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Type 2 diabetes: your questions answered

Brenda Li
BSc MBChB MRCP
GP Registrar
Crown Dale Medical Centre
London

Eighty-five percent of all patients with diabetes have type 2 diabetes (T2DM).(1) Because this has a long asymptomatic preclinical phase, screening has important implications for individual health, daily clinical practice, and public health policy. In 1998 the UK Prospective Diabetes Study (UKPDS) demonstrated that tight control of blood glucose and blood pressure significantly reduced long-term complications in patients with T2DM (see Box 1).(2)

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In order to achieve optimal glycaemic control, patients with T2DM often require insulin therapy in addition to oral hypoglycaemic agents. Novel drugs and modes of insulin delivery are currently being developed, intended to encourage compliance and improve glycaemic control. This article aims to answer some common questions regarding screening for diabetes and the management of T2DM.

Who should be screened for diabetes and how often? How often should glucose levels be checked in patients with impaired fasting glucose?
The optimal screening protocol for T2DM in the general population remains controversial. However, annual screening for patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) is advisable. In other groups at risk, checking a fasting glucose every two to five years is a pragmatic option (see Box 2).

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Impaired fasting (IFG) and impaired glucose tolerance (IGT) are indicators of impaired glucose regulation in the fasting and postprandial states, respectively (see Box 3). Both IFG and IGT are not disease entities in themselves but are associated with an increased risk of developing diabetes and cardiovascular disease;(3) in fact, a significant proportion - approximately 5%, but up to 20% in some populations  - will already have diabetes.(4)

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The 2005 International Diabetes Federation guidelines suggest that if a random plasma glucose level is between 5.6 mmol/l and 11.1 mmol/l on opportunistic screening, it should be repeated fasting, or an oral glucose tolerance test performed.(5)

When should someone with T2DM be converted to insulin and what is the favoured regimen? Should oral hypoglycaemics be continued?
UKPDS established the importance of glucose control in prevention of vascular complications in newly diagnosed type 2 patients with diabetes; the lowest risk of nonacute complications was in those with an average glycosylated haemoglobin (HbA1c) in the normal range (Although decisions to initiate insulin may be guided by targets, there are two concerns. First, current targets may not be stringent enough to prevent macrovascular disease; and second, guidelines may inhibit patients who could and should do better than the guidelines suggest, when age, ethnicity and life expectancy are taken into account. An individualised assessment and approach is therefore crucial, with the ultimate aim of reducing risk of complications.
Diabetes is a progressive condition, and insulin therapy should be considered in T2DM when an acceptable level of glycaemic control becomes unattainable and/or there are persistent symptoms secondary to hyperglycaemia despite maximally tolerated oral therapy (see Box 4).

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The goals of insulin therapy are to reach a target HBA1c level with a low rate of hypoglycaemia and minimal weight gain. Background bedtime insulin therapy in combination with oral hypoglycaemic therapy is effective at least initially, is convenient, and produces less weight gain than full insulinisation. A favoured regimen includes commencing an intermediate-acting insulin, such as bedtime isophane insulin, while continuing metformin and the sulphonylurea at maximally tolerated doses. Insulin requirements are titrated to achieve fasting glucose levels of 4-6 mmol/l without hypoglycaemia. Combination therapy of oral agents with insulin improves glycaemic control, counteracts weight gain, and reduces insulin requirements.(6) Thiazolidinediones are currently contraindicated with insulin.
The use of once-daily peakless insulin analogues instead of conventional intermediate-acting insulins may also be a viable option since there is a reduced frequency of nocturnal hypoglycaemia. However, issues of cost and lack of long-term safety data may make more traditional options favourable, as the risk of significant hypoglycaemia in the early stages of insulin deficiency in T2DM is not high.

When are the meglitinides used?
Repaglinide and nateglinide were introduced in 2003 as a new class of oral hypoglycaemics with a rapid-onset and short-lasting stimulating effect on insulin secretion. They were developed to improve early meal-mediated insulin secretion and are administered at the start of meals; the main associated side-effect is hypoglycaemia.
Both meglitinides are licensed for combination therapy with metformin in T2DM inadequately controlled by maximally tolerated doses of metformin alone. Repaglinide is also licensed for monotherapy and can improve fasting as well as postprandial  hyperglycaemia; nateglinide has little to no effect on fasting hyperglycaemia.(7) The drugs, however, may have a limited place in patients with irregular meal times or where minimal doses of longer-acting agents cause hypoglycaemia.

What is the role of thiazolidinediones and their effect on liver enzymes?
Rosiglitazone and pioglitazone are insulin sensitisers
and belong to the thiazolidinediones class of oral hypoglycaemic agents. They are licensed for use alone or in combination with metformin and/or with a sulphonylurea; rosiglitazone has recently been approved by NICE for use as triple therapy with metformin and a sulphonylurea. Both glitazones are contraindicated for use with insulin. Improved glycaemic control is associated with reductions in both fasting and postprandial glucose after six to eight weeks of therapy.
Unlike the first marketed glitazone (troglitzone), long-term safety data have shown rosiglitazone and pioglitazone to have much safer profiles; only mild and reversible levels of liver dysfunction have been seen.(8) Manufacturers currently recommend that liver enzymes are monitored before a glitazone is initiated, two months after initation, and repeated "periodically" thereafter. The initation of a glitazone should be avoided in patients with raised liver enzymes (ALT) 2.5 times above the upper limit of normal.

What is the definition of microalbuminuria and what are the recommendations for blood pressure targets?
Microalbuminuria, defined as a urinary albumin:creatinine ratio of > 2.5- 3.5-The threshold for initiation of antihypertensive medication in patients with T2DM is 140/90 mmHg with a treatment target of 130/80 mmHg (or 125/75 mmHg in patients with proteinuria).(11) While achievement of optimal blood pressure control by any means remains important, ACEI or ARBs titrated to maximum tolerated doses should be used for patients with T2DM and microalbuminuria, irrespective of blood pressure, in order to delay progression to nephropathy. If patients experience symptomatic hypotension, antihypertensives should be reduced accordingly. Renal function should be checked one to two weeks after initation of an ACEI, paying particular attention to a rise in creatinine and/or potassium levels.

When is inhaled insulin going to be available and who will be eligible?
Several inhaled insulins are at various stages of development. NICE has prepared its Health Technology Appraisal (HTA) for Exubera (Pfizer/sanofi-aventis), which obtained its European licence in January 2006. Studies in patients with both types of diabetes showed premeal inhaled insulin enabled them to achieve similar glycaemic control to conventional subcutaneous regimens.(12-15) However, exclusion criteria for these studies included HBA1c > 11%, body mass index > 30-35 kg/m2, history of two or more severe hypoglycaemic episodes in the previous six months, unstable asthma or chronic obstructive pulmonary disease (COPD), current smoking, and abnormal pulmonary function at screening. Exubera is contraindicated for current smokers, those with severe asthma or COPD (GOLD stage III/IV), and is not recommended for use in those with congestive heart failure.(14)
The use of inhaled insulin is not without concerns. Lack of long-term safety data should caution clinicians against unduly promoting its use. Inhaled insulin has been shown to be associated with increased treatment-related respiratory adverse events (mostly cough) and raised insulin antibody titres, the latter especially in type 1 diabetes. Although the clinical significance of elevated antibody titres is unknown, persistently elevated titres may potentially have ramifications such as postprandial hyperglycaemia or even hypoglycaemia if insulin is bound and then released from large antibody-bound pools.(16) Moreover, present inhalation devices do not provide flexibility in dose adjustments. In the current Exubera system, insulin is packaged as a dry powder in single-dose blister packs containing 1 mg or 3 mg; the 1 mg blister corresponds to approximately three units of insulin. Patients who are particularly sensitive to insulin will need to be cautious in titrating dosages.
The NICE appraisal committee is not currently recommending inhaled insulin for routine use but only for those who are unable to start or intensify their insulin therapy primarily due to needle phobia or severe problems with injection sites (see below).

Summary of NICE recommendations on inhaled insulin
Inhaled insulin is recommended as a treatment option for people with type 1 or type 2 diabetes mellitus who have a HbA1c level of 9% or higher, despite other interventions (including appropriate diet and oral hypoglycaemic agents and adequate educational support), and who are unable to start or intensify insulin therapy because of either:

  • A proven injection phobia diagnosed by a psychiatrist or psychologist.
  • Severe persistent problems with injection sites (for example, as a consequence of lipohypertrophy).

In patients receiving inhaled insulin, treatment should only be continued beyond six months if there is evidence of sustained improvement in HBA1c that will reduce the overall risk of developing long-term complications for diabetes.
Initiation of inhaled insulin treatment and monitoring of response should be carried out only at a specialist centre.

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References

  1. World Health Organization and International Diabetes Federation. Diabetes action now: an initiative of the World Health Organization and the International Diabetes Federation. Geneva, Switzerland: WHO; 2004.
  2. UKPDS. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-52.
  3. Unwin N, Shaw J, Zimmet P, Alberti GMM. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med 2002;19:708-23.
  4. World Health Organization. Definition diagnosis and classification of diabetes mellitus and its complications. Geneva, Switzerland: WHO; 1999.
  5. IDF Clinical Guidelines Task Force. Global guidelines for type 2 diabetes. Brussels: IDF; 2005
  6. DeWitt D, Hirsch I. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus. JAMA 2003;289:2254-64.
  7. Willett LL, Albright ES. Achieving glycemic control in type 2 diabetes: a practical guide for clinicians on oral hypoglycemics. South Med Assoc 2004;97:1088-92.
  8. Isley WL. Hepatotoxicity of thiazolidinediones. Exp Opin Drug Safety 2003;2:581-6.
  9. Parving HH, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-8.
  10. ACE inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001;134:370-9.
  11. Joint Specialty Committee on the Renal Medicine of the Royal College of Physicians of London and the Renal Association. Chronic kidney disease in adults: UK guidelines for identification, management and referral. London: Royal College of Physicians; 2006.
  12. Heinemann L. Alternative delivery routes: inhaled insulin. Diabetes Nutr Metab 2002;15:417-22.
  13. Quattrin T, Belagner A, Bohannon NJV, Swartz SL. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care 2004;27:2622-7.
  14. Hollander PA, Blonde L, Rowe R, et al. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care 2004;27:2356-62.
  15. Rosenstock J, Zinman B, Murphy LJ, et al. Inhaled insulin improves glycaemic control when substituted for or added to oral combination therapy in type 2 diabetes. Ann Intern Med 2005;143:549-58.
  16. Stoever JA, Palmer JP. Inhaled insulin and insulin antibodies: a new twist to an old debate. Diabetes Technol Ther 2002;4:157-61.