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T2DM- Presentation and complications Flashcards

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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

Study These Flashcards
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

Study These Flashcards
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

Study These Flashcards
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

Study These Flashcards
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
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
26
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)
27
What are incretins
Peptide that stimulate insulin release | broken down by dipeptidyl peptidase 4 inhibitors
28
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)
29
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
30
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
31
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
32
Describe long acting insulin analogues
• Different alterations in the molecule to try and attain a plateau like concentration over time.
33
Summarise long acting insulin analogues
• Different alterations in the molecule to try and attain a plateau like concentration over time.
34
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
35
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.
36
Describe insulin Detemir
* 14 carbon fatty acid chain attached to B29. * Delayed onset 7h * Can be used as part of basal bolus.
37
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)
38
Compare C-peptide levels in T2DM to T1DM
T2DM- raised | T1DM- none
39
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
40
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.
41
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.
42
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.
43
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
44
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)
45
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.
46
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
47
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.
48
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 ```
49
• How long will it take them to prevent death? SGLT2i
6 months
50
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
51
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

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