Type 2 diabetes is characterised by hyperglycaemia, insulin resistance and a relative insulin secretion deficit. Most morbidity and mortality in type 2 diabetes results from chronic, rather than acute, complications. These can be divided into microvascular and macrovascular.

Microvascular disease is composed of retinopathy, nephropathy and neuropathy. Data from patients with type 1 diabetes shows that intensive glucose control reduced the risk of retinopathy and nephropathy.¹ The UKPDS study randomised patients with newly diagnosed type 2 diabetes to intensive treatment (HbA1c 53mmol/mol) or conventional treatment (HbA1c 63mmol/mol).² The intensively treated group showed a 25% risk reduction in microvascular disease. More recently, the ADVANCE trial showed a decrease in the incidence of nephropathy in the intensively treated group (mean HbA1c 48mmol/mol) versus standard (mean HbA1c 56mmol/mol) There is no threshold value at which HbA1c reduces the risk of complications, but rather risk of complications falls continually with decreasing HbA1c. Data also shows evidence of continued long-term benefit of an initial period of intensive glucose control.

Macrovascular disease shows a less clear-cut relationship with glycaemic control. Observational data shows an increased risk of cardiovascular events with rising HbA1c, but studies examining the effect of intensive control on cardiovascular outcomes show varying results. Evidence from patients with type 2 diabetes suggested a reduction in cardiovascular events with intensive glucose control. Three recent large trials addressed this issue in patients with type 2 diabetes. ADVANCE³ showed no difference in cardiovascular outcome in the intensively treated versus standard therapy group at five years, and the VADT study⁴ showed no difference in the first occurrence of cardiovascular disease in the intensive treatment group.

The ACCORD study,⁵ however, was stopped early, at a median of 3.5 years, due to a 22% higher incidence of deaths in the intensively treated arm (median HbA1c 46mmol/mol). The reasons for this excess have been debated at length (occult hypoglycaemia, excessive weight gain, rate of decrease of HbA1c, large proportion of patients taking rosiglitazone) but no definitive aetiology has been demonstrated. All subjects were subsequently transferred to the standard control arm, yet five-year follow-up data still shows an excess all cause (but not cardiovascular) mortality of 19% in the original intensive group. The UKPDS however showed no difference in macrovascular outcomes at 10 years in the intensive versus control group, but did show an all cause and cardiovascular mortality reduction at 17 years, despite similar HbA1c.⁶

With regard to glycaemic targets overall, the key principles are that the incidence of microvascular complications is reduced by intensive glycaemic control, but that, although good glycaemic control appears to improve long-term cardiovascular outcomes in patients with newly diagnosed type 2 diabetes, too strict control may be harmful. Therefore, treatment needs to be tailored to each patient, and caution should be exercised in patients with long-standing diabetes or with several cardiovascular risk factors. All major professional bodies (EASD, ADA, WHO) currently recommend a target HbA1c of 53mmol/mol, while emphasising the need for individualisation of therapy.

Pathophysiology

A hereditary component is evident in patients with type 2 diabetes, with 39% of older patients having at least one parent with a history of diabetes. Although specific monogenetic forms of diabetes are well described, the majority appear to result from a more complex interplay of genetic factors and environmental influences.

Obesity is an increasingly prevalent risk factor associated with the development of type 2 diabetes, and weight gain has been shown to precede the development of type 2 diabetes. Obesity causes peripheral insulin resistance, and may decrease beta cell glucose sensitivity.

In patients with type 2 diabetes and fasting hyperglycaemia, hepatic glucose output, is increased. Also, the insulin-dependent uptake of glucose by skeletal muscle (the major site of peripheral glucose uptake – approximately 80%) is reduced. Glucose uptake by other tissues, eg. liver and adipose tissue, is also reduced, although this contributes to a lesser extent. Uptake of glucose by the central nervous system remains the same in subjects with or without type 2 diabetes.

Glucose targets/self-monitoring of blood glucose

Over recent years, the availability of convenient portable glucose meters has meant that many patients now check their blood glucose levels themselves – self-monitoring of blood glucose (SMBG). The American Diabetes Association recommends its use in patients on multiple daily injections of insulin, and recommends that it may be considered in other groups of patients.⁷

The use of SMBG is widespread in patients with type 2 diabetes in Ireland, and indeed glucose meters are available direct to consumers without prescription. Although it may be useful in selected patients not on glucose-lowering agents, it is not without cost, both from a comfort perspective (excessive fingerprick testing) and an economic perspective, with the cost running at approximately e50 per 50 strip box (this is free of charge to patients on the long-term illness scheme or who have a medical card). Therefore, although SMBG tends to be offered to most patients with a diagnosis of type 2 diabetes, it seems to be a reasonable approach to follow HbA1c as the sole marker of glycaemic control in most patients on diet or metformin alone.

A target HbA1c of 53mmol/mol equates to an average plasma glucose of 8.6mmol/l. Translating the HbA1c target into SMBG targets is not straightforward, and no good evidence exists for this. However, attaining a HbA1c of 53mmol/mol would be taken by most clinicians to translate to a fasting glucose range of approximately 4-7mmol/l, and postprandial values of 5-9mmol/l. Less strict targets may be appropriate in some patients where the risk of hypoglycaemia outweighs the benefit of tight glycaemic control, particularly in frail older adults, and patients with a limited life expectancy (eg. less than five years). These should of course be correlated with HbA1c values obtained at least twice yearly.

Non-pharmacological treatment

Lifestyle modification

Diet was for many years the first-line treatment for the patient with newly diagnosed type 2 diabetes. Although its use as sole treatment is now not recommended, it still forms a vital part of management.

Caloric restriction itself reduces glucose levels, thought to be the result of a reduction in hepatic glucose output. Longer-term benefit is the consequence of weight loss, but this can be difficult to achieve and maintain. Drug therapy for weight loss is now confined to the use of orlistat, a malabsorptive agent, since the withdrawal of both sibutramine and rimonabant from the market. 

Surgical treatment for obesity will also decrease blood glucose in patients with diabetes as a consequence of weight loss, but an independent, early onset glucose-lowering effect is seen in those patients with diabetes who have undergone Roux-en-Y gastric bypass surgery for treatment of obesity. This is thought to be due to the so-called ‘incretin effect’ resulting from changes in glucagon-like peptide-1 (GLP-1) concentration. 

Compounding this difficulty is the propensity for drugs used in the treatment of type 2 diabetes to increase weight. Although diet as a sole measure for glucose control has been shown to be suboptimal,² dietary advice, ideally by a dietitian with experience in the field of diabetes management, remains an essential part of diabetes care. Clarifying the amount of calorie reduction needed to reduce weight may also be important, ie. approximately 3,500kcal per 1lb of weight, eg. 500 fewer calories per day for one week.

The other essential aspect of lifestyle management is exercise. The benefits go beyond weight loss. Exercise improves insulin resistance in muscle, increasing glucose uptake, and lowering glucose levels. However, patients with type 2 diabetes may have reduced exercise capacity, for example in the setting of obesity or cardiovascular disease. Thorough evaluation of such patients is necessary prior to recommending an exercise regime to avoid precipitating adverse cardiovascular events. 

With regard to weight loss achievable by exercise, this varies significantly from person to person, depending on baseline weight, exercise intensity, etc. As a guide, brisk walking for an hour will burn approximately 300kcal. 

Pharmacological treatment

Metformin

Metformin is the first-line treatment of choice for patients with newly diagnosed type 2 diabetes. Metformin acts by suppressing hepatic glucose output, reducing fasting plasma glucose. It also increases insulin sensitivity (which may be due partly to the glucose-lowering effect). It does not increase insulin secretion, and therefore does not cause hypoglycaemia. 

One of the advantages of metformin is that it does not cause weight gain, and modest weight loss may even be seen. With regard to its effect on glycaemic control, a HbA1c reduction of approximately 16-27mmol/mol can be expected with monotherapy.⁸

Metformin has a favourable side-effect profile, and although gastrointestinal effects are common, they rarely require cessation. Gradually up-titrating the dose and taking it with meals may help tolerability. Usual starting dose is 500mg or 850mg twice daily, with 3,000mg per day being the maximum recommended dose. 

The other notable side-effect is lactic acidosis, a serious, but very rare complication, which delayed approval of the drug in the US until 1995. It is now known that this occurs infrequently (< 1 in 10,000 patients), and occurs in patients with factors predisposing to lactic acidosis, namely renal failure (creatinine clearance < 60ml/min), sepsis, contrast administration, or conditions causing tissue hypoxia, eg. acute myocardial infarction, cardiac failure, hepatic insufficiency, or shock. Its use should therefore be avoided in such patients. 

In addition to the benefit seen with glycaemic control, as described above in the UKPDS study, a reduction in cardiovascular outcomes was noted. This effect persisted through follow-up, with a 33% reduction in myocardial infarction seen in patients whose regime included metformin.

Sulphonylureas

Sulphonylureas (eg. glipizide, glibenclamide, gliclazide) are one of the oldest, and commonly prescribed class of drugs used for the treatment of type 2 diabetes. They act by stimulating insulin release from the pancreatic beta cells. One of the side-effects therefore is hypoglycaemia, which is mostly mild and occurs in 2-4% of patients. 

Modest weight gain (3kg in UKPDS) is another side-effect of sulphonylurea treatment.² Monotherapy with a sulphonylurea can be expected to lower HbA1c levels by 16-22mmol/mol. However, another characteristic of sulphonylurea therapy is gradual loss of effect with time (secondary failure), at a rate of approximately 3-10% per year.

Meglitinides

Meglitinides (eg. repaglinide). Like the sulphonylureas they increase insulin secretion, but do not do so in the absence of glucose. They have a shorter duration of action and as such, are taken before meals. They may be useful in patients in whom a prolonged period of increased insulin secretion is not desirable, eg. patients with renal failure, and elderly patients. 

They are rarely used as monotherapy, but studies show a HbA1c decrease of 9mmol/mol when used alone.⁹ Weight gain is seen, but to a lesser extent than with sulphonylurea treatment. Hypoglycaemia, although again, mostly mild, is a side-effect of treatment.

Alpha-glucosidase inhibitors

Acarbose is the only drug of this class currently available and acts by inhibiting the enzymatic breakdown of ingested carbohydrates in the gut. It therefore targets post-prandial hyperglycaemia specifically. Although it causes neither hypoglycaemia nor weight gain, its efficacy is less than the other classes of oral agents (up to 9mmol/mol reduction in HbA1c when added to metformin or sulphonylurea). Gastrointestinal side-effects are common.

Thiazolidinediones (TZDs)

TZDs act to increase insulin sensitivity, chiefly in adipose tissue. Rosiglitazone use was limited following a 2007 meta-analysis suggesting excessive cardiovascular risk, and was ultimately withdrawn in Europe in 2010.¹⁰ This leaves pioglitazone as the only remaining available TZD. France and Germany, however, have suspended its use due to studies suggesting an increased incidence of bladder cancer in patients taking the drug. It continues to be available here pending further review of the data.

TZDs lower HbA1c by up to 16mmol/mol, but again are rarely used in isolation. TZDs do not cause hypoglycaemia but do cause weight gain, and may also cause oedema. An increased fracture rate has also been observed in female patients on TZDs.¹¹

Incretin therapies

Incretin therapies are the newest class of treatment available. They fall into two categories – dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists. The so- called ‘incretin effect’, first noted in patients post gastric bypass surgery, showed a reduction in post prandial hyperglycaemia due to slowing of absorption of ingested carbohydrate. This is mediated by GLP-1, and also has the effect of satiety and weight loss. Pharmacological treatments are aimed at prolonging this effect of GLP-1.

DPP-4 inhibitors

DPP-4 inhibitors (eg. sitagliptin, saxagliptin, vildagliptin, linagliptin) are a newer class of oral agents available for the treatment of type 2 diabetes. Sitagliptin now carries a licence as a first-line agent, but has been used as a second or third-line agent. The advantages of these drugs are that they do not cause weight gain, can be used at a reduced dose in certain patients with renal impairment (although dosage adjustment is not necessary with linagliptin), and do not cause hypoglycaemia when used alone. DPP-4 is ubiquitously expressed in tissues however, and long-term effects of its inhibition are unknown.

GLP-1 agonists

GLP-1 agonists are subcutaneously injected therapies, which act at the GLP-1 receptor to lower blood glucose levels in response to ingested carbohydrate, and also reduce weight. They are also a newer class of drugs. Exenatide (twice daily) was the first available GLP-1 agonist, introduced in 2007, followed by liraglutide, a human GLP-1 analogue (once daily) in 2009, and extended release exenatide (once weekly) in 2011. 

These are licensed for use in patients who are not adequately controlled on monotherapy, and given their weight loss effect, their main use has been in obese patients as add-on therapy to metformin or additional oral agents. Their side-effect profile, however, can limit their use.

Several cases of acute pancreatitis have been reported in association with exenatide treatment, and liraglutide was associated with medullary cell carcinoma of the thyroid in rats. More commonly, however, gastrointestinal side-effects are prominent and may necessitate cessation of therapy. In those patients who can tolerate treatment however, they are a useful adjunctive therapy, particularly in obese patients.

Insulin

Insulin is the oldest and best validated pharmacological treatment for diabetes, including type 2 diabetes, having been introduced into clinical use by Banting and Best in 1922. Many patients with type 2 diabetes will ultimately require insulin therapy to achieve good glycaemic control, due to progressive pancreatic beta cell failure over time.¹²

Insulin therapy is uncommonly used as first-line treatment in the management of type 2 diabetes, but has a place in some patients, particularly those with a high HbA1c at diagnosis (eg. > 86mmol/mol), and those patients who are symptomatic (eg. fasting blood glucose > 13mmol/l). Transition to oral therapy may be possible at a later stage in such patients, as initial high glucose levels do not necessarily represent a very advanced stage of beta-cell failure. Hyperglycaemia itself can cause a temporary worsening of beta-cell function, and therefore some insulin secretory capacity may be restored as glucose levels return to normal. Insulin is also a treatment option if diagnostic uncertainty exists as to the type of diabetes (ie. type 1 vs. type 2 diabetes).

Insulin is more commonly used in type 2 diabetes as add-on therapy for failure of oral agents, and, as can be seen from the ADA/EASD algorithm in Figure 1, can be added at an early stage, as early as a second-line treatment if HbA1c remains above 58mmol/mol on two consecutive occasions. Frequently, however, insulin is introduced at a later stage than this, and follows failure of two or more oral agents to control HbA1c optimally.

Regimes fall into three broad categories – once or twice-daily basal (long-acting insulin) alone, biphasic insulin (premixed) twice daily, and intensive insulin therapy (long-acting insulin with pre-meal rapid-acting insulin). 

The choice of insulin regime will vary from patient to patient. Once-daily basal analogue insulin (eg. glargine or detemir) in addition to oral agents has the advantage of convenience – the rationale behind such treatment is suppression of hepatic glucose output by the insulin, decreasing fasting glucose levels, while allowing oral agents to manage post-prandial hyperglycaemia. 

If this approach fails, prandial insulin will be necessary, and can be given in the form of twice daily mixed insulin, or a multiple daily injection (MDI) regime. Twice-daily mixed insulin again has the advantage of convenience, while better glycaemic control can potentially be obtained with an MDI regime, although this of course will not be suitable for every patient. 

The principal side-effects of insulin therapy are weight gain and hypoglycaemia. Weight gain is common, may be large, and is greater in magnitude in patients on an MDI versus those on biphasic insulin or basal insulin alone. Continuation of oral agents while on biphasic or intensive insulin may help to limit weight gain due to reduced insulin dosage. Hypoglycaemia is the other principal side-effect of insulin therapy. Again, this is most common in patients on an MDI, followed by those on a biphasic regime, with the lowest incidence in those patients on basal insulin alone.¹³

Whichever regime is chosen, the individual patient must be considered when recommending a change to treatment. Will the patient (or carer) be able to administer insulin, or multiple injections? Will they be able to monitor glucose levels with the required frequency (four times/day for intensive regimes)? Do the risks of hypoglycaemia in this patient outweigh the potential benefits of intensive glycaemic control (eg. the frail, the elderly, and those with a limited life expectancy)?

Summary

In summary, the first task in deciding which treatment fits your patient is deciding on appropriate glycaemic targets. A HbA1c of 53mmol/mol or less, without significant hypoglycaemia, should be the goal for all patients, except the very frail, the very elderly, and those with a limited life expectancy. A lower HbA1c target, eg. 48mmol/mol, can be considered in selected patients, eg. those without known ischaemic heart disease or high cardiovascular risk factor profile, or those patients newly diagnosed with type 2 diabetes. 

Metformin is the first line treatment of choice for all patients without contraindications. In patients who are symptomatic, or have marked hyperglycaemia at presentation, insulin may be considered as initial therapy. 

HbA1c should be assessed on a three-monthly basis, and if targets are not met, additional therapy should be considered. 

Second-line treatment choice differs between patients. Sulpohonylurea treatment is a common choice. However, a GLP-1 agonist may be the logical choice in patients with marked obesity, a DPP-4 inhibitor may be useful in those patients where hypoglycaemia is deemed unacceptable, or insulin may be considered in those who remain markedly hyperglycaemic. 

Third-line therapy would follow similar considerations if targets are still not met, and with time, many patients will require insulin due to progressive beta-cell failure. It should also be noted that the level of HbA1c reduction will differ for any given mono- or combination therapy as the baseline HbA1c differs – a greater reduction will be seen in those with a higher baseline HbA1c. At least some degree of lifestyle modification will also be helpful in almost all patients also.

Eoin Noctor is a specialist registrar in endocrinology and diabetes and Fidelma Dunne is a consultant endocrinologist at Galway University Hospital

References 

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11. Meier C et al. Use of Thiazolidinediones and Fracture Risk. Arch intern Med 2008; 168(8)
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