27
Q

What are incretins

A

Peptide that stimulate insulin release

broken down by dipeptidyl peptidase 4 inhibitors

28
Q

Summarise insulin use in T2DM

A
  • 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)
29
Q

What is the problem with soluble natural insulin

A

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

30
Q

Describe some insulin analagoues

A
  • 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
31
Q

Describe short acting insulin analogues

A
  • 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
32
Q

Describe long acting insulin analogues

A

• Different alterations in the molecule to try and attain a plateau like concentration over time.

33
Q

Summarise long acting insulin analogues

A

• Different alterations in the molecule to try and attain a plateau like concentration over time.

34
Q

Describe insulin glargine (Lantus)

A
  • 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

35
Q

What are the benefits of insulin Glargine

A
  • 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.
36
Q

Describe insulin Detemir

A
  • 14 carbon fatty acid chain attached to B29.
  • Delayed onset 7h
  • Can be used as part of basal bolus.
37
Q

What are the advantages of insulin

A
  • 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)
38
Q

Compare C-peptide levels in T2DM to T1DM

A

T2DM- raised

T1DM- none

39
Q

What are the disadvantages of insulin

A
  • 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
40
Q

Why do we get weight Gain in insulin

A
  • 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.
41
Q

Summarise GLP-1 analogues

A
  • 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.
42
Q

Describe the role of incretins in glycaemic control

A

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.

43
Q

Describe some other effects of GLP-1

A
  • Reduces gastric emptying
  • Increases hypothalamic satiety.
  • (directly on hypothalamic GLP-1 receptors).
  • Animal studies showed this in 1996.

Increase satiety

44
Q

Describe the different incretins used as drugs

A

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)

45
Q

Describe why considering incretins is important

A
  • 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.

46
Q

What is important to remember about incretins

A
  • Exercise for weight reduction must not be forgotton
  • Exenatide
  • Gliptins: vildagliptin and sitagliptin
  • Both seem effective strategies in weight reduction in type 2 DM
47
Q

Describe renal glucose handling in the nephron of a healthy individual

A
  • 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.

48
Q

Describe the side effects of SGLT2 inhibitors

A
  • 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
49
Q

• How long will it take them to prevent death? SGLT2i

A

6 months

50
Q

Describe the lessons learned from the EMPA-REG outcome on SGLT2 inhibitors

A

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

51
Q

Summarise what we make of SGLT2 inhibitors overall

A

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

DPD (2 decks)

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