Frequency Of Hypoglycaemia In Type Diabetes

Mild hypoglycaemia is defined by the ability to self-treat, while the need for external assistance denotes a severe episode. The frequency of hypoglycaemia in people with type 1 diabetes is described in Chapter 3. Mild hypoglycaemia occurs on average around twice weekly (Pramming et al., 1991; Pedersen-Bjergaard et al., 2004) and the estimated incidence of severe hypoglycaemia ranges from 1.0 to 1.7 episodes per patient per year (MacLeod et al., 1993; ter Braak et al., 2000; Pedersen-Bjergaard et al., 2004) with an annual prevalence of between 30% (MacLeod et al., 1993; The Diabetes Control and Complications Trial Research Group, 1993; Stephenson et al., 1994) and 40% (ter Braak et al., 2000).

The frequency of hypoglycaemia in type 2 diabetes cannot be summarised in an equally succinct manner because of the heterogeneity of this disorder and the range of treatment modalities available. Furthermore, many people with type 2 diabetes are elderly and the frequency of hypoglycaemia is often underestimated in this group (McAulay et al., 2001). Most studies have been conducted retrospectively and both the definitions of hypoglycaemia and the nature of the treatment modalities that have been examined differ between studies, thus hindering comparison. Studies have demonstrated that individuals with type 1 diabetes can reliably remember the occurrence of severe hypoglycaemia after an interval of one year, but that recall of mild hypoglycaemia becomes unreliable after a one week period (Pramming et al., 1991; Pedersen-Bjergaard et al., 2003). In people with insulin-treated type 2 diabetes, recall of severe hypoglycaemia is similarly robust over a period of one year (Akram et al., 2003) but the reliability of their recall of mild hypoglycaemia has not been examined. Finally, the treatment regimens and patient inclusion criteria used in clinical trials may not be representative of the patient characteristics observed and the therapeutic interventions employed within an unselected diabetic out-patient population and this may limit the extent to which such data can be extrapolated. Table 11.2b summarises available epidemiological data on hypoglycaemia in type 2 diabetes.

Hypoglycaemia and Oral Antidiabetic Agents

Hypoglycaemia caused by oral antidiabetic agents is primarily associated with the insulin secretagogues. It is seldom a side-effect of treatment with thiazolidinediones or alpha-glucosidase inhibitors, and has been reported only infrequently in association with metformin, usually when food intake is restricted (UK Prospective Diabetes Study (UKPDS) Group 1998a, United Kingdom Prospective Diabetes Study Group 1998c). The frequency of hypo-glycaemia secondary to sulphonylurea therapy is considerably lower than that attributed to insulin (UK Prospective Diabetes Study (UKPDS) Group 1998b; Miller et al., 2001; Leese et al., 2003) but is probably underestimated (Hartling et al., 1987). In a retrospective six-month study in England of 219 people with type 2 diabetes treated with sulphonylureas and metformin, 20% of those taking sulphonylureas (either alone or in combination with metformin) had experienced hypoglycaemic symptoms (Jennings et al., 1989). Sulphony-lureas can also cause severe hypoglycaemia. Over a seven-year period, the Swedish Adverse Drug Reactions Advisory Committee reported 19 cases of glipizide-associated severe hypoglycaemia presenting with reduced consciousness, with two deaths (Asplund et al., 1991). Incidences of severe hypoglycaemia of 0.224 episodes per 100 person-years with long-acting sulphonylureas versus 0.075 episodes per 100 patient-years were reported among 28 patients (median age 73 years) who were admitted to hospital with severe hypoglycaemia in Switzerland (Stahl and Berger, 1999). The frequency of severe hypoglycaemia may be underestimated in this study as patients receiving treatment in the community were excluded. A recent study, A Diabetes Outcome Progression Trial (ADOPT), in which newly diagnosed patients with type 2 diabetes were randomised to treatment with rosiglitazone, metformin and glibenclamide for a median of four years, prospectively recorded the hypoglycaemic events associated with each treatment (Kahn et al., 2006). One (0.1%) serious and 142 (9.8%) total events were recorded for rosiglitazone, one (0.1%) serious and 168 (11.6%) total events for metformin and eight (0.6%) serious and 557 (38.7%) total events for glibenclamide.

The frequency of hypoglycaemia relates to the individual pharmacokinetic properties of each sulphonylurea (Table 11.3), with the long-acting agents such as chlorpropamide, glibenclamide and long-acting glipizide being associated with the greatest risk (Stahl and Berger, 1999; Del Prato et al., 2002; Rendell 2004). Glibenclamide is associated with a greater risk of severe hypoglycaemia than gliclazide (Tessier et al., 1994) because active metabolites prolong its hypoglycaemic effects for 24 hours (Jonsson et al., 2001; Rendell 2004). Glibenclamide also attentuates the glucagon response to hypoglycaemia in non-diabetic volunteers (ter Braak et al., 2002) and in people with type 2 diabetes (Landstedt-Hallin et al., 1999; Banarer et al., 2002). Several drugs may potentiate the hypoglycaemic effects of sulphonylureas (Table 11.4). Risk factors for severe hypoglycaemia associated with sulphonylurea therapy include age, a past history of cardiovascular disease or stroke, renal failure, reduced food intake, alcohol ingestion and interactions with other drugs (Hartling et al., 1987; Seltzer et al., 1989; Asplund et al., 1991; Campbell et al., 1994; Shorr et al., 1997; Ben-Ami et al., 1999; Burge et al., 1999; Harrigan, et al., 2001).

Table 11.2a Prevalence of severe hypoglycaemia (hypos) in type 2 diabetes (adapted from Zammitt and Frier, 2005).

UKPDS 33,

Hepburn,

Abraira,

Miller,

Henderson,

Leese,

Donnelly,

Akram,

Study

Jennings, 1989

1998

1993*

1995

2001

2003

2003

2005

2006

Design

Retrospective,

Prospective,

Retrospective

Prospective,

Retrospective

Retrospective

Population-

Prospective

Retrospective

structured interview

multicentre RCT

questionnaire

multicentre RCT

interview

questionnaire

based dataset

questionnaire

analysis

Subjects

T2DM, OHA only

T2DM, OHA and

Insulin-treated

All T2DM

Type 2

Insulin-treated

69 T1DM;

Insulin-treated

Insulin-treated

insulin

T1DM and

T2DM

T2DM SU

T1DM &

T2DM

T2DM

(22), insulin

T2DM

(66)

Number

219 (203: SU, 16:

3935

104T1DM, 104

153

1055

215

160

94T1DM

401

metformin)

T2DM

173 T2DM

Duration

6 months

10 years

1 year

18-35 months

7 months

1 year

I year

One month

1 year

PREVALENCE

OHA: all

Metformin 0%

NA

NA

16%

NA

NA

NA

NA

hypos

SUs:

Glibenclamide 31.3%

Glibenclamide 17.0%

20.2%

Chlorpropamide 13.6%Chlorpropramide

overall

Gliclazide 13.1%

11.0%

OHA: SH

Glibenclamide

NA

NA

0%

NA

0.8%

NA

NA

0.6%

Chlorpropramide

0.4%

Insulin: all

NA

36.5%

82.7%

56% conventional

30%

64%

NA

45%

NA

hypos

93% intensive

Insulin: SH

NA

2.3%

10%

NA

0%

15%

7.3%

3%

16.5%

Abbreviations: T1DM =type 1 diabetes; T2DM =type 2 diabetes; NA = not applicable; SH = severe hypoglycaemia; SU= sulphonylurea; LOC = loss of consciousness; RCT = randomised clinical trial; OH A = oral hypoglycaemic agent; Hypos = hypoglycaemia; * = only figures for type 2 DM given

Table 11.2b Incidence of severe hypoglycaemia (hypos) in type 2 diabetes. Figures are expressed as events per patient per year (adapted from Zammitt and Frier, 2005)

Study VA-CSDM 1995 Henderson 2003 Leese 2003 Donnelly 2005 Akram, 2006

INCIDENCE

Study VA-CSDM 1995 Henderson 2003 Leese 2003 Donnelly 2005 Akram, 2006

INCIDENCE

OHA: all hypos

NA

NA

NA

NA

NA

OHA: SH

NA

NA

SU: G.GG9

NA

NA

Metformin: G.GGG5

Insulin: all hypos

1.5 (standard)

NA

NA

16.37

NA

16.5 (intensive)

Insulin: SH

G.G2

0.28

0.12 (T1 and T2DM)

G.35

0.44

Abbreviations: T1DM = type 1 diabetes; T2DM = type 2 diabetes; NA = not applicable; SH = severe hypoglycaemia; SU = sulphonylurea; LOC = loss of consciousness; RCT = randomised clinical trial; OHA = oral hypoglycaemic agent; Hypos = hypoglycaemia

Abbreviations: T1DM = type 1 diabetes; T2DM = type 2 diabetes; NA = not applicable; SH = severe hypoglycaemia; SU = sulphonylurea; LOC = loss of consciousness; RCT = randomised clinical trial; OHA = oral hypoglycaemic agent; Hypos = hypoglycaemia

Table 11.3 Pharmacokinetics of the sulphonylureas (data sourced from Kobayashi et al. (1984); Campbell et al. (1994); DeFronzo (1999); Harrower (2000); Harrigan et al. (2001); Schernthaner (2003))

Generation

Name

tmax (hours)

t1/2 (hours)

Duration of action (hours)

Renal excretion of active metabolite

First

Chlorpropamide

2-7

36

60

Yes

Tolbutamide

3-4

3-28

6-12

Insignificant

Second

Glipizide

1-3

7

12-24

No

Glipizide GITS

6-12

7

24

No

(Glucotrol XL)

Glibenclamide

2-6

10

12-24

Yes

Gliclazide

2-3

12-14

Minimal (5%)

Gliclazide MR

4-6

24

Minimal

Third

Glimepiride

2-3

5-9

16-24

Yes (?)

tmax = time to peak; t^ = half-life tmax = time to peak; t^ = half-life

Table 11.4 Drugs that potentiate the effects of sulphonylurea drugs used to treat type 2 diabetes (data sourced from Campbell et al. (1994); Harrigan et al. (2001))

Mechanism

Decreased hepatic metabolism

Decreased renal excretion

Displacement of SU from albumin binding sites

Increases plasma concentration

Inhibition of gluconeogenesis

Drugs

Chloramphenicol H2 blockers Ciprofloxacin Warfarin Sulphonamides Monoamine-oxidase inhibitors

Allopurinol Probenecid Aspirin

Fibrates

Trimethoprim

Aspirin

Warfarin

Sulphonamides

Fluconazole, Miconazole

Alcohol

Some of the newer sulphonylureas such as glimepiride are associated with a lower risk of hypoglycaemia. In a population-based study in Germany, the incidence of hypoglycaemia was examined in people with type 2 diabetes who had attended a hospital emergency department over a four-year period (Holstein et al., 2001). A total of 45 episodes were recorded in individuals who had been taking a sulphonylurea, of which 38 were associated with gliben-clamide. Glimepiride was implicated in only six episodes, despite more frequent prescribing of glimepiride. Glimepiride was compared with a modified release form of gliclazide in a multicentre, European trial (Schernthaner et al., 2004a). Glycated haemoglobin values improved by around 1.0% in both groups but modified release gliclazide was implicated in fewer cases of hypoglycaemia (3.7%) compared to glimepiride (8.9%). Severe hypogly-caemia did not occur in either group.

The oral glucose prandial regulators, repaglinide and nateglinide, induce less frequent hypoglycaemia than the sulphonylureas because of their rapid onset of action and their selective stimulation of insulin secretion in the presence of carbohydrate but not in the fasting state (Strange et al., 1999; Nattrass and Lauritzen, 2000; Culy and Jarvis, 2001). In a randomised multi-centre trial comparing repaglinide with nateglinide, slightly lower HbA1c values were achieved after 16 weeks on repaglinide at the expense of mild hypoglycaemic episodes in 7% of patients compared to no episodes in the nateglinide group (Rosenstock et al., 2004).

Studies Comparing Hypoglycaemia Secondary to Insulin or Oral Antidiabetic Agents

It is often difficult to compare the frequency of hypoglycaemia ascribed to insulin and oral antidiabetic agents because in many studies the participants were receiving treatment with both modalities. The United Kingdom Prospective Diabetes Study Group (1998a) reported the prevalence of hypoglycaemia in people with type 2 diabetes using different therapies. A higher frequency of hypoglycaemia was observed in association with intensive, compared to conventional, treatment whether using sulphonylureas or insulin. The prevalence of hypoglycaemia across the different treatment groups is summarised in Table 11.5. Of the oral agents used in this study, metformin had the lowest recorded rate of hypoglycaemia while glibenclamide had the highest. With intensive treatment, hypoglycaemia occurred most frequently in the insulin-treated patients, and the prevalence of hypoglycaemia was lower in the first decade of the study than in later years. The prevalence of hypoglycaemia was lower when the groups were analysed on an 'intention to treat' basis because several patients in the conventional-treatment groups required an increasing number of different therapies with escalating doses as their glycaemic control deteriorated. Although the patients were questioned about the occurrence of hypoglycaemia at every four-monthly review, only the most severe episode was recorded each time. This study cannot therefore provide an accurate estimate of the incidence of hypoglycaemia in type 2 diabetes and the overall prevalence of severe hypoglycaemia of 2% is deceptive as it does not indicate the rise in prevalence with increasing duration of type 2 diabetes (United Kingdom Prospective Diabetes Study Group, 1998a).

A systematic review of randomised controlled trials comparing insulin monotherapy with combination therapy with insulin and oral antidiabetic agents confirmed the relative safety of the latter treatment regimen and 13 out of 14 studies did not show any significant difference

Table 11.5 Hypoglycaemia episodes per year by intention to treat analysis and actual therapy for intensive and conventional treatment in the UKPDS: non-overweight patients (data sourced from UK Prospective Diabetes Study (UKPDS) Group (1998a; 1998b))

Mean proportion of patients per year with hypoglycaemia (%)

Conventional Chlorpropamide Glibenclamide Insulin Metformin

Table 11.5 Hypoglycaemia episodes per year by intention to treat analysis and actual therapy for intensive and conventional treatment in the UKPDS: non-overweight patients (data sourced from UK Prospective Diabetes Study (UKPDS) Group (1998a; 1998b))

Mean proportion of patients per year with hypoglycaemia (%)

Conventional Chlorpropamide Glibenclamide Insulin Metformin

> 1 episode

Normal BMI

1.2

11.0

17.7

36.5

MH in first

Overweight

0.9

12.1

17.5

34.0

4.2

10 years

participants

> 1 episode

Normal BMI

0.1

0.4

0.6

2.3

-

SH in first

Overweight

0.7

0.6

2.5

0.3

0

10 years

participants

> 1 episode

Normal BMI

10

16

21

28

-

MH in first

Overweight

7.9

15.2

20.5

25.5

8.3

10 years

participants

(intention

to treat)

> 1 episode

Normal BMI

0.7

1.0

1.4

1.8

-

SH in first

Overweight

0.7

1.2

1.0

2.0

0.6

10 years

participants

(intention

to treat)

MH = mild hypoglycaemia; SH = severe

hypoglycaemia; BMI

= body mass index

in hypoglycaemia rates between the two therapeutic strategies (Goudswaard et al., 2004). A randomised multicentre study compared the use of twice daily human Mixtard 30 (Novo Nordisk) with once daily insulin glargine in combination with metformin and glimepiride and observed that the combination regimen of insulin and oral agents achieved better glycaemic control with fewer confirmed episodes of hypoglycaemia (4.07 versus 9.97 episodes perpatient-year, p < 0.0001) (Janka et al., 2005). In an observational study of 41 people with type 2 diabetes treated with oral antidiabetic drugs and bedtime isophane (NPH) insulin, 49% had experienced mild hypoglycaemia since commencing insulin with an incidence of four episodes per patient per year and no episodes of severe hypoglycaemia (Allen et al., 2004).

Several studies have compared the frequency of hypoglycaemia secondary to oral antidiabetic agents compared to that associated with insulin treatment. A retrospective population-based study in Tennessee examined the frequency of 'serious' hypoglycaemia over a four-year period in 19932 Medicaid patients with type 2 diabetes aged 65 or older (Shorr et al., 1997). 'Serious' hypoglycaemia was defined as an episode resulting in a fatal outcome or requiring hospital treatment. The frequency of severe hypoglycaemia was therefore underestimated by excluding events other than those that culminated in hospitalisation or death of the patient. The reported incidence of 'serious' hypoglycaemia with sulphonylureas was 1.23 episodes per 100 person-years and 2.76 episodes per 100 person-years with insulin treatment.

In Atlanta, a six-month, retrospective survey was conducted of 1055 patients with type 2 diabetes, treated with oral antidiabetic drugs or insulin and who were predominantly female

African-Americans (Miller et al., 2001). A quarter of the group had experienced at least one episode of hypoglycaemia during the study period. The prevalence of hypoglycaemia increased with more intensive treatment, the highest rate being associated with insulin. Severe hypoglycaemia occurred in 0.5% of patients, all of whom had been treated with insulin. However, this study is limited by its reliance on patient recall of hypoglycaemia and the ethnicity and gender of the study group, which makes it impossible to extrapolate the outcomes to European populations.

A 12-month prospective multicentre British study tested the hypothesis that the risk of hypoglycaemia in individuals with insulin-treated type 2 diabetes of short duration is comparable to those taking sulphonylureas and is lower than in patients with newly diagnosed type 1 diabetes (UK Hypoglycaemia Study Group, 2007). Monthly questionnaires were used to record self-reported hypoglycaemia and a 72-hour period of continuous blood glucose monitoring was used at the beginning and end of the study period to detect asymptomatic hypoglycaemia. No difference was observed in the prevalences of severe hypoglycaemia in those with type 2 diabetes treated with sulphonylureas, and in individuals with type 2 diabetes treated with insulin for less than two years (7% in both groups). Symptomatic hypoglycaemia in patients with type 2 diabetes recently commenced on insulin therapy (< 2 years) was considerably lower than in those with type 1 diabetes of less than five years duration (median rate one versus 22 episodes per subject per year, p< 0.001) (Figure 11.3), but was higher in patients with type 2 diabetes > 5 years, showing a significantly higher prevalence in those with a longer duration of insulin therapy.

type 2 treated with sulphonylureas type 2 < 2 yrs insulin type 2 > 5 yrs insulin type 1 < 5 yrs insulin type 1 > 15 yrs insulin

Figure 11.3 Proportion of patients with type 1 diabetes for < 5 years and > 15 years, and type 2 diabetes in different treatment groups (sulphonylureas, insulin < 2 years, insulin > 5 years), who experienced one or more episodes of self-reported severe hypoglycaemia during 9-12 months of follow-up in the UK Hypoglycaemia Group Study. Reproduced from UK Hypoglycaemia Study Group (2007), Diabetologia, with kind permission of Springer Science and Business Media type 2 treated with sulphonylureas type 2 < 2 yrs insulin type 2 > 5 yrs insulin type 1 < 5 yrs insulin type 1 > 15 yrs insulin

Figure 11.3 Proportion of patients with type 1 diabetes for < 5 years and > 15 years, and type 2 diabetes in different treatment groups (sulphonylureas, insulin < 2 years, insulin > 5 years), who experienced one or more episodes of self-reported severe hypoglycaemia during 9-12 months of follow-up in the UK Hypoglycaemia Group Study. Reproduced from UK Hypoglycaemia Study Group (2007), Diabetologia, with kind permission of Springer Science and Business Media

Hypoglycaemia and Insulin

In the USA, the Veterans Affairs Cooperative Study in type 2 Diabetes (VA CSDM) examined glycaemic control and complications and compared a simple ('standard') insulin regimen (administered once daily) with an intensive ('stepped') regimen (Abraira et al., 1995). The participants in this trial had diabetes of relatively short duration (mean ± SD 7.8 ± 4 years), were all insulin-treated males, and were followed up for only 18-35 months. The overall incidence of severe hypoglycaemia was 0.02 episodes per patient per year with no significant difference between the standard and stepped treatment groups. The frequency of mild hypoglycaemia was significantly higher in the intensively treated group (stepped versus standard: 16.5 versus 1.5 episodes per patient per year). However, blood glucose was monitored less frequently in the standard treatment group, which may have caused under-reporting of asymptomatic hypoglycaemia.

The participants in the VA CSDM study had a relatively short duration of diabetes. A retrospective survey in Edinburgh of 215 people with insulin-treated type 2 diabetes observed that the frequency of hypoglycaemia increased with the duration of insulin therapy and the duration of type 2 diabetes (Henderson et al., 2003) (Figure 11.4) and was inversely proportional to HbA1c concentration. The annual prevalence of severe hypoglycaemia was 15% with an overall incidence of 0.28 episodes per patient per year.

The relationship between duration of insulin treatment and prevalence of severe hypoglycaemia has been replicated in a more recent 12-month prospective multicentre British survey (UK Hypoglycaemia Study Group 2007) (Figure 11.3). A similar incidence was reported in a retrospective study in Denmark of 401 patients with insulin-treated type 2 diabetes, 66 (16.5%) of whom had experienced at least one episode of severe hypogly-caemia in the preceding year giving an overall incidence of 0.44 episodes per patient

40

35

30

)

25

e

c >

n le

20

al

>

re

15

CL

10

5

Duration of insulin therapy (years)

Figure 11.4 Prevalence of severe hypoglycaemia in relation to duration of insulin therapy in patients with type 2 diabetes. Reproduced from Henderson et al. (2003) by permission of Blackwell Publishing per year, but no relationship to HbA1c was observed (Akram et al., 2006). A retrospective study of 600 unselected insulin-treated diabetic patients performed a decade earlier in Edinburgh had observed an incidence of severe hypoglycaemia of 0.73 episodes per patient per year in the 56 people with type 2 diabetes compared with 1.7 episodes per patient per year in the 544 with type 1 diabetes (MacLeod et al., 1993). An earlier survey in the same centre compared the frequency of severe hypoglycaemia in 86 people with insulin-treated type 2 diabetes with 86 people with type 1 diabetes, matched for duration of insulin treatment and insulin dose (Hepburn et al., 1993). The frequency of severe hypo-glycaemia was similar in the two groups and a positive correlation was found between the frequency of severe hypoglycaemia and duration of treatment with insulin (r = 0.39, p< 0.001).

The introduction of insulin analogues has been claimed to lower the risk of hypoglycaemia and several studies have compared the risk of hypoglycaemia in people with type 2 diabetes treated with either conventional insulin or insulin analogues. The risk of hypoglycaemia has been reported to be lower with long-acting insulin glargine in some studies (Yki-Järvinen et al., 2000; Rosenstock et al., 2001; Rosenstock et al., 2003; Riddle et al., 2003) and with insulin detemir (Hermansen et al., 2006) compared with isophane (NPH) insulin. In one study (Riddle et al., 2003), symptomatic hypoglycaemia was significantly lower using combination treatment with metformin and glargine compared to metformin and isophane (NPH) insulin, but no difference in biochemically confirmed hypoglycaemia was observed between the two groups. Insulin glargine was also associated with a lower frequency of hypoglycaemia than premixed insulins (Janka et al., 2005; Raskin et al., 2005). Rapid-acting insulin analogues, such as lispro and glulisine, also appeared to limit the frequency of hypoglycaemia in people with type 2 diabetes when compared to short-acting soluble (regular) insulins (Anderson et al., 1997; Bastyr et al., 2000; McAulay and Frier, 2003; Dailey et al., 2004). However, several studies have not observed a significantly lower incidence of hypoglycaemia when using insulin analogues in comparison with conventional insulin (Ross et al., 2001; Raslova et al., 2004; Schernthaner et al., 2004b; Haak et al., 2005).

Continuous subcutaneous insulin infusion (CSII) is associated with a lower risk of severe hypoglycaemia in type 1 diabetes (Weissberg-Benchell et al., 2003). This method of insulin delivery is not routinely employed in people with type 2 diabetes, but a 12-month prospective randomised study of 107 adults with insulin-treated type 2 diabetes showed no significant difference in the rates of mild or severe hypoglycaemia between CSII and multiple insulin injections (Herman et al., 2005).

Hypoglycaemia and Newer Treatment Modalities for type 2 diabetes

Inhaled insulin

An alternative route of delivery of insulin is by inhalation into the lungs. Inhaled insulin has been compared with subcutaneous insulin in several studies and the frequency of hypoglycaemia is equivalent to that of subcutaneous administration of insulin (Hermansen et al., 2004; Hollander et al., 2004).

Incretin mimetics

Glucagon-like peptide 1 (GLP-1) is an incretin hormone that promotes glucose-dependent insulin secretion and inhibition of glucagon production. GLP-1 is rapidly degraded in vivo by the ubiquitous enzyme Dipeptidyl Peptidase IV (DPP-IV) and no stable oral preparation is available. GLP-1 mimetics are associated with improvements in glycaemic control (Zander et al., 2002; Fineman et al., 2003; Koltermann et al., 2003; Degn et al., 2004a) without appearing to cause hypoglycaemia in people with type 2 diabetes (Knop et al., 2003; Madsbad et al., 2004). Exenatide, a synthetic GLP-1 receptor agonist, stimulates insulin release only in the presence of glucose (Degn et al., 2004b) and, although it suppresses glucagon production, the effect on glucagon suppression is abolished during hypoglycaemia and the counterregulatory response to insulin-induced hypoglycaemia is preserved (Nauck et al., 2002, Degn et al., 2004b). Although incretin mimetics may cause reactive hypoglycaemia in non-diabetic individuals (Meier and Nauck, 2005), they do not appear to cause hypoglycaemia in people with type 2 diabetes (Knop et al., 2003, Vilsb0ll et al., 2001). Few studies to date have quantified the risk of hypoglycaemia associated with DPP-IV inhibitors. In a one-year placebo-controlled trial in which the DPP-IV inhibitor, vildagliptin was added to metformin, only four confirmed episodes of mild (self-treated) hypoglycaemia were recorded in the 51 patients in the treatment arm (with no episodes in the placebo arm) and severe hypoglycaemia did not occur (Ahren et al., 2004).

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