Introduction

Type 2 diabetes mellitus (herein, T2DM) is a chronic, progressive condition characterised by high blood glucose levels due to insulin resistance as well as progressive loss of insulin secretion, with a typical onset in adulthood. It is an increasingly common condition due to the increase in obesity as the major cause, with the current number of cases at 3.15 million in the UK alone, and 370 million cases worldwide. The majority of patients can be treated with improved diet and exercise, with or without oral medications, and only a small proportion requiring insulin therapy. It is important to identify and manage T2DM effectively due to the significant increase in morbidity and mortality as a result of the condition, with an overall increase in mortality by 15% compared to the general population.

Epidemiology

  • Incidence: 233.00 cases per 100,000 person-years
  • Peak incidence: 60-70 years
  • Sex ratio: more common in males 1.5:1
Condition Relative
incidence
Type 2 diabetes mellitus1
Type 1 diabetes mellitus0.02
Diabetes insipidus0.004
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

Risk factors
  • South Asian descent
  • a history of gestational diabetes
  • obesity
  • family history

Pathophysiology

The pathophysiology of T2DM is complicated due to the combination of both insulin resistance and relative insulin deficiency, as a result of multiple genetic and environmental factors. Often there is a genetic component for T2DM, with a family history of the condition often present, with approximately 40% of patients with T2DM having at least one parent with the condition. However, there is also a large environmental component, where those who are overweight or obese, with significant physical inactivity, will be more likely to develop the condition.

  • Insulin resistance
    • Insulin resistance is one of the driving factors in T2DM and is one of the major mechanisms which leads to poor glucose control and subsequent hyperglycaemia
    • May be related to substances secreted by adipocytes (adipokines) including leptin, adiponectin, TNFa, and resistin
    • Leptin – in obesity, leptin deficiency and leptin resistance is associated with insulin resistance
    • Adiponectin – lower levels are related to insulin resistance
    • TNFa – release of TNFa from adipose is related to impaired insulin action

  • Impaired insulin secretion
    • The secretion of insulin requires glucose to be transported into the cell, and this is partly mediated by the glucose transporter 2 (GLUT-2)
    • Alterations in GLUT-2 are present in T2DM and this results in impaired insulin secretion, therefore reducing the amount of available insulin to control and normalise glucose homeostasis
    • Furthermore, alongside reduced insulin secretion, with increases in the amounts of adipose tissue in obesity, there is simply not enough insulin to act at these sites proportionally

  • Impaired insulin processing
    • Normally, insulin is cleaved from pro-insulin
    • In T2DM, there may be an impairment in this process and there is an increase in pro-insulin levels in those with T2DM
    • As a result, there is a reduction in normal insulin required to act to normalise glucose concentrations

  • Hyperglycaemia
    • Hyperglycaemia itself impairs pancreatic beta-cell function and therefore exacerbates insulin resistance
    • This leads to a vicious cycle of hyperglycaemia which goes on to worsen itself via this process

Clinical features

Most typically, T2DM is a silent disease and tends to be diagnosed on screening or routine investigations, rather than as a result of symptoms. However, a proportion of patients will present with a subacute onset of several months or even years of symptoms, and a very small proportion may have an acute presentation.

Asymptomatic disease
  • These patients tend to be asymptomatic, with T2DM identified on routine screening
  • Approximately 70% of patients diagnosed with T2DM will be asymptomatic on diagnosis
  • Hyperglycaemia
    • Fasting plasma glucose > 6.9mmol/L
    • Random plasma glucose > 11.1mmol/L
    • HbA1c > 48mmol/L (>6.5%)
    • 2-hour post-75g glucose load >11.1mmol/L
  • Glycosuria

Subacute presentation
  • Polyuria (33%)
    • Due to osmotic diuresis that results when blood glucose levels exceed the renal threshold (glycosuria)
  • Fatigue (25%)
  • Blurred vision (20%)
  • Polydipsia (20%)
    • Due to resulting loss of fluid and electrolytes and osmotic diuresis
  • Weight loss
    • Due to fluid depletion and accelerated breakdown of fat and muscle secondary to insulin deficiency
  • Nocturia
  • Pruritis vulvae or balanitis (Candida infection occurs secondary to glycosuria)

Acute presentation
  • Polyuria
  • Polydipsia
  • Very rarely, patients may present with a hyperosmolar hyperglycaemic state (HHS)
    • Marked hyperglycaemia
    • Severe dehydration
    • Without ketoacidosis

Complications as presenting feature
  • A proportion of patients may present with complications of the condition as their presenting complaint (see below)
  • Approximately 25% of patients with T2DM will already have microvascular complications at time of diagnosis

Diagnosis

The diagnosis of type 2 diabetes mellitus can be made by either a plasma glucose or a HbA1c sample. Diagnostic criteria vary according to whether the patient is symptomatic (polyuria, polydipsia etc) or not.

If the patient is symptomatic:
  • fasting glucose greater than or equal to 7.0 mmol/l
  • random glucose greater than or equal to 11.1 mmol/l (or after 75g oral glucose tolerance test)

If the patient is asymptomatic the above criteria apply but must be demonstrated on two separate occasions.


Diagram showing the spectrum of diabetes diagnosis


In 2011 WHO released supplementary guidance on the use of HbA1c on the diagnosis of diabetes:
  • a HbA1c of greater than or equal to 48 mmol/mol (6.5%) is diagnostic of diabetes mellitus
  • a HbAlc value of less than 48 mmol/mol (6.5%) does not exclude diabetes (i.e. it is not as sensitive as fasting samples for detecting diabetes)
  • in patients without symptoms, the test must be repeated to confirm the diagnosis
  • it should be remembered that misleading HbA1c results can be caused by increased red cell turnover (see below)

Conditions where HbA1c may not be used for diagnosis:
  • haemoglobinopathies
  • haemolytic anaemia
  • untreated iron deficiency anaemia
  • suspected gestational diabetes
  • children
  • HIV
  • chronic kidney disease
  • people taking medication that may cause hyperglycaemia (for example corticosteroids)

Impaired fasting glucose and impaired glucose tolerance

A fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l implies impaired fasting glucose (IFG)

Impaired glucose tolerance (IGT) is defined as fasting plasma glucose less than 7.0 mmol/l and OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l

Diabetes UK suggests:
  • 'People with IFG should then be offered an oral glucose tolerance test to rule out a diagnosis of diabetes. A result below 11.1 mmol/l but above 7.8 mmol/l indicates that the person doesn't have diabetes but does have IGT.'

Differential diagnosis

Type 1 diabetes mellitus
  • Similarities
  • Differences
    • Patients with T1DM tend to present with acute symptoms, while those with T2DM tend to be diagnosed on routine screening
    • Although not always, patients with T2DM tend to features other signs of metabolic syndrome (e.g. central adiposity, hypertension, hypercholesterolaemia), while T1DM are more likely to have a lean body habitus with no features of metabolic syndrome
    • T1DM tends to present in the younger population, mostly childhood to adolescence, whilst T2DM tends to be a disease of adulthood
    • There may be a strong family history of T1DM or autoimmune disease (e.g. autoimmune thyroid disease) in those with T1DM
    • In patients with T1DM, they are likely to have one or more auto-antibodies present at time of diagnosis, whereas these will not be found in T2DM

Gestational diabetes
  • Similarities
    • Both will have hyperglycaemia
    • May present with similar symptoms e.g. polyuria, polydipsia, fatigue
  • Differences
    • Gestational diabetes can only occur during pregnancy
    • Gestational diabetes is usually asymptomatic and will be identified on routine pregnancy screening via oral glucose tolerance test
    • While typically it resolves after pregnancy, it does increase the risk of long-term development of T2DM

Transient/stress hyperglycaemia
  • This is essentially hyperglycaemia which is as a result of stress, typically during severe illness, which should disappear shortly after the illness is resolved
  • Is a consequence of many stress responses in the body, including increased concentrations of:
    • Cortisol
    • Catecholamines
    • Glucagon
    • Growth hormone
  • Similarities
    • Both will have hyperglycaemia on blood glucose testing
    • May have glycosuria
  • Differences
    • Will be transient and not long-term, will resolve on follow-up
    • Tend not to present with symptoms consistent with diabetes (e.g. polyuria, polydipsia)
    • T2DM is a chronic condition in an otherwise well person, while those with transient hyperglycaemia are often unwell at time of hyperglycaemia

Management

NICE updated its guidance on the management of type 2 diabetes mellitus (T2DM) in 2015. Key points are listed below:
  • HbA1c targets have changed. They are now dependent on what antidiabetic drugs a patient is receiving and other factors such as frailty
  • there is more flexibility in the second stage of treating patients (i.e. after metformin has been started) - you now have a choice of 4 oral antidiabetic agents


It's worthwhile thinking of the average patient who is taking metformin for T2DM, you can titrate up metformin and encourage lifestyle changes to aim for a HbA1c of 48 mmol/mol (6.5%), but should only add a second drug if the HbA1c rises to 58 mmol/mol (7.5%)


Dietary advice
  • encourage high fibre, low glycaemic index sources of carbohydrates
  • include low-fat dairy products and oily fish
  • control the intake of foods containing saturated fats and trans fatty acids
  • limited substitution of sucrose-containing foods for other carbohydrates is allowable, but care should be taken to avoid excess energy intake
  • discourage use of foods marketed specifically at people with diabetes
  • initial target weight loss in an overweight person is 5-10%


HbA1c targets

This is area which has changed in 2015
  • individual targets should be agreed with patients to encourage motivation
  • HbA1c should be checked every 3-6 months until stable, then 6 monthly
  • NICE encourage us to consider relaxing targets on 'a case-by-case basis, with particular consideration for people who are older or frail, for adults with type 2 diabetes'
  • in 2015 the guidelines changed so HbA1c targets are now dependent on treatment:

Lifestyle or single drug treatment

Management of T2DMHbA1c target
Lifestyle48 mmol/mol (6.5%)
Lifestyle + metformin48 mmol/mol (6.5%)
Includes any drug which may cause hypoglycaemia (e.g. lifestyle + sulfonylurea)53 mmol/mol (7.0%)

Practical examples
  • a patient is newly diagnosed with HbA1c and wants to try lifestyle treatment first. You agree a target of 48 mmol/mol (6.5%)
  • you review a patient 6 months after starting metformin. His HbA1c is 51 mmol/mol (6.8%). You increase his metformin from 500mg bd to 500mg tds and reinforce lifestyle factors

Patient already on treatment

Management of T2DMHbA1c target
Already on one drug, but HbA1c has risen to 58 mmol/mol (7.5%)53 mmol/mol (7.0%)


Drug treatment

The 2015 NICE guidelines introduced some changes into the management of type 2 diabetes. There are essentially two pathways, one for patients who can tolerate metformin, and one for those who can't:


Tolerates metformin:
  • metformin is still first-line and should be offered if the HbA1c rises to 48 mmol/mol (6.5%)* on lifestyle interventions
  • if the HbA1c has risen to 58 mmol/mol (7.5%) then a second drug should be added from the following list:
  •    → sulfonylurea
  •    → gliptin
  •    → pioglitazone
  •    → SGLT-2 inhibitor
  • if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then triple therapy with one of the following combinations should be offered:
  •    → metformin + gliptin + sulfonylurea
  •    → metformin + pioglitazone + sulfonylurea
  •    → metformin + sulfonylurea + SGLT-2 inhibitor
  •    → metformin + pioglitazone + SGLT-2 inhibitor
  •    → OR insulin therapy should be considered

Criteria for glucagon-like peptide1 (GLP1) mimetic (e.g. exenatide)
  • if triple therapy is not effective, not tolerated or contraindicated then NICE advise that we consider combination therapy with metformin, a sulfonylurea and a glucagonlike peptide1 (GLP1) mimetic if:
  •    → BMI >= 35 kg/m² and specific psychological or other medical problems associated with obesity or
  •    → BMI < 35 kg/m² and for whom insulin therapy would have significant occupational implications or
weight loss would benefit other significant obesityrelated comorbidities
  • only continue if there is a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body weight in 6 months

Practical examples
  • you review an established type 2 diabetic on maximum dose metformin. Her HbA1c is 55 mmol/mol (7.2%). You do not add another drug as she has not reached the threshold of 58 mmol/mol (7.5%)
  • a type 2 diabetic is found to have a HbA1c of 62 mmol/mol (7.8%) at annual review. They are currently on maximum dose metformin. You elect to add a sulfonylurea

Cannot tolerate metformin or contraindicated
  • if the HbA1c rises to 48 mmol/mol (6.5%)* on lifestyle interventions, consider one of the following:
  •    → sulfonylurea
  •    → gliptin
  •    → pioglitazone
  • if the HbA1c has risen to 58 mmol/mol (7.5%) then a one of the following combinations should be used:
  •    → gliptin + pioglitazone
  •    → gliptin + sulfonylurea
  •    → pioglitazone + sulfonylurea
  • if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then consider insulin therapy

Starting insulin
  • metformin should be continued. In terms of other drugs NICE advice: 'Review the continued need for other blood glucose lowering therapies'
  • NICE recommend starting with human NPH insulin (isophane, intermediate acting) taken at bed-time or twice daily according to need


Risk factor modification

Blood pressure
  • target is < 140/80 mmHg (or < 130/80 mmHg if end-organ damage is present)
  • ACE inhibitors are first-line

Antiplatelets
  • should not be offered unless a patient has existing cardiovascular disease

Lipids
  • following the 2014 NICE lipid modification guidelines only patients with a 10-year cardiovascular risk > 10% (using QRISK2) should be offered a statin. The first-line statin of choice is atorvastatin 20mg on

Graphic showing choice of statin.

*this is a bit confusing because isn't the diagnostic criteria for T2DM HbA1c 48 mmol/mol (6.5%)? So shouldn't all patients be offered metformin at diagnosis? Our interpretation of this is that some patients upon diagnosis will elect to try lifestyle measures, which may reduce their HbA1c below this level. If it then rises to the diagnostic threshold again metformin should be offered

Complications

The complications of type 2 diabetes are generally divided into microvascular or macrovascular complications, depending on the size of the blood vessels effected. These complications occur secondary to years of insulin-resistance, low-grade inflammation and hastened atherogenesis as a result of poor glucose control.

Macrovascular complications
  • Stroke
    • Likely due to a combination of uncontrolled hyperglycaemia, related hypertension and hyperlipidaemia
    • The lifetime risk of developing a stroke is higher in women than men with T2D
  • Myocardial infarction
    • Adults with T2D are twice as likely to die from a myocardial infarction compared to those without diabetes
    • Requires careful management of concurrent blood pressure and dyslipidaemia to further reduce the risk
  • Peripheral arterial disease
    • The most typical manifestation of this is presence of ulcers and subsequent infections
    • Typically these are as a result of repetitive trauma, however due to poor sensation, one may not identify the damage
    • Those with T2D are more at risk of serious infection and therefore this can lead to resulting osteomyelitis which requires further treatment
    • Long term, complications of uncontrolled blood glucose reduces the amount of blood flow to the peripheries, which can lead to subacute ischaemic disease and resulting amputation (the incidence of lower extremity amputation approximately 3 per 1000 people with diabetes per year)

Microvascular complications
  • Diabetic retinopathy
    • Results in vision decline and potential vision loss
    • Non-proliferative diabetic retinopathy exists in the early stages of disease and is less severe, and may require ongoing observation
    • Proliferative retinopathy occurs in the later and more severe stages of disease, and may result in haemorrhage, leading to permanent vision loss
  • Nephropathy
    • Diabetic nephropathy occurs in approximately 40% of patients with T2D, resulting in chronic kidney disease over time
    • Although this tends to remain chronic and progressive, less than 1% of these patients have resultant end-stage renal disease and require haemodialysis
  • Neuropathy
    • This is one of the most common complications of T2D
    • Often patients will be asymptomatic, however a number may identify reduced sensation or pain in affected regions (usually the peripheries)
    • Other manifestations may include erectile dysfunction (occurring in 10% of patients), orthostatic hypotension, gastroparesis