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TypeFeature 2 diabetesFeature

MANAGING GLYCAEMIA IN DIABETES

Glycaemic management of Beneﬁcial effects of HbA1c reduction on vascular type 2 diabetes complications Effects of 1% reduction in updated mean HbA1c on complications of Balasubramanian T Srinivasan type 2 diabetes Melanie Davies Complication Risk reduction

Any diabetes-related complication 21% Abstract Myocardial infarction 14% Type 2 diabetes mellitus (T2DM) is a chronic multifactorial disorder asso- Microvascular disease 37% ciated with hyperglycaemia and long-term end-organ damage. This end- Death due to diabetes 21%

organ damage is due to hyperglycaemia and the accompanying risk fac- Source: UKPDS (35). Br Med J 2010; 321(7258): 405e12. tors such as hypertension, dyslipidaemia and obesity, leading to increased risk of cardiovascular disease and mortality. It is essential to Table 1 adopt effective multifactorial risk reduction strategies. Pharmacological and non-pharmacological management aimed at improving glycaemic In a randomized control trial (RCT)6 824 adults with T2DM control in patients with T2DM is ever evolving. Over the last decade, recruited from 207 general practices were randomized to receive new anti-hyperglycaemic agents have been launched that act via non- intervention with structured education or usual care. The inter- traditional mechanisms and drug development in this area remains very vention was a curriculum-based group education programme active. delivered by trained healthcare professionals and quality assured.

Keywords DESMOND; glycaemic management; incretin therapy; insulin HbA1c after 1 year was lower in the intervention arm ( 1.49% vs. � therapy; oral anti-hyperglycaemic agents; type 2 diabetes mellitus 1.21%) but this was non-significant after adjusting for baseline � and cluster. The intervention group had a significantly greater weight loss ( p 0.027) along with a greater change in illness belief ¼ The landmark UK Prospective Diabetes Study (UKPDS) clearly scores ( p <0.001) and lower depression scores ( p <0.05). The demonstrated beneficial effects of intensive glycaemic manage- odds ratio in relation to giving up smoking was 3.56 in the inter- ment of type 2 diabetes (T2DM) on microvascular complications vention group ( p 0.033).7 As a result, the 10-year modelled ¼ and recently reduction in macrovascular complications, as well cardiovascular risks were significantly lower in the intervention as all-cause mortality.1,2 Epidemiological analysis of the UKPDS arm. A subsequent cost-effectiveness analysis determined that the data shows impressive reductions in microvascular as well as DESMOND programme was cost effective even under modest 3 macrovascular risk with each 1% reduction in HbA1c conditions and the assumption that the benefits were lost after the (Table 1).The National Institute for Health and Care Excellence 1-year trial period.8 Data from programmes in people with estab- (NICE) undertook a comprehensive review of current evidence lished diabetes have also demonstrated significant biomedical and and issued national guidelines for the management of T2DM psychosocial benefits.9 Structured education programmes ful- including use of newer anti-hyperglycaemic agents.4 The Amer- filling nationally agreed criteria should be offered to all people with ican Diabetes association has recently issued clinical practice T2DM from diagnosis.10 guidelines that can be used as a guide to algorithmic approach to drug treatment in those with T2DM.5 Dietary and lifestyle interventions Patient education and new approaches to self-management Dietary modification and lifestyle intervention remain the initial mainstays of treatment of T2DM. Most patients with T2DM are The DESMOND Collaborative Project (Diabetes Education Self- overweight and have features of metabolic syndrome, and weight Management Ongoing Newly Diagnosed) set out to develop an reduction reduces insulin resistance and improves other cardio- evidence-based structured education and self-management pro- vascular risk factors. Early and continued involvement of a die- gramme for people with T2DM. DESMOND is built on a clearly titian with an interest in diabetes is important. It should be noted stated philosophy and explicit principles of care that are used to that dietary and lifestyle management are key components of the develop the individual’s understanding of diabetes, the specific structured education programme referred to above. monitoring and goal-setting skills necessary for effective self- management, and the confidence necessary to take charge of General aims of dietary intervention their own diabetes. Energy intake and expenditure balance should be adjusted to achieve a body mass index of 20e25 kg/m2. In clinical practice, however, realistic and individual targets should be set for weight Balasubramanian T Srinivasan MD FRCP (Glasg) is a Consultant Physician e at the Department of Diabetes and Endocrinology, United Lincolnshire loss. With an exercise programme, weight loss of 1 2 kg/month Hospitals NHS Trust, UK. Competing interests: none declared. can be achieved by reducing the caloric intake below that required for weight maintenance by at least 500 kcal/day. Melanie Davies MB ChB MD FRCP FRCGP is Professor of Diabetes Medicine at the University of Leicester and an Honorary Consultant Physician in the Benefits of exercise University Hospitals of Leicester NHS Trust, Leicester, UK. Competing Regular physical activity increases muscle-related energy expen- interests: none declared. diture, improves insulin sensitivity, reduces blood pressure and

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improves lipid proﬁle. Exercise improves glycaemic control in below 48 mmol/mmol (6.5%) should be avoided in patients with T2DM. Generally, any form of exercise with a duration of 30 mi- longer duration of diabetes and in the presence of cardiovascular nutes is recommended to aid weight loss, when accompanied by an disease.15 Data from the ACCORD study suggests that tight gly- appropriate diet. However, whereas a recent study conﬁrmed that caemia is achievable with intensive therapy but is associated 30 minutes of moderate-intensity exercise on most days was asso- with increased risk of hypoglycaemia and mortality in patients ciated with a reduction in blood pressure and serum concentrations with existing cardiovascular disease.15 Post-hoc analysis of these of total cholesterol and triglyceride, 60e75 minutes on most days data suggests that this risk is higher in patients with poor base- was required to reduce weight, waist circumference, fasting glucose line glycaemic control and in patients who do not show

and low-density lipoprotein cholesterol, increase high-density li- improvement in HbA1c despite the intensiﬁcation of anti- poprotein (HDL) and reduce overall 10-year cardiovascular risk.11 hyperglycaemic therapy. In this subgroup of patients, attention should be directed towards patient education and adherence to Oral anti-hyperglycaemic agents (OAA) treatment rather than intensifying glycaemic therapy further.17,18

Whereas insulin resistance is a general feature of T2DM, hyper- Metformin glycaemia results from significant b-cell depletion, suggesting Biguanides have been the mainstay of OAA treatment since 1950, that optimal glycaemic control requires glucose-lowering agents but metformin is the only one currently used in clinical practice. that act through both increased b-cell function and enhanced 12e14 Its mechanism of action is unclear, but probably involves tissue responsiveness to insulin. reducing hepatic gluconeogenesis through effects on mitochon- drial function, thereby reducing insulin resistance. Metformin Targets of therapy also has cardioprotective benefits, as shown in UKPDS and other Following recent data from studies suggesting that targeting major studies.19 It is the first-line agent in overweight patients. It intensive glycaemic control may increase mortality, the current can be given as monotherapy or in combination with almost any consensus is that HbA targets should be individualized.15 In- 1c other glucose-lowering agent. sulin therapy is recommended if HbA remains above 58 mmol/ 1c The most common adverse effects are gastrointestinal and mol (7.5%) despite use of appropriate and tolerated OAA16 include diarrhoea, nausea, vomiting and flatulence; about 10% (Figure 1). Aggressive glycaemic therapy to achieve HbA1c

Blood-glucose-lowering therapy

HbA1c more than 6.5% after lifestyle and dietary modifications

Commence metformin with active dose titration

HbA1c ≤6.5% HbA1c >6.5%

Sulfonylureas

Appropriate Not appropriate

Add on sulfonylurea Add DPP-4 inhibitor Add glitazones

HbA1c >7.5% HbA1c >7.5%

Add third agent: Metformin + SU + Insulin Start or intensify insulin.

Metformin + SU + Exenatide HbA1c >7.5% Only continue the agents Metformin + SU + DPP-4 inhibitor licensed with insulin therapy Metformin + SU + Glitazones

Adapted from National Institute for Clinical Excellence. Type 2 diabetes: newer agents. London: NICE, 2009.

Figure 1

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of patients stop taking it because of these effects. Tolerability started at a dose of 0.5 mg taken 15 minutes before meals and may be improved by using a smaller initial dose, gradual dose adjusted to a maximum of 16 mg/day or a maximum single dose titration, taking the drug with meals, and using modiﬁed-release of 4 mg. Nateglinide is started at 60 mg taken three times daily preparations. The dosage should be reviewed if the eGFR is less with meals and adjusted to a maximum of 180 mg three times than 45 ml/min or serum creatinine >130 mmol/L. It should be daily. Meglitinides are more expensive than sulfonylureas. discontinued if eGFR falls below 30 ml/min or serum creatinine rises above 150 mmol/L. Metformin should also be avoided if Thiazolidinediones are insulin sensitizers and act primarily by there is clinical or laboratory evidence of liver dysfunction and in activating the peroxisome proliferator-activated receptor g patients with unstable or acute congestive heart failure, due to (PPAR-g), the key transcription factor in fat cell differentiation the rare possibility of lactic acidosis. It should be discontinued and function (but also present in liver, skeletal muscles and other temporarily in the event of sepsis or dehydration, in association tissues). This activation enhances the effects of endogenous in- with use of radiographic contrast media, during the peri- sulin on target organs, reducing insulin resistance. Rosiglitazone

operative period and immediately following coronary events. and pioglitazone were shown to reduce HbA1c by up to 1.5%. They do not generally cause hypoglycaemia. One meta-analysis Sulfonylureas involving 42 studies concluded that rosiglitazone was associ- The sulfonylureas are insulin secretagogues that bind to a ated with a significant increase in the risk of myocardial infarc- membrane receptor of the pancreatic b cell, promoting closure of tion and a borderline significant finding for death from hyperpolarizing ATP-dependent potassium channels, cell mem- cardiovascular causes.21 An unplanned interim analysis of brane depolarization and exocytosis of insulin secretory vesicles. ‘Rosiglitazone Evaluated for Cardiovascular Outcomes (RE- They are licensed for monotherapy or in combination with other CORD) study’ was inconclusive regarding the effect of rosiglita- OAAs except meglitinides. They are effective in reducing fasting zone on the overall risk of hospitalization or death from 22 plasma glucose and in reducing HbA1c by about 1.5e2.0%, but cardiovascular causes. More importantly, this analysis did not are associated with weight gain and an increased risk of hypo- provide any reassurance regarding the safety of rosiglitazone in glycaemia. Gliclazide is commenced at a dosage of 40e80 mg respect of the risk of myocardial infarction. The European Med- given once or twice a day and increased to a maximum of 160 mg icines Evaluation Agency (EMEA) suspended rosiglitazone from twice a day. Gliclazide MR is a modified-release preparation the European market in 2010, although it remains available in the given once a day at the starting dose of 30 mg/day (equivalent to USA. These agents are associated with fewer hypoglycaemic 80 mg/day of standard-release gliclazide). Glimepiride is taken episodes than they occur with sulfonylureas, but lead to once a day up to a maximum dosage of 4 mg/day, which can be increased peripheral oedema, weight gain and an increased risk increased to 6 mg/day in exceptional circumstances. In the of distal fractures, especially in postmenopausal women. UKPDS, 7% of patients taking a sulfonylurea experienced at least Thiazolidinediones have been licensed for use as mono- 20 one severe hypoglycaemic episode over 9e12 months. These therapy and in combination with metformin, a sulfonylurea and episodes can be prolonged and potentially dangerous with long- with insulin. NICE recommends their use in addition to a first- acting agents such as glibenclamide. Predisposing factors for line agent (either metformin or a sulfonylurea) if another the development of hypoglycaemia are age, liver, renal and second-line agent (a sulfonylurea or metformin respectively) is cognitive impairment, and other interacting medications (listed poorly tolerated or contraindicated. Thiazolidinediones are rec- in the BNF e British National Formulary e Appendix 1). Patients ommended as third-line agents in addition to metformin and a presenting with hypoglycaemia secondary to sulfonylurea use sulfonylurea for patients in whom insulin therapy is unaccept- should be hospitalized and their blood glucose monitored for 24 able. Pioglitazone can be combined with insulin, but the com- e48 hours; this is particularly important in older patients with bined use is associated with significant weight gain. A recent renal impairment. Agents such as glibenclamide and tolbutamide meta-analysis has demonstrated an increased risk of developing are very rarely used in practice and have been replaced by newer bladder cancer in those taking pioglitazone (hazard ratio 1.23 agents such as gliclazide that are relatively short acting. with 95% CI);23 the drug has been withdrawn from sale for this reason in France, Canada, Australia, New Zealand, India and Prandial glucose regulators (meglitinides) have been developed Japan. Pioglitazone and rosiglitazone have also been shown to to target early phase insulin secretion, which is one of the earliest increase fracture risk in women. pathophysiological manifestations of T2DM. Repaglinide Pioglitazone has been shown to reduce the incidence of fatal and nateglinide are currently available rapid-acting insulin and non-fatal myocardial infarction in those with T2DM.24 secretagogues with a fast onset and short duration of action. Meglitinides act on a different b-cell membrane receptor from Insulin therapy sulfonylureas, but also promote closure of ATP-dependent potassium channels. However, this class of medicines still appears In the UKPDS, more than 50% of patients required additional in- to be associated with weight gain and increased risk of hypo- sulin therapy by 6 years; this was largely attributed to the fact that b-cell function worsened from about 53% at diagnosis to about glycaemia, similar to the sulfonylureas. 25 Meglitinides are licensed for use as monotherapy, as an add- 28% after 6 years of follow-up. General indications for insulin are on to metformin when the latter alone is insufficient for glycae- shown in Table 2. The topic should be approached sensitively; the mic control, and in combination with insulin. Flexible dosing is decision to start insulin should be made in partnership with the possible, suiting shift-workers and individuals with a flexible patient and the choice of regimen tailored to the individual’s needs. lifestyle, though multiple doses must be taken. Repaglinide is The patient should agree with the decision and understand the

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reasonable starting dose of insulin is 10 units twice daily for Indications for insulin and early insulin use in type 2 twice-daily mixtures and 10e12 units daily for once-daily NPH diabetes (neutral protamine Hagedorn) and insulin analogues. The 4T

C All previous attempts to achieve desired target (lifestyle mea- study was designed to compare three types of insulin regimen sures, maximal oral therapy) have failed (basal, prandial or biphasic) in addition to OAA in patients with T2DM. Although the risk of hypoglycaemia and weight gain was C Persistent failure to achieve optimal HbA1c C Symptomatic patient (weight loss, lethargy) greater in patients using biphasic or prandial insulins, by 3 years C Corticosteroid-induced diabetes the majority of patients required a ‘complex’ insulin regimen. C Gestational diabetes; women with type 2 diabetes who become This study supports the initial use of basal insulin, followed by 26 pregnant or are planning pregnancy intensiﬁcation with a basaleprandial regimen. The 4T study C Post-acute myocardial infarction also demonstrated that was no increased risk of hypoglycaemia C Intolerance to oral agents when initiating insulin using a proactive regimen. C More suited to patient’s lifestyle C Acute neuropathy (e.g. proximal amyotrophy) Incretin-based therapy

In the following clinical scenarios, insulin is considered at presenta- An oral glucose load stimulates increased insulin release from tion pancreatic b cells, whereas a glucose load administered intrave- C Patients with newly diagnosed diabetes, with random plasma nously has an isoglycaemic effect. This is known as the incretin 27 glucose >11.1 mmol/L presenting with myocardial infarction, effect. Two main gut hormones e glucose-dependent insuli- severe intercurrent illness (e.g. sepsis), ketonaemia/ketonuria or notropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) hyperosmolar non-ketotic state e are released from intestinal cells in response to food. These C Patients with fasting plasma glucose >15 mmol/L and/or random hormones are called ‘incretins’. GLP-1 is a potent incretin and glucose >24 mmol/L who are increasingly symptomatic

Table 2 Common insulin regimens in type 2 diabetes

C Twice-daily pre-mixed insulin includes conventional mixtures of benefits of insulin and the implications of its use. Access to short-acting and isophane insulins (e.g. Humulin M3, Insuman appropriate dietary and lifestyle advice is essential. Comb 15,25). The percentage of short-acting insulin ranges from 10% to 50%, the most commonly used ratio is 30:70. Short- Potential barriers to insulin therapy: the main barriers to in- acting insulin analogue mixtures such as Novomix 30, Humalog sulin therapy are hypoglycaemia, weight gain and fear of in- Mix25 and Humalog Mix50 have become available and may have jections. Occupational factors may also be a barrier (e.g. in heavy advantages in terms of patient convenience (no need to wait goods vehicle drivers). Generally, patients taking insulin gain before eating). They are widely used in the UK, particularly due to weight, mainly because of improved glycaemic control. To limit their ease of use. However, a fixed combination is not this, one should determine the patient’s appropriate weight and ‘physiological’, and achieving optimal glycaemic control in some discuss the fact that additional ‘snacks’ are not automatically patients may be difficult with this relatively rigid regimen. required; they should be tailored to the individual’s needs and C Once-daily basal insulin in combination with an oral anti- the type of insulin regimen. hyperglycaemic agent includes a sulfonylurea or a prandial glucose regulator, with metformin if tolerated. Evidence suggests Insulins that conventional isophane insulin, when used in this regimen, is Porcine and bovine insulins were the very first insulin prepara- best administered in the evening or before bedtime. Basal insulin tions available before the advent of human and analogue in- analogues, including glargine and detemir, have been suggested sulins. They now account for only about 7% of insulin for once-daily use in combination with oral agents, because they prescriptions in the UK and are predominantly used in patients have advantages in terms of nocturnal hypoglycaemia. with T1DM. All insulin formulations are now produced at a C Twice-daily isophane insulin used as basal insulin therapy: concentration of 100 units/ml. For individual patients requiring although data suggest that once-daily basal insulin analogues are high doses, insulin can be produced on a named-patient basis at effective in lowering HbA1c and carry a reduced risk of a concentration of 500 units/ml (Humulin R). The rate of insulin hypoglycaemia, other factors such as cost and choice of insulin absorption differs between sites, being fastest in the abdomen device may lead to continued use of twice-daily isophane insulin and slowest in the thigh and buttocks. The site of insulin injec- (human Insulatard or Humulin I). tion should be varied to prevent lipohypertrophy. C Formal basalebolus regimen comprises four injections of insulin per day. Short-acting insulin or short-acting analogues are taken Insulin regimens in T2DM: (Table 3) the individual insulin before each main meal, together with basal insulin (once-daily or regimen should be tailored to address both fasting and post- twice-daily isophane insulin, or once-daily long-acting insulin prandial glycaemic excursions. Fasting hyperglycaemia is analogue (glargine or detemir)). This regimen is often used in addressed by isophane (medium-acting) insulin given twice daily type 1 diabetes, and is seldom the first choice in patients with e or by one of the long-acting analogues glargine, detemir or type 2 diabetes. degludec. Post-meal glucose excursions (prandial) can be targeted using short-acting insulins alone or as mixed insulin. A Table 3

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has a variety of favourable metabolic effects. It inhibits glucagon particularly when used in combination with other agents that can secretion, delays gastric emptying and reduces food intake cause a fall in eGFR (like Angiotensin Converting enzyme in- leading to weight loss. It has also been shown to increase b-cell hibitors). Improvement in glycaemic control can be sustained over proliferation. Since its release is glucose dependent, it is unlikely a period of 3 years with continued exenatide therapy.28 to be associated with hypoglycaemia. Liraglutide is a once-daily preparation with 97% amino-acid The discovery of these favourable effects of GLP-1 led to the sequence identity with endogenous GLP-1. Its prolonged long development of new therapeutic agents targeted to mimic or half-life results from formation of heptamers at the injection site, augment the action of this important molecule; unfortunately, leading to slow absorption and reversible binding with albumin; the half-life of endogenous GLP-1 is about 2 minutes, as it is this results in delayed renal clearance as well as degradation by rapidly degraded by enzyme dipeptidyl peptidase 4 (DPP-4). DDP-4 enzyme and this drug requires only once a day adminis- Incretin-based therapy is broadly divided into two groups. The tration. It is licensed for use along with metformin, a sulfonyl- agents targeted towards inhibition of DPP-4 enzyme, leading to urea or in combination with insulin detemir. It is available in 0.6 increased activity of endogenous GLP-1, are called DPP-4 in- mg, 1.2 mg and 1.8 mg doses given by subcutaneous injection. hibitors (incretin enhancers) and are taken orally. Agents that are Currently the BNF recommends that it be avoided in patients analogous to GLP-1 but partially resistant to degradation by with eGFR less than 60 ml/min, pending the results of further endogenous DPP-4 are called GLP-1 agonists (incretin mimetics) trials, which are underway to study the safety of liraglutide in and are administered as subcutaneous injections. patients with GFR down to 30 ml/min. A long-acting once-weekly formulation of exenatide (exena- DPP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin and lina- tide LAR) is also available, well tolerated and associated with

gliptin are currently licensed for the treatment of T2DM in the UK. greater reduction of HbA1c (1.9% vs. 1.5%) than twice-daily NICE recommends their use in addition to a ﬁrst-line agent (either exenatide over a 30-week period, an effect that is sustained metformin or a sulfonylurea) when sulfonylurea use is contra- after 52 weeks. It is used as a 2 mg once-weekly dose. indicated owing to the risk of hypoglycaemia, or metformin has Increasingly, GLP-1 receptor agonists are being used in combi- been poorly tolerated. Sitagliptin is recommended as a third-line nation with basal insulin to optimize glycaemia, reduce weight and agent in addition to metformin and a sulfonylurea for patients in optimize insulin dose requirements. Lixisenatide is the latest agent whom insulin therapy is unacceptable (Figure 1).4 DPP-4 in- in this series to be licensed for use in combination with OAAs, and is hibitors may be preferred to a thiazolidinedione if the latter is also licensed for use in combination with basal insulin glargine. contraindicated, or has led to weight gain or peripheral oedema. NICE recommends use of exenatide in addition to metformin Sitagliptin is licensed for use along with metformin and/or a and or a sulfonylurea in patients with BMI >35 kg/m2 whose

sulfonylurea at a dose of 100 mg orally once a day. Vildagliptin is glycaemic control is inadequate (HbA1c >58 mmol/mol (7.5%)). given in a dosage of 50 mg orally twice daily in combination with It should be continued only if HbA1c is reduced by 1% and metformin or thiazolidinedione, or 50 mg once daily with con- weight loss of 3% is achieved at 6 months. Indications for use of current sulfonylurea therapy Saxagliptin is given in a dosage of 5 liraglutide are fairly similar to that of exenatide; head-to-head mg orally once a day. The dosage of all three of these agents trials show that the two drugs have similar effects on weight

should be reduced in patients with moderate to severe renal but liraglutide treatment leads to greater reduction in HbA1c and impairment (see BNF section 6.1.3). Linagliptin is not excreted less persistent nausea. via the renal route and its dosage (5 mg orally once a day) need In comparison to orally available DPP-4 inhibitors, GLP-1 not be adjusted if renal function is impaired. Generally, these agonists are associated with more weight loss and greater

agents are tolerated well with occasional gastrointestinal effects reduction in HbA1c. and peripheral oedema. Liver function should be monitored before treatment and every 3 months for the first year (and SGLT2 inhibitors: sodium glucose co-transporter 2 (SGLT2) is periodically thereafter during vildagliptin therapy) owing to the present in proximal renal tubules, and plays a major role in rare incidence of liver toxicity. DPP-4 inhibitors are generally reabsorbing glucose from the tubular fluid. Inhibition of this co- weight neutral and less likely to be associated with hypo- transporter leads to calorie loss by increasing urinary glucose glycaemia than sulfonylureas. The risk of hypoglycaemia is excretion. As a result, glycaemic control is improved without risk increased in patients taking a concomitant sulfonylurea or In- of weight gain or hypoglycaemia as this approach is insulin insulin, the dose of which should be reduced if necessary. dependent. Increased glycosuria leads to increased diuresis and urogenital infections. This class of agents, which currently GLP-1 agonists/incretin mimetics: exenatide and liraglutide are comprises dapagliflozin and canagliflozin, has an insulin- the two compounds in this class and are administered subcuta- independent mode of action and has the potential to confer a neously. Exenatide is the first incretin mimetic licensed to be used lesser risk of hypoglycaemia. in patients with T2DM. It shares 53% amino-acid identity with Dapagliflozin is recommended by NICE for use in T2DM in endogenous GLP-1. It is currently licensed for use as monotherapy combination with metformin in the same way as the DPP-4 in- or in combination with metformin and/or a sulfonylurea. The hibitors.29 Dapagliflozin results in significant and sustained

initial dosage is 5 mg twice daily, increased to a maximum dose of reduction in HbA1c with an added beneﬁt of weight loss when 10 mg twice daily after 1 month if tolerated. Exenatide should be added to existing treatment with metformin.30 These effects appear used with caution when eGFR is between 30 and 50 ml/min and to be sustained when compared to those of a sulfonylurea at 4 should be avoided if eGFR is below 30 ml/min. In clinical practice, years.31 Canagliﬂozin, the second agent in this class, has a mar- more frequent monitoring of renal functions may be needed, keting authorization but is currently under appraisal by NICE.

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Head-to-head trials comparing SGLT2 inhibitors and DPP-4 3 Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with

inhibitors have shown equivalent reduction in HbA1c with the macrovascular and microvascular complications of type 2 diabetes added benefit of weight loss in the case of SGLT2 inhibitors.32,33 (UKPDS 35): prospective observational study. Br Med J 2000; 321: 404e12. Discontinued agents: pioglitazone has been withdrawn in 4 National Institute for Health and Clinical Excellence. Type 2 diabetes: France, Canada, Australia, New Zealand, India and Japan, while newer agents for blood glucose control in type 2 diabetes. Depart- Rosiglitazone has been withdrawn in Europe due to concerns ment of Health, 2009. about increased cardiovascular mortality. 5 Standards of medical care in diabetese2014. Diabetes Care 2014; 37(suppl 1): S14e80. The future 6 Davies MJ, Heller S, Khunti K, Skinner TC. The DESMOND (Diabetes education and self management for ongoing and newly diagnosed) Several other incretin-based agents and SGLT2 inhibitors are at programme: from pilot phase to randomised control trial in a study of different stages of drug development. structured group education for people newly diagnosed with type 2 Dual PPAR-a and PPAR-g agonists: agents activating diabetes mellitus. Diabet Med 2005; 22. S2:P233. both PPAR-a receptors, improving dyslipidemia, and 7 Davies MJ, Heller S, Skinner TC, et al. Effectiveness of the diabetes PPAR-g receptors, reducing insulin resistance, are also on education and self management for ongoing and newly diagnosed the horizon. One of these agents, aleglitazar, has been (DESMOND) programme for people with newly diagnosed type 2 shown to improve HbA by 0.36e1.35% in a dose- 1c diabetes: cluster randomised controlled trial. BMJ 2008; 336: 491e5. dependent manner during a placebo-controlled trial over 8 Gillett GR. In search of a good death: good death is achievable if task 16 weeks. Phase III trials and longer preclinical studies are becomes easing death, not prolonging life. BMJ 2003; 327: 225. needed to confirm the safety of these agents. 9 Deakin TA, Cade JE, Williams R, Greenwood DC. Structured patient Glucokinase activators: are molecules that activate the education: the diabetes X-PERT programme makes a difference. glucokinase enzyme present in hepatic cells and pancreatic Diabet Med 2006; 23: 944e54. b cells, leading to increased glycogen synthesis and 10 Department of Health, Diabetes UK. Structured patient education in glucose release. This effect has proved beneficial in diabetes. Report from the Patient Education Working Group. 15-6- reducing plasma glucose in animal models and the role of 2005. these drugs in humans is currently being tested. 11 Di Loreto C, Fanelli C, Lucidi P, et al. Make your diabetic patients SGLT1 inhibitors: SGLT1 receptors are predominantly walk: long-term impact of different amounts of physical activity on present in the small intestine contributing to intestinal type 2 diabetes. Diabetes Care 2005; 28: 1295e302. glucose absorption but contribute to under 10% of renal 12 Turner RC, Holman R, Mathews D, Hockaday TDR, Peto J. Insulin reabsorption of glucose. Blockade of these present a novel deficiency and insulin resistance interaction in diabetes: estimation way of improving glucose tolerance and provide exciting of their relative contribution by feedback analysis from basal avenues for the treatment of T2DM. Molecules that exhibit plasma insulin and glucose concentrations. Metabolism 1979; 28: selective and variable SGLT1 and SGLT2 affinity are in 1086e96. various trial stages. 13 Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, Glucagon receptor antagonists: glucagon is secreted by sulfonylurea, metformin, or insulin in patients with type 2 diabetes pancreatic a-cells and plays a vital role in maintaining mellitus: progressive requirement for multiple therapies (UKPDS 49). glucose homeostasis. It prevents hypoglycaemia and UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999; 281: counteracts the effects of insulin by stimulating hepatic 2005e12. glucose synthesis and mobilization. In patients with 14 Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of T2DM, glucagon/insulin ratio is increased leading to glu- insulin secretory dysfunction and insulin resistance in the patho- cogenesis and glycogenolysis. Experimental studies have genesis of type 2 diabetes mellitus. J Clin Invest 1999; 104: 787e94. shown a state of hyperglucagonaemia in patients with 15 Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose T2DM and suppression of this excess glucagon levels or lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545e59. activity resulted in improvement of glycaemic control. One 16 National Collaborating Centre for Chronic Conditio. Type 2 diabetes: such agent, Bay 27-9955, has been shown to reduce the national clinical guideline for management in primary and secondary glucagon-induced hyperglycaemia in adults. Various pep- care (update). London: Royal College of Physicians, 2008. tide and non-peptide based glucagon receptor antagonists 17 Bonds DE, Miller ME, Bergenstal RM, et al. The association between are currently being tested in animals and humans. A symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ REFERENCES 2010; 340. b4909. 1 UKPDS 33. UK Prospective Diabetes Study Group. Intensive blood- 18 Miller ME, Bonds DE, Gerstein HC, et al. The effects of baseline char- glucose control with sulphonylureas or insulin compared with con- acteristics, glycaemia treatment approach, and glycated haemoglobin ventional treatment and risk of complications in patients with type 2 concentration on the risk of severe hypoglycaemia: post hoc epide- diabetes (UKPDS 33). Lancet 2007; 352: 837e53. miological analysis of the ACCORD study. BMJ 2010; 340. b5444. 2 Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year 19 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive follow-up of intensive glucose control in type 2 diabetes. N Engl J blood-glucose control with metformin on complications in overweight Med 2008; 359: 1577e89. patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854e65.

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20 Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment 28 Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, modalities and their duration. Diabetologia 2007; 50: 1140e7. obesity, cardiovascular risk factors and hepatic biomarkers in pa- 21 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial tients with type 2 diabetes treated for at least 3 years. Curr Med Res infarction and death from cardiovascular causes. N Engl J Med 2007; Opin 2008; 24: 275e86. 356: 2457e71. 29 National Institute for Clinical Excellence. Dapaliflozin in combination 22 Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated therapy for use in type 2 diabetes mellitus. NICA TA 288. 15-6-2013. for cardiovascular outcomesean interim analysis. N Engl J Med 2007; NICE TA. 357: 28e38. 30 Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin 23 Ferwana M, Firwana B, Hasan R, et al. Pioglitazone and risk of in patients with type 2 diabetes who have inadequate glycaemic bladder cancer: a meta-analysis of controlled studies. Diabet Med control with metformin: a randomised, double-blind, placebo- 2013; 30: 1026e32. controlled trial. Lancet 2010; 375: 2223e33. 24 Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of 31 Del Prato S, et al. Presented at the 72nd American diabetes associ- cardiovascular events in patients with type 2 diabetes mellitus. JAMA ation scientific sessions. Chicago, USA June 2013; 2007; 298: 1180e8. 21e5. Abstract 62- LB. 2013. 25 UKPDS 16. U.K. prospective diabetes study 16. Overview of 6 years’ 32 Rosenstock J, Seman LJ, Jelaska A, et al. Efficacy and safety of therapy of type II diabetes: a progressive disease. U.K. Prospective empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as Diabetes Study Group. Diabetes 1995; 44: 1249e58. add-on to metformin in type 2 diabetes with mild hyperglycaemia. 26 Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of com- Diabetes Obes Metab 2013; 15: 1154e60. plex insulin regimens in type 2 diabetes. N Engl J Med 2009; 361: 33 Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared 1736e47. with sitagliptin for patients with type 2 diabetes who do not have 27 Perley MJ, Kipnis DM. Plasma insulin responses to oral and intrave- adequate glycemic control with metformin plus sulfonylurea: a 52- nous glucose: studies in normal and diabetic subjects. J Clin Invest week randomized trial. Diabetes Care 2013; 36: 2508e15. 1967; 46: 1954e62.

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Modern strategies for What’s new? management of glycaemia in C Structured education gives patients freedom to adjust insulin type 1 diabetes doses to food and lifestyle C Insulin pumps are increasingly popular although used by less Sankalpa Neupane than 10% of patients with type 1 diabetes in UK C Continuous glucose monitoring is available but less established Mark L Evans C Insulin pumps and continuous glucose monitoring can be coupled, and may incorporate a ‘threshold suspend’ feature Abstract that may benefit those with intractable hypoglycaemia The last decade has seen significant advances in the management of type C Pancreas and islet cell transplantation may give insulin inde- 1 diabetes. The usual management of type 1 diabetes involves ‘physio- pendence but are reserved for those with complications and/or logical’ basal bolus regimens with multiple daily insulin injections, but hypoglycaemia use of insulin pumps (continuous subcutaneous insulin infusion) is growing. Structured education programmes are of great importance in realizing the potential of the flexible insulin regimens that are now tech- regimens (Figure 1). Insulin therapy and blood glucose moni- nically possible; these now offer patients with type 1 diabetes standard- toring are described in more depth in the article on Modern ized support and education in counting carbohydrates (and perhaps fat technologies for glucose monitoring and insulin replacement on and protein) and in adjusting doses for other behavioural factors. Evolu- pages 703e706 of this issue. tion of continuous glucose monitors from being tools for ‘forensic’ retrospective monitoring to ‘real-time’ devices for continuous use has led to major interest in strategies for glycaemic control that involve insulin Structured patient education pumps linked to continuous glucose monitoring, with the hope that The flexibility offered by modern variable insulin regimens pre- this will provide increasing automation of insulin delivery. Data from sents a challenge for patients, who need to learn and use many many devices e meters, pumps and continuous glucose monitors e are self-management skills beyond simply checking blood glucose downloadable and can be analysed and/or shared with healthcare pro- concentration and administering insulin. For example, many viders. In this chapter, we describe how modern glucose monitoring people with T1DM adjust doses of meal-time rapid-acting insulin and insulin replacement can be used strategically together with education depending on the carbohydrate content of food, meaning that they to manage glycaemia in type 1 diabetes. need training to count carbohydrates accurately. Evidence-based Keywords Continuous glucose monitoring; continuous subcutaneous structured educational packages have emerged in the UK over insulin infusion; hypoglycaemia; insulin pumps; islet transplantation; the last decade. The largest and best established of these is the pancreas transplantation; structured education DAFNE programme (Dose Adjustment For Normal Eating), described below, but a number of broadly similar smaller structured education programmes are also being used in UK services. DAFNE is based on a patient education model developed in Dusseldorf.€ In a randomized controlled trial, DAFNE improved Introduction blood glucose control and patient well-being.1 It was introduced as clinical service in the UK in 2002. By June 2014, there were 75 Many technical and healthcare changes have occurred over the last few years in type 1 diabetes mellitus (T1DM). New insulin analogues (engineered either to act more rapidly or be more long lasting) continue to be developed and have been widely adopted in T1DM. The combination of rapid-acting ‘bolus’ insulin given before meals and/or as ad hoc doses to correct high blood glucose values, with long-acting background insulin replacement (by convention termed ‘basal’ if delivered by insulin pump) allows patients to use more ‘physiological’ basal bolus insulin

Sankalpa Neupane MBBS MRCP is a Clinical Research Fellow at Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge and Cambridge University Hospitals (Addenbrooke’s), Cambridge, UK. Conﬂicts of interest: none declared.

Mark L Evans MD FRCP is University Lecturer/Honorary Consultant at Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge and Cambridge University Hospitals (Addenbrooke’s), Cambridge, UK. Conﬂicts of interest: none declared. Figure 1

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centres in the UK and Ireland delivering DAFNE to 31,000 patients and growing at a rate of 4000e5000 per annum. It has also been adopted in Australia, New Zealand and Singapore. DAFNE continues to be effective with improved glycaemic and patient- reported outcomes.2 Patients experience not only lower average

blood glucose concentrations, reflected by lower HbA1c values, but also less hypoglycaemia and improvement in their ability to detect a falling blood glucose sooner. DAFNE and similar programmes provide education in skills required to self-adjust insulin doses, such as carbohydrate counting, adjustment for exercise/activity, illness, stress, alcohol, travel and the menstrual cycle (Figures 2 and 3). The DAFNE approach teaches patients to count carbohydrate intake in 10 g portions and then apply an individualized insulin:carbohydrate ratio to calculate prandial insulin. Other programmes may also use portions (for simplicity) or grammes of carbohydrate. DAFNE is delivered in group sessions over 5 days. In common with the Dusseldorf€ programme, DAFNE also has a supporting structure with a clear philosophy, written curriculum, processes for training and accrediting educators, quality assurance process including regular external peer review and audit of process and outcomes, with an anony- Figure 3 mized database. Patient education also highlights the increasing role of non-medical staff as part of a multidisciplinary team Early CSII models were cumbersome and unreliable but the approach, with specialist nurse educators and diabetes dieticians last decade has seen increased uptake in many developed being highly trained and skilled in delivering and supporting countries in both children and adults. Used judiciously, CSII can 3 education. improve glucose control but they are more complex technically The efficacy of structured educational packages in children/ and medically and thus unlikely to replace injections as standard adolescents with T1DM has not yet been established. treatment for insulin-requiring diabetes in the near future. Particular advantages of modern pumps over multiple daily Continuous subcutaneous insulin infusion (‘insulin pumps’) injections are: The ability to pre-programme variable basal insulin de- With continuous subcutaneous insulin infusion (CSII), a rapid- livery e useful for patients with marked circadian vari- acting insulin is pumped in constantly as a basal insulin ability in insulin requirements. replacement via an indwelling subcutaneous infusion cannula, Temporary basal rates, where basal insulin delivery can be self-inserted typically into abdomen, buttock, thigh or arm. Pa- adjusted for a defined period of time e especially useful for tients can then use the pump to deliver an insulin bolus to cover lowering insulin delivery with unplanned or unexpected meals and/or corrections for high glucose values as needed activity to reduce risk of hypoglycaemia. (Figure 4). Typically, every 3 days, the infusion set is removed and a fresh set inserted at a different site.

Figure 2 Figure 4

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The delivery of small amounts of insulin accurately e Importantly, CGM does not remove the need for finger-prick useful for children and some adults with low insulin re- testing. Patients still need to do this for calibration and to quirements in whom it is difficult to deliver small doses confirm glycaemic excursions e particularly hypoglycaemia. accurately with injections. Accuracy of CGM is improving but is still frustratingly inaccu- Complex bolus options, allowing meal time insulin de- rate for some. Perhaps as a consequence of this, current trial livery to be extended over a protracted time period e evidence suggests only modest benefits in glycaemic outcomes useful for slowly absorbed foods (for example for large from CGM5 and use of CGM in clinical practice is still relatively meals with mixed carbohydrates and fat slowing absorp- low. tion, such as pizza) or in patients with diabetic gastroparesis. Linking pumps with continuous glucose monitoring Bolus-calculating software, which calculates a suggested An obvious pathway forward for this technology is to link the insulin dose from patient-specific indices such as the car- real-time CGM information to control insulin delivery by CSII e bohydrate:insulin ratio and insulin sensitivity factors e the popularly referred to as an ‘artificial pancreas’ but perhaps better latter feature may remove some of the potential for arith- described as a closed-loop system. Closed-loop pumps, either metic errors with calculation of insulin doses. with insulin or the combination of insulin and glucagon in- Data from pumps can also be downloaded for personal records fusions, are undergoing clinical testing and show promise6,7 but and/or shared with clinical teams. Increasingly this can be per- are not yet available. Pump systems that receive and display formed remotely. This carries its own challenges for healthcare CGM data, referred to as ‘sensor augmented pumps’ are available providers and patients, with a danger of ‘data overload’. To aid but, with one exception (described below), do not currently use with this, some professional CSII software can now also analyse glucose information to adjust insulin delivery. patterns from downloaded data from CSII and/or CGM. The first approved automated feature has been a threshold suspend option, which can be set so that insulin delivery from Drawbacks of continuous subcutaneous insulin infusion the pump ceases if CGM glucose falls below a set point and pa- Drawbacks of CSII are: tients fail to react to alarms. Data are starting to emerge sug- The risk of a more rapid deterioration in health if insulin gesting that this low-glucose suspend feature can help reduce risk delivery is interrupted with the absence of long-acting of hypoglycaemia.8e10 background insulin, meaning that interrupted insulin delivery rapidly results in insulopenia and ketosis. Transplantation Being connected constantly to a device (a new generation Whole-organ pancreas transplantation has a reasonable success of small, aesthetically acceptable pumps may overcome rate for graft survival and insulin independence. In the UK as in this for some patients). many countries, this is largely combined with kidney trans- CSII is not currently an ‘artificial pancreas’ system so that a plantation but pancreas alone transplantation may be performed high level of engagement and effort is need by patients to where indicated e usually by recalcitrant severe hypoglycaemia. harness pumps safely, let alone effectively. Similarly, islet transplantation involves a lesser procedural The higher cost of CSII compared with injections means that, in complexity but, like whole-organ transplantation, the risks of many countries, CSII is reserved for a subset of patients who have anti-rejection therapy including immunosuppression must be struggled to achieve appropriate control of their diabetes (e.g. with weighed against the benefits. ongoing hypoglycaemia and/or hyperglycaemia) or where rapid control is desired (e.g. pregnancy or young children). Currently in Non-insulin therapy to manage glycaemia in T1DM the UK, NICE (National Institute for Care Excellence) guidance is that, in adults, CSII should be considered in those with T1DM only As for type 2 diabetes, metformin may be used as an insulin where optimized therapy with injections has ‘failed’, meaning an sensitizer in T1DM. There is current interest in examining other

HbA1c value of greater than 69 mmol/mol (8.5%) and/or hypo- drugs used to treat type 2 diabetes, such as pramlintide (slow glycaemia is a significant problem.4 gastric emptying) glucagon-like peptide-1 (GLP-1) agents, sodium glucose co-transporter-2 (SGLT-2) inhibitors and others in Continuous glucose monitoring T1DM but all of these are unlicensed and need further testing. Glucagon emergency pens are prescribable and, administered by Continuous glucose monitoring (CGM) consists of a self-inserted a third party, useful for treating severe hypoglycaemia. A subcutaneous sensor linked wirelessly to a receiver. CGM receivers can be stand-alone handheld devices or linked to an insulin pump that acts as the receiver. The sensor detects changes REFERENCES in interstitial tissue glucose and patients need to calibrate the 1 DAFNE Study Group. Training in flexible intensive insulin manage- system by performing finger-prick testing. Receivers can display ment to enable dietary freedom in people with type 1 diabetes: dose real-time information about both absolute blood glucose values adjustment for normal eating (DAFNE) randomised control trial. BMJ and indicate the direction and speed of change. The system can 2002; 325: 746e9. be set to alert the patient if values are outside target ranges or, 2 Hopkins D, Lawrence I, Mansell P, et al. Improved biomedical and with predictive algorithms, to sound an alarm if glucose values psychological outcomes 1 year after structured education in flexible are changing rapidly and/or predicted to move outside the target insulin therapy for people with type 1 diabetes: the U.K. DAFNE range. experience. Diabetes Care 2012; 35: 1638e42.

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3 Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in 8 Choudhary P, Shin J, Wang Y, et al. Insulin pump therapy with auto- type 1 diabetes: meta-analysis of multiple daily insulin injections mated insulin suspension in response to hypoglycemia: reduction in compared with continuous subcutaneous insulin infusion. Diabet nocturnal hypoglycemia in those at greatest risk. Diabetes Care 2011; Med 2008; 25: 765e74. 34: 2023e5. 4 National Institute for Health and Care Excellence, Diabetes-insulin 9 Ly TT, Nicholas JA, Retterath A, Lim EM, Davis EA, Jones TW. Effect of pump therapy (TA151), Available at: http://www.nice.org.uk/TA151. sensoraugmented insulin pump therapy and automated insulin sus- 5 Langendam M, Luijf YM, Hooft L, Devries JH, Mudde AH, Scholten RJ. pension vs standard insulin pump therapy on hypoglycemia in pa- Continuous glucose monitoring systems for type 1 diabetes mellitus. tients with type 1 diabetes: a randomized clinical trial. JAMA 2013; Cochrane Database Syst Rev 2012. Issue 1. Art. No.:CD008101. 310: 1240e7. 6 Elleri D, Allen JM, Kumareswaran K, et al. Closed-loop basal insulin 10 Bergenstal RM, Klonoff DC, Garg SK, et al. ASPIRE In-Home Study delivery over 36 hours in adolescents with type 1 diabetes: ran- Group. Threshold-based insulin-pump interruption for reduction of domized clinical trial. Diabetes Care 2013; 36: 838e44. hypoglycemia. N Engl J Med 2013; 369: 224e32. 7 Castle JR, Engle JM, El Youssef J, et al. Use of glucagon in a closed- loop system for prevention of hypoglycemia in type 1 diabetes. Diabetes Care 2010 Jun; 33: 1282e7.

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available around 1945, but plasma glucose became measurable Modern technologies for only during the mid 1950s after development of glucose oxidase- based systems. It was not till 1980 that the first portable home glucose monitoring and glucose monitoring systems were developed.1 Current meters require very small volumes of capillary blood [0.30e1.50 mL] and insulin replacement provide readings within 5 seconds. They calculate glucose concentration based on enzymatic reactions that are generally Christine HM Leong dependent on either glucose oxidase (GOX) or glucose dehy- Anand Velusamy drogenase (GDH). GOX meters can be affected by ambient oxy- Pratik Choudhary gen concentrations, while GDH systems can be affected by other sugars such as maltose xylose and icodextrin [found in peritoneal dialysate]. Several other drugs, including ascorbic acid, para- Abstract cetamol, dopamine and mannitol, can also interfere with both Self-monitoring of blood glucose (SMBG) is an integral part of diabetes GDH and GOX based devices. Most meters have a large memory, care, allowing patients to identify patterns, calculate doses and identify which can be used to download readings to spreadsheets or hypoglycaemic or hyperglycaemic excursions. Structured education on proprietary software, making the data much more accessible for interpretation of the results and algorithms to calculate insulin doses, pattern recognition. From 2014, meters will have to adhere to structured and automated approaches to pattern recognition, and auto- new ISO guidelines that require 95% of readings to be within mation of data collection through these devices can contribute to 0.83 mmol/L (15 mg/dL) of the gold standard. It is important to improved glycaemic control. remember that capillary glucose meters read whole blood, and Insulin delivery has not changed much since it was first used in 1921. then are calibrated to produce a ‘plasma equivalent’ glucose Although therapy has moved from impure animal insulins to genetically reading, assuming a normal haematocrit. Apart from haematoc- modified rapid- and long-acting analogues, the mode of insulin delivery rit, hypertriglyceridaemia and paraproteinaemia can also affect through subcutaneous injections remains the same. With the increasing the technical accuracy of blood glucose readings by causing use of continuous subcutaneous insulin infusions (CSII) or insulin pseudohypoglycaemia. pumps, greater precision in delivery is possible, but recent advances such as intraperitoneal insulin delivery and the combination of contin- New developments uous glucose monitoring with insulin pumps, using algorithms to produce Bolus advisors: Despite being taught how to adjust insulin closed-loop systems, herald a new future for insulin delivery. dosage based on carbohydrate intake [using insulin to Keywords CGM; continuous glucose monitoring; continuous subcutaneous carbohydrate ratios] and current glucose concentrations insulin infusions; CSII; insulin pumps; insulin therapy; self-monitoring of [using insulin sensitivity factors] patients miscalculate blood glucose; SMBG rapid-acting insulin doses more than 50% of the time.2 Some newer meters can be pre-programmed with these ratios, and can perform these calculations for the patient. 3 Intermittent glucose monitoring Initial studies showed significant reductions in HbA1c. Pattern recognition: Some meters and download software Although glucose has been identified in urine as a symptom of can analyse glucose readings and identify patterns of diabetes mellitus for centuries, its quantification became possible recurrent hypoglycaemia or hyperglycaemia.4 only in 1908 with the development of Benedict’s reaction. The Ò Connectivity: Meters are now offering connectivity to in- first home urine monitoring system [Clinitest strips] became sulin pumps, making it easier for patients to react to readings. They can also connect to mobile phones, and through these to cloud-based databases. Christine H M Leong MBBS MRCP (UK) is a Specialist Registrar in Diabetes and Endocrinology at King’s College Hospital NHS Foundation Trust, Continuous glucose monitoring (CGM) London, UK. She Qualified from Guy’s, King’s and St Thomas’ School of Medicine, London and trained in London and Kent. Conflicts of interest: CGM allows almost continuous display of glucose measured from none declared. the interstitial fluid using small sensors (coated with glucose oxidase) placed subcutaneously. They generate a current pro- Anand Velusamy MBBS MRCP UK is a Specialist Registrar in Diabetes and portional to glucose concentrations, which can be read as a Endocrinology at King’s College Hospital NHS Foundation Trust, glucose value. However, interstitial glucose lags approximately London, UK. Conflicts of interest: none declared. 10e15 minutes behind plasma glucose, and this lag increases 5 Pratik Choudhary MBBS MRCP (UK) MD is a Senior Lecturer and Consultant with increased rate of change. This can mean that concurrent in Diabetes at King’s College Hospital NHS Foundation Trust, London, readings from CGM devices and capillary glucose meters are UK. He qualified in India and after completing his MD from the quite likely to be slightly different, and patients often feel that the University Sheffield is now a senior lecturer in London. His research CGM devices have missed the event, especially when patients interests include type 1 diabetes and insulin pumps. Conflicts of rapidly drop into hypoglycaemia. CGM can be used over 7 days interest: advisory boards, travel support and speaker honoraria for as a diagnostic tool, often with data blinded from the patient to NovoNordisk, Lilly, Sanofi, Medtronic, Roche, Johnson and Johnson and identify patterns, and as a guide for adjusting therapy. They can Abbott Ltd. also be used therapeutically by patients, who can use the real-

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time information of glucose, including direction and rate of delivered into the systemic circulation, rather than into the portal change, and respond to alarms if glucose falls outside pre-set circulation as in physiology, which means that it is almost thresholds.6 Some of these devices can ‘pair’ with insulin impossible to mimic completely normal physiology. pumps, allowing display of glucose on the insulin pump, and in the case of the Medtronic VeoÒ, allow the pump to suspend in- Animal insulin: porcine (pork) insulin has one amino acid and sulin delivery for up to 2 hours if the patient fails to respond to a bovine (beef) insulin has three amino acids different from human ‘hypoglycaemia’ alarm (termed low-glucose suspend [LGS]).7 insulin. From the late 1930s, protamine and zinc were added to Key issues with currently available CGM relate to the accuracy the insulin suspension to increase the duration of action (the and longevity of the sensors. Current sensors have approximately effects of lente and ultralente insulin lasted between 18 and 36 80% sensitivity and specificity for hypoglycaemia.8 hours). These preparations are now largely obsolete, although neutral protamine Hagedorn insulin (NPH), developed in the New developments 1950s, is still widely used. Novel sensors: fluorescent based sensors are currently under trial which aim to offer a longer duration of use, or Human insulin: insulin was the first peptide to be sequenced provide redundancy and better fault detection to improve and the first peptide to be generated using recombinant DNA 9 reliability. technology. When human insulin was first introduced a number Closed-loop platforms: there are a number of systems in of patients complained of loss of warning signs of hypo- clinical trials which use algorithms to use the sensor glycaemia, and rapid unpredictable hypoglycaemia. Even though glucose values and modulate insulin delivery. Current no difference was ever shown in controlled studies, many of versions have shown efficacy in increasing time in target these patients have continued to use animal insulin. overnight, with almost complete avoidance of nocturnal hypoglycaemia, and some benefits through the day as Analogue insulin: insulin exists in solution as hexamers held 10 well. together by a zinc molecule. The rate of dissociation into monomers after injection into the subcutaneous tissue de- Insulin delivery termines the speed of onset and duration of action. Making some Insulin is delivered by subcutaneous injection using syringes, alterations to the amino acid sequence of insulin can speed up pens or insulin pumps. When injected through the skin, insulin is the onset of action; this has led to development of rapid-acting

Insulin types and action proﬁles

Insulin preparations Manufacturer Type Onset Peak Effective duration

Rapid-acting 5e15 min 1 h 2e4h Insulin aspart (NovorapidÒ) Novo Nordisk analogue 5e15 min 30e90 min 3e5h Insulin lispro (HumalogÒ) Eli Lilly analogue 5e15 min 30e90 min 4e6h Insulin glulisine (ApidraÒ) Sanoﬁ-Aventis analogue 20 min 60e90 min 3e5h Short-acting 30 min 2e4h 6e8h Actrapid Novo Nordisk human 30e60 min 2e3h 6e8h Humulin S Eli Lilly human 30e60 min 2e3h 6e8h U-500 Regular insulin Eli Lilly human 30e60 min 4e8 h Up to 12 h Intermediate 30 min 4e8 h 14e16 h Insulatarda Novo Nordisk human 2e4h 4e10 h 10e16 h Humulin I Eli Lilly human 2e4h 4e10 h 10e16 h Long-acting; Basal 1e4 h Peakless 18e24 h Insulin detemir (LevemirÒ) Novo Nordisk analogue 0.8e2h 3e9 h (to peak action) 16e20 h Insulin glargine (LantusÒ) Sanoﬁ-Aventis analogue 2e4 h 4 h (to peak action) 16e20 h Insulin degludec (TresibaÒ) Novo Nordisk analogue 1e2h 8e12 h Up to 42 h Pre-mixed insulin Variable depending on mixture NovoMix30 70/30b Novo Nordisk analogue 5e15 min 2e12 h 10e16 h Humulin M3c Eli Lilly analogue 5e15 min Dual 10e16 h HumalogMix25 75/25d Eli Lilly analogue 5e15 min 30e90 min 10e16 h HumalogMix50 50/50e Eli Lilly analogue 5e15 min 3e5 h 10e16 h

a Pork insulatard is also available. b 30% aspart and 70% Protamix-crystallized aspart. c 30% soluble insulin, 70% isophane. d 25% lispro and 75% neutral protamine lispro. e 50% lispro and 50% neutral protamine lispro.

Table 1

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analogues such as aspart (NovoRapidÒ), lispro (HumalogÒ) and infusion set and cannula have to be replaced or else they become glulisine (ApidraÒ).11 Some alterations can prolong the action of prone to occlusions, which can cause non-delivery of insulin. insulin to generate more steady pharmacodynamic profiles, Patch pumps such as the OmniPod are attached directly to the leading to development of long-acting ‘peakless’ insulins such as body without additional tubing, and are often preferred by pa- detemir (LevemirÒ), glargine (LantusÒ) and, recently, degludec tients. Most pumps have an integral dose calculator. These can (TresibaÒ). The ultra long-acting insulin degludec forms large be pre-programmed with insulin: carbohydrate ratios in insulin soluble multihexamers at the subcutaneous injection site, sensitivity factors, allowing quick calculation of appropriate proving a much more stable and reproducible long-acting pro- doses if the patient enters the current glucose concentration and file.12 These newer analogue insulins provide a more reproduc- estimated carbohydrate intake. As mentioned previously, some ible pharmacodynamic profile, reducing day-to-day variability by of the latest pumps can be connected to continuous glucose up to a third, and have been shown to cause less hypoglycaemia, sensors (sensor augmented pumps). especially in type 1 diabetes. However, there is still controversy In the USA, up to 45% of patients with type 1 diabetes use about the health economic benefits of their use in the majority of CSII, but only 20e30% in France, Germany and Scandinavia.15 patients with type 2 diabetes. Insulin glargine exhibits prolonged In the UK, the latest national audit found <6% of patients with binding to the IGF-1 receptor, leading to theoretical concerns type 1 diabetes were using CSII. The criteria currently used in about increased cancer risk. However, data from a recent large England for CSII are outlined in Table 2.16 RCT is reassuring13 (Table 1). New developments Continuous subcutaneous insulin infusion (CSII) Patch pumps: over the next few years, we will see the emergence of patch pumps, which do away with the long The first clinical report of the use of CSII was published by Prof tubing, and are often controlled remotely with handsets, or John Pickup in 1979. The key advantage of CSII is the ability to may even be controlled by apps on mobile phones. alter basal insulin infusion, in particular overnight, allowing in- Intraperitoneal insulin delivery e systems such as the sulin delivery to match physiological requirements with lower DiaPort allow insulin to be delivered into the portal sys- insulin delivery through the early night and increased basal in- 14 tem, redressing the imbalance of portal to systemic insulin sulin delivery in the early hours of the morning. Pumps also that occurs when insulin is injected subcutaneously. offer much more precise insulin delivery, especially at lower However, concerns over infections and occlusions will doses, proving significant benefit in very young children. Pa- need to be addressed. tients can also alter basal rates based on exercise or illness. Inhaled insulin: delivering insulin to the lungs offers ad- Classical pumps are referred to as ‘tethered’ pumps, as the pump vantages in terms of ease of delivery and speed of action, is attached via variable lengths of infusion sets to a cannula, but concerns around dose precision and effects on the inserted into the skin. Every 3 or 4 days, the insulin reservoir, lungs remain. Oral insulin: insulin is a peptide that is broken down by intestinal peptidases, but newer formulations that protect against this are being developed. A Current Indications for continuous subcutaneous insulin infusion (CSII) use in England REFERENCES C According to NICE guidance, CSII can be considered a therapeutic 1 Clarke SF, Foster JR. A history of blood glucose meters and their role option in the treatment of type 1 diabetes in adults and children in self-monitoring of diabetes mellitus. Br J Biomed Sci 2012; 69: of 12 years or above where: 83e93. patients have experienced disabling hypoglycaemia whilst 2 Ahola AJ, Makimattila€ S, Saraheimo M, et al. Many patients with type 1 trying to achieve target HbA1c while using multiple-dose in- diabetes estimate their prandial insulin needs inappropriately. sulin (MDI) or J Diabetes 2010; 2: 194e202. HbA1c has remained 8.5% during MDI therapy despite high 3 Cavan DA, Ziegler R, Cranston I, et al. Use of an insulin bolus advisor level of clinical care facilitates earlier and more frequent changes in insulin therapy pa- C CSII can be considered in children below 12 years: rameters in suboptimally controlled patients with diabetes treated where MDI would be inappropriate or impractical with multiple daily insulin injection therapy: results of the ABACUS where a trial of MDI between ages 12 and 18 years will be trial. Diabetes Technol Ther 2014; 16: 310e6. undertaken 4 Choudhary P, Genovese S, Reach G. Blood glucose pattern manage- C CSII should be commenced only by a trained specialist team that ment in diabetes: creating order from disorder. J Diabetes Sci Technol can provide insulin pump therapy support with a diabetes 2013; 7: 1575e84. specialist nurse and dietitian 5 Steil GM, Rebrin K, Hariri F, et al. Interstitial fluid glucose dynamics C Structured education programmes need to be provided for during insulin-induced hypoglycaemia. Diabetologia 2005; 48: patients on CSII 1833e40. C CSII therapy should continue if improvement in glycaemic control 6 JDRF CGM Group. JDRF randomized clinical trial to assess the efficacy is demonstrated or there is a reduction in the number of of real-time continuous glucose monitoring in the management of hypoglycaemic episodes type 1 diabetes: research design and methods. Diabetes Technol Ther 2008; 10: 310e21. Table 2

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