Clinical Review: Type 2 diabetes mellitus

Assessing the risks and managing the complications of type 2 diabetes . By Dr Supreeth Rudrappa and Professor Iskandar Idris

Monitor blood glucose every two to six months according to individual needs until stable (Photograph: SPL)

Section 1: Epidemiology and aetiology

It is estimated that more than one in 20 people in the UK has diabetes mellitus (DM), with a prevalence of 4.45%.1 An estimated 850,000 people with diabetes remain undiagnosed.

By 2025, it is estimated 5m people will have diabetes in the UK.2 Data from the DH showed that 90% of adults with diabetes in the UK have type 2 DM.

Globally, the five countries with the largest numbers of people with diabetes are China, India, the US, Russia and Brazil, according to International Diabetes Federation estimates in 2011.3 The prevalence of type 2 DM among children in the UK is rising.

Type 2 DM is a heterogeneous disorder caused by a combination of environmental and genetic factors which adversely affect pancreatic beta-cell function and insulin sensitivity of tissues.4

The underlying disorder is usually that of a background of insulin insensitivity plus a failure of pancreatic insulin secretion to compensate.

Himsworth and Kerr were first to report that lean patients with early-onset DM were sensitive to exogenous injection of insulin, whereas obese patients with late-onset diabetes were resistant to insulin.5

This study pointed out that insulin resistance is an important pathophysiological process in type 2 DM, an argument later supported by measurement of increased plasma insulin levels in type 2 DM patients both fasting and postprandially, suggesting insulin resistance.

Longitudinal and cross-sectional studies have demonstrated that people who develop type 2 DM pass through five stages, which include:

1. Birth; glucose homeostasis is normal but there is genetic predisposition for type 2 DM

2. Decreased insulin sensitivity due to lifestyle and environmental factors

3. Beta-cell function deteriorates to a point that postprandial glucose tolerance becomes abnormal

4. Further beta-cell dysfunction, leading to a rise in fasting plasma glucose

5. Fasting and postprandial glucose levels reach levels diagnostic of type 2 DM due to overall decline in beta-cell function.6-10

Section 2: Making the diagnosis

The typical symptoms of type 2 DM are polyuria, polydipsia and weight loss occurring over months, but it may be asymptomatic and may only be diagnosed on a routine examination or laboratory test.

These symptoms result from an osmotic diuresis as a consequence of hypergylcaemia. Type 2 DM may present with complications of diabetes, which may be either microvascular or macrovascular.

An initial diagnosis of type 2 DM during acute MI or stroke is not uncommon. Foot ulceration can sometimes be a presenting feature of type 2 DM.

Gestational diabetes, which occurs during pregnancy and usually resolves after delivery, is associated with high risk for future type 2 DM.

Cataracts typically develop 10 years earlier in people with diabetes. Other rare presentations include altered taste or excessive salivation in people with diabetes.11,12


Patient with symptoms of diabetes

  • Random venous plasma glucose ≥11.1mmol/L OR
  • Fasting plasma glucose ≥7mmol/L OR
  • Two-hour plasma glucose after 75g oral glucose tolerance test (OGTT) ≥11.1mmol/L (OGTT) OR
  • Laboratory HbA1c >48mmol/mol (6.5%)

Asymptomatic patient

Two samples, either random, fasting, or after OGTT, are needed to confirm diagnosis. Samples should be taken on different days.

Most cases can be confirmed with a random glucose measurement and OGTT is often not necessary.

Source: WHO 2011


Although routine screening for type 2 DM has important implications for individual health, day-to-day clinical practice and public health policy, there is currently no direct evidence that this strategy will reduce the vascular risk for affected individuals.15 There is, however, some merit in screening individuals at risk of developing type 2 DM.

Central obesity is a known risk factor for type 2 DM (Photograph: Jim Varney)

Risk factors

Risk factors associated with type 2 DM are increasing age, obesity (especially central), dietary excess, dietary factors such as increased intake of animal fats and carbonated drinks, sedentary lifestyle, positive family history, history of gestational diabetes, polycystic ovary syndrome, severe mental illness, hypertension, hyperlipidaemia and cardiometabolic risk factors.

Central obesity is a major risk factor for developing type 2 DM and accounts for 80-85% of the overall risk and underlies the global spread of the disease.

Type 2 DM usually appears in middle-aged or older people, although more frequently it is being diagnosed in younger overweight people and it is known to affect South Asian people at a younger age.

It is very important to identify diabetes as early as possible because data suggest that up to 50% of patients with newly diagnosed type 2 DM already have one or more complications at the time of diagnosis.16

Section 3: Managing the condition

The treatment approach should involve patient-centred care, which means management should take into account individual needs and preferences.

Good communication is essential, supported by evidence-based information, to allow patients to reach informed decisions about their care.

Structured care plan

The following structured care plan is adapted from NICE recommendations.17

  • Provide structured education to every patient (and carer); review and reinforce annually.
  • Dietary advice should be provided in a form that is sensitive to the patient's needs, culture and beliefs, being sensitive to their willingness to change and their quality of life. Integrate other lifestyle modification, such as physical exercise and individualised weight loss targets.
  • Individualise HbA1c target level, which may be above the general target of 6.5%. Offer appropriate therapy (lifestyle and medication) to help achieve and maintain the HbA1c target.
  • Monitor blood glucose every two to six months (according to individual needs) until stable on unchanging therapy.
  • Offer self-monitoring of plasma glucose to a patient newly diagnosed with type 2 DM only as an integral part of self-management education.
  • Use appropriate oral glucose control therapies as recommended to control blood glucose. Glucose control deteriorates continually with time in most people with type 2 DM because it is not a chronic stable condition. Accordingly, therapy has to be stepped up with time, one drug added to another until such time as only exogenous insulin replacement will suffice (see algorithm in NICE CG87).
  • If other measures do not keep HbA1c under 7.5% (or other agreed target), discuss benefits and risks of insulin treatment. Initiate insulin with a structured programme and begin with human NPH (neutral protamine hagedorn) insulin taken at bedtime or twice daily according to need. Alternatively, consider a once-daily long-acting insulin analogue (insulin detemir, insulin glargine) if twice-daily insulin is difficult to manage.
  • Patients with type 2 DM are at high risk of cardiovascular disease, eye damage and renal disease. These adverse outcomes are known to be reduced by improved BP control.
  • Aim to reduce BP below 140/80mmHg (below 130/80mmHg if there is kidney, eye or cerebrovascular damage) with lifestyle changes and an antihypertensive agent; first-line therapy should be a once-daily ACE inhibitor. Exceptions to this are people of African-Caribbean descent or women for whom there is a possibility of becoming pregnant.
  • Review cardiovascular risk status annually by assessment of cardiovascular risk factors and start on statin according to guidelines.
  • Annual measurement of albumin creatinine ratio (ACR), creatinine and eGFR is paramount and consider treating albuminuria with ACE inhibitors.
  • Arrange for structured eye surveillance annually, because eye damage from diabetes is the single largest cause of blindness before old age, with a progressive incidence in people with type 2 DM.
  • Consider appropriate management of other diabetes complications, such as foot disease, neuropathic pain and erectile dysfunction.

New developments

There is a continuing need for new and improved agents to manage patients with type 2 DM, because treatments that are currently available do not reinstate normal glucose homeostasis or eliminate the threat of long-term complications.

The progressive nature of type 2 DM poses a continuing challenge and a requirement for novel and additional blood glucose lowering therapies.

Newer agents include longer- acting (once-daily and once-weekly injected) analogues of the incretin hormone GLP-118 and dipeptidyl peptidase-4 (DPP-4) inhibitors.19

Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors have been developed, which prevent glucose reabsorption from renal tubules and facilitate urinary glucose excretion.20

Clinical trials of SGLT2 inhibitors have reported significant reductions in HbA1c levels, with beneficial effects in weight and BP reduction.

Section 4: Prognosis

The prognosis for patients with type 2 DM predominantly depends on the degree of glucose control, as well as appropriate and effective management of cardiovascular risk factors.

On the whole, mortality is two to three times higher among people with type 2 DM than it is for the general population.

Among people with type 2 DM, 75% will die of heart disease and 15% of stroke.21

For every 1% increase in HbA1c level, the risk of death from a diabetes-related cause increases by 21% (95% CI 15-27%; p<0.0001).22

Approximately half of all patients in whom type 2 DM cannot be controlled by diet alone will require more than one glucose-lowering drug at three years after diagnosis. This proportion increases to three-quarters by nine years.23 This is likely to be due to the natural progression of the disease.


As is the case for patients with any other chronic disease, appropriate follow-up and timely referral to specialist care if required are essential for patients with diabetes.

It is accepted practice that multidisciplinary teams of healthcare professionals with expertise in diabetes, as well as working in collaboration with the patient and family, can provide the best care for patients who have type 2 DM.

Section 5: Case study

SW is a 76-year-old patient with type 2 DM. She reports tiredness and has recurrent episodes of collapse associated with hypoglycaemia. She takes metformin 500mg three times a day and gliclazide 80mg twice a day. Her HbA1c was 8.7%.

Her age and symptoms raise concern about sulfonylurea-induced hypoglycaemia. She is symptomatic from her hyperglycaemia and at risk of long-term vascular complications.

Consideration should be made of the use of glucose- lowering agents with limited risks of hypoglycaemia, such as DPP-4 inhibitors, thiazolidinediones, or even a newer class of agents such as SGLT2 inhibitors. DPP-4 and SGLT2 inhibitors are more favourable towards weight (weight neutral or potentially inducing small weight loss), but the latter is associated with a slightly increased risk of genitourinary infections.

Thiazolidinediones are contraindicated in patients with cardiovascular disease and heart failure.

If required, the addition of an intermediate/long-acting insulin can be considered. Long- acting analogues such as detemir and glargine are associated with a slightly lower risk of nocturnal hypoglycaemia compared with NPH insulin. More recently, insulin degludec was shown to have a slightly lower rate of nocturnal hypoglycaemia compared with insulin glargine.

Section 6: Evidence base

In 2008, three cardiovascular studies were published:

  • Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE)24
  • Action to Control CardiOvascular Risk in Diabetes (ACCORD)25
  • Veterans Affairs Diabetes Trial (VADT)26

ACCORD reported a surprising increase in mortality in a group intensively treated to lower HbA1c toward 6%.

This finding was not supported by ADVANCE – the largest trial of cardiovascular disease in type 2 DM.

In the intensive-control group, there was a reduced incidence in the combined endpoint of major macrovascular events (hazard ratio 0.9; 95% CI: 0.82-0.98; p = 0.01), as well as that of major microvascular events (9.4% v 10.9%; hazard ratio 0.86; 95% CI, 0.77-0.97; p = 0.01), primarily because of a reduction in the incidence of nephropathy (hazard ratio 0.79; 95% CI, 0.66-0.93; p = 0.006).

VADT, a much smaller study, showed no significant difference between the two groups in any component of the primary outcome or the rate of death from any cause.

In contrast, UKPDS post-trial monitoring showed benefits of tight glucose control from the outset of diagnosis of diabetes. In this study, despite equivalent glucose control, the lower incidence of microand macrovascular complications was maintained.27

Based on these findings, it is reassuring to note that NICE advocates two thresholds for HbA1c target: 6.5% for patients on dietor tablet-controlled diabetes, and 7.5% for patients on injectable therapies.


  • Dr Supreeth Rudrappa, Royal Derby Hospital, and Professor Iskandar Idris, associate professor in diabetes and honorary consultant physician, Royal Derby Hospital and University of Nottingham


1. Diabetes in the UK April 2012

2. Quality and outcomes framework 2011.

3. International Diabetes Federation (2011). Diabetes atlas, fifth edition.

4. Holt RI, Cockram C, Flyvbjerg A et al. Textbook of Diabetes (fourth edition). Oxford, Blackwell Publishing, 2010.

5. Himsworth H, Kerr R. Clin Sci 1939; 4: 119-52.

6. Pratley R, Weyer C. Diabetologia 2001; 44: 929-45.

7. Vaag A, Henriksen J, Madsbad S et al. J Clin Invest 1995; 95: 690-8.

8. Johnston C, Ward K, Beard C et al. Diabetic Med 1990; 7: 119-25.

9. Pimenta W, Kortytkowski M, Mitrakou A et al. JAMA 1995; 273: 1855-61.

10. Ferrannini E, Gastaldelli A, Miyazaki Y et al. J Clin Endocrinol Metab 2005; 90: 493-500.

11. Borrell LN, Kunzel C, Lamster I et al. J Periodontal Res 2007; 42: 559-65.

12. Gibson J, Lamey PJ, Lewis M et al. J Oral Pathol Med 1990; 19: 284-7.

13. World Health Organization. Report of a WHO Consultation 1999.

14. Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. Abbreviated Report of a WHO Consultation, 2011.

15. IDF Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Brussels, International Diabetes Federation, 2005.

16. UKPDS Group. Diabetes Res 1990; 13: 1-11.

17. NICE. Type 2 diabetes: the management of type 2 diabetes – update. London, NICE, 2009.

18. NICE. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes (CG87). London, NICE, 2009.

19. NICE. Type 2 diabetes - newer agents (a partial update of CG66): NICE guideline. London, NICE, 2009.

20. Jabbour SA, Goldstein BJ. Int J Clin Pract 2008; 62: 1279-84.

21. Diabetes UK. Weight management. Managing diabetes in primary care. Diabetes UK. 2004.

22. UK Prospective Diabetes Study Group, Stratton IM, Adler AI et al. BMJ 2000; 321: 405-12.

23. UK Prospective Diabetes Study Group. JAMA 1999; 281: 2005-12.

24. ADVANCE Collaborative Group. N Engl J Med 358(24): 2560-72.

25. Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358(24): 2545-59.

26. Duckworth W, Abraira C, Moritz T et al. N Engl J Med 2009; 360: 129-39.

27. Holman RR, Paul SK, Bethel MA et al. N Engl J Med 2008; 359: 1577-89.


These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Hold a meeting with practice colleagues to ensure everyone is familiar with the diagnostic criteria for diabetes.
  • Perform a search for type 2 DM patients who do blood glucose tests at home. Is this necessary in all of these patients?
  • Search for patients who have recently had an OGTT performed. Ensure OGTT is only performed if absolutely necessary.

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