Frequency and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes: a literature survey

Journal of Diabetes and Its Complications 20 (2006) 402 – 408

Frequency and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes: a literature survey Kamran Akrama,T, Ulrik Pedersen-Bjergaarda,b, Knut Borch-Johnsena, Birger Thorsteinssonb a Steno Diabetes Center, Gentofte, DK-2820 Denmark Endocrinology Section, Division of Internal Medicine I, Hillerød Hospital, Hillerød, Denmark

b

Received 6 April 2005; received in revised form 19 July 2005; accepted 8 August 2005

Abstract Intensive treatment regimens including early initiation of insulin treatment are important to prevent late complications in type 2 diabetes. The assumed risk of severe hypoglycemia (SH) is a major barrier to initiation of insulin treatment. To assess the relevance of this risk we evaluated the frequency of SH as reported in the literature. Using Medline and Embase search we identified 11 studies (5 retrospective and 6 prospective) including at least 50 patients with insulin-treated type 2 diabetes followed for at least 6 months in which frequency of SH was reported. The incidence of SH in the retrospective studies varied from 15 to 73 episodes per 100 patient-year with a proportion of the patients having one or more episodes between 1.4 to 15%. In the prospective studies, both incidence rate and proportion of the patients having one or more episodes of SH were lower than in the retrospective studies. Only few studies looked into the impact of risk factors on the rate of SH. Impaired hypoglycemia awareness, high age, long duration of diabetes and insulin therapy increased the risk, while no association was found with HbA1c and insulin dose. The present knowledge of SH in insulin-treated type 2 diabetes is characterized by the paucity of data and the heterogeneity of the few studies available. Large and long-lasting studies with SH as primary endpoint are warranted in order to further clarify the occurrence of SH and influence of the risk factors in unselected patients with insulin-treated type 2 diabetes. D 2006 Elsevier Inc. All rights reserved. Keywords: Hypoglycemia; Type 2 diabetes; Insulin therapy; Intensive therapy; Hypoglycemia unawareness

1. Introduction Strict metabolic control may prevent or delay the onset of late complications in type 2 diabetes (Gaede et al., 2003; Ohkubo et al., 1995; UK Prospective Study Group, 1998). Therefore, the generally accepted treatment goal is near normoglycemia (De Backer et al., 2003). To achieve this target, an increasing number of people with type 2 diabetes will need insulin therapy. One major barrier towards implementation of intensive insulin therapy is the risk of hypoglycemia, which is a common and potentially hazardous side effect of treatment with insulin. Beyond the unpleasant milder symptoms managed by the patients themselves, hypoglycemia may eventually progress into T Corresponding author. Tel.: +45 44430225; Mobile: +45 30750225. E-mail address: [email protected] (K. Akram). 1056-8727/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2005.08.005

severe hypoglycemia with need of assistance from others for treatment. Such episodes may result in serious consequences like coma, seizures, injury to patients or relatives and in rare instances even to death. In type 1 diabetes, fear of hypoglycemia has been shown to impact the quality of life of both patients (Pramming, Thorsteinsson, Bendtson, & Binder, 1991) and their relatives (Jorgensen, PedersenBjergaard, Rasmussen, & Borch-Johnsen, 2003), but for insulin-treated type 2 diabetic patients similar data are not available. In type 2 diabetes - comprising more than 85% of the entire diabetic population in Europe (World Health Organization, 1994) - the frequency of hypoglycemia has not been studied with same intensity as in type 1 diabetes and there is considerable inconsistency in published rates (Frier, 2002). Furthermore, the impact of risk factors for severe hypoglycemia as apparent in type 1 diabetes is less known in type 2 diabetes.

K. Akram et al. / Journal of Diabetes and Its Complications 20 (2006) 402–408

The aim of this paper is to review the literature on hypoglycemia in insulin-treated type 2 diabetes in order to assess the rate of severe hypoglycemia and to evaluate the impact of potential risk factors.

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because of the generally believed rarity in occurrence of severe hypoglycemia in type 2 diabetes an observational time of at least 6 months was regarded most appropriate.

3. Outcome of studies on severe hypoglycemia in insulin-treated type 2 diabetes

2. Materials and methods The search strategy involved conducting a literature search in the bibliographic databases Medline/PubMed and Embase from 1977 to 2005 for all pertinent published studies on severe hypoglycemic episodes in insulin-treated type 2 diabetes, defined as those episodes in which assistance from other people is needed to restore normal blood glucose concentrations. Search terms included bType 2 diabetesQ, bNIDDMQ, bDiabetes mellitus non-insulin-dependentQ, bHypoglycaemiaQ or bHypoglycemiaQ, bInsulin therapyQ, bDrug therapy Q, bIntensive therapyQ, bCounterregulationQ, bGlucose counterregulationQ, bAwarenessQ, and ‘‘UnawarenessQ. The search was restricted to English language and human adult population above 19 years of age. All papers concerning hypoglycemia in insulin-treated type 2 diabetes were regarded eligible for evaluation in this review, but only studies lasting at least six months and with at least 50 participants were included in the final analysis of the rate and risk factors of severe hypoglycemia. This limitation was set to bring forward more comprehensive work and

The literature search identified 464 papers fulfilling the initial eligibility criteria. One reviewer screened the titles in order to estimate their relevance, resulting in the exclusion of 345 papers with titles clearly outside the aim of the study. For the remaining 119 papers, reviewers read the abstracts and found 72 to be irrelevant for the study, leaving 47 papers for full text reading. Only 11 of these papers met the inclusion criteria: 5 retrospective (Gu¨rlek, Erbas, & Gedik, 1999; Henderson, Allen, Deary, & Frier, 2003; Hepburn, MacLeod, Pell, Scougal, & Frier, 1993; MacLeod, Hepburn, & Frier, 1993; Miller et al., 2001) and 6 prospective studies (Abraira et al., 1995; Murata et al., 2005; Ohkubo et al., 1995; Saudek et al., 1996; UK Prospective Study Group, 1998; YkiJarvinen et al., 1999). 3.1. Frequency of severe hypoglycemia The studies reporting retrospectively recorded rates of severe hypoglycemia (Gu¨rlek et al., 1999; Henderson

Table 1 Retrospective studies Reference

Hepburn et al., (1993)

Macleod et al., (1993)

Gu¨rlek et al., (1999)

Miller et al., (2001)

Henderson et al., (2003)

Study characteristics Year of publication Origin of study Design

1992 Scotland Questionnaire

1993 Scotland Questionnaire

1999 Turkey Medical records

2003 Scotland Questionnaire

Sequentially selected 1

Randomly selected 1

Unselected

2001 USA Standardized Interview Selected

104 63F9 (39 – 81) 12 (3 –26) 4 (1–22)

56 NS NS NS

1: 26% 2: 74% 0.7F0.3 (0.2–1.6) 27F5 (18 – 49) 10.5F2.2 (4.5 – 8.0; HbA1) NS

NS

NS

73

15

NS

NS

Study Population Duration of follow-up (years) Characteristics of subjects No. of subjects Age (years) Duration of diabetes (years) Duration of insulin therapy (years) Number of insulin injections Insulin dose (IU/kg) BMI (kg/m2) Glycosylated haemoglobin (%) (normal range; method) C-peptide (nmol/l) Characteristics of SH episodes Incidence of SH (per 100 patient-years) Proportion that encountered one or more event of SH (% patients per year)

10.5

NS NS NS NS

7 months

Randomly selected 1

114 59F10 (32–77) 13F8 (1– 42) NS

633 NS NS NS

215 68 (27– 87) 13 (1– 40) 4 (1–24)

1: 4% 2: 96% NS 30F5 (24 – 33) NS NS

NS

2: 94% 3+: 6% NS NS 8.6F1.5 (5.0 – 6.5; HbA1c) NS

3.3

NS NS 8.1F0.1 (SEM) (3.5 – 6.0; HbA1c) NS NS 1.4

Abbreviations. SH: severe hypoglycemia; NS: not specified; Data are meanFSD (or SEM as indicated), and median and range.

28 15

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K. Akram et al. / Journal of Diabetes and Its Complications 20 (2006) 402–408

et al., 2003; Hepburn et al., 1993; MacLeod et al., 1993; Miller et al., 2001) included a total of 1,122 patients (Table 1) covering roughly 1,100 patient-years. In the studies reporting retrospectively recorded rates of severe hypoglycemia (Gu¨rlek et al., 1999; Henderson et al., 2003; Hepburn et al., 1993; MacLeod et al., 1993; Miller et al., 2001), three mentioned incidence rates (Gu¨rlek et al., 1999; Henderson et al., 2003; MacLeod et al., 1993), while two reported the proportion of patients that encountered one or more events of severe hypoglycemia (% patients per year) (Hepburn et al., 1993; Miller et al., 2001). The studies reporting prospectively recorded rates of severe hypoglycemia (Abraira et al., 1995; Murata et al., 2005; Ohkubo et al., 1995; Saudek et al., 1996; UK Prospective Study Group, 1998; Yki-Jarvinen et al., 1999), comprising a total of 1,711 patients, are shown in Table 2.

The estimated time of observation is approximately 10,500 patient-years, including the large contribution from one study (UKPDS) of around 9,000 patients-years (UK Prospective Study Group, 1998). Most of the prospective studies were clinical trials (Abraira et al., 1995; Ohkubo et al., 1995; Saudek et al., 1996; UK Prospective Study Group, 1998; Yki-Jarvinen et al., 1999), where hypoglycemia was not the primary endpoint but was observed along with other endpoints. Both incidence rate and proportion of the patients that encountered one or more events of severe hypoglycemia (% patients per year) are lower than rates observed in retrospective studies except in one study (Murata et al., 2005). Patients in the prospective studies (Abraira et al., 1995; Ohkubo et al., 1995; Saudek et al., 1996; UK Prospective Study Group, 1998) had a shorter duration of diabetes

Table 2 Prospective studies Reference Study characteristics Year of publication Origin of study Design Study Population Duration of study (years) Characteristics of subjects No. of subjects Age (years) Duration of diabetes (years) Duration of insulin therapy (years) Number of insulin injections Treatment with OHA included Insulin dose (IU/kg) BMI (kg/m2) Glycated haemoglobin (%) (normal range; method) C-peptide (nmol/l) Characteristics of SH episodes Incidence of SH (per 100 patient-years) Proportion that encountered one or more event of SH (% patients per year)

Ohkubo et al (1995)

Abraria et al (1995)

Saudek et al (1996)

UK Prospective Study Group (1998)

Yki-Jarvinen et al (1999)

Murata et al (2005)

1995 Japan RCT, monocenter Selected 6

1995 USA RCT, multicenter Selected 2 1/4

1996 USA RCT, multicenter Selected 1

1998 UK RCT, multicenter Selected, new DM 10 (9–13)

1999 Finland RCT, multicenter Selected 1

2005 USA Observational Selected 1

102 49F12 8F5

153 60F6 8F4

113 56F9 9F5

911 54F8 10 (9 –13)

88 58F2 NS

344 65F9 14F9

NS

NS

NS

10 (9 –13)

1-2: 49% (CT)

NS (CT)

2.3FNS

NS

2:24

NS

N3: 51% (MT) No

1– 4 (IT) Yes

No

No

1:64 Yes

Yes

0.4F0.2

CT:~ NS IT:~NS 31F5 CT: ~ 9.5 IT: ~ 7 (NS; HbA1c) NS

0.7FNS

0.4FNS

24F3a

64F43

31F4 7.5F0.8

27F5 7.1FNS

29F1 7.8FNS

31F6 8.0F1.7

(5.1F0.5; HbA1c) 0.7F0.5

(4.5– 6.2; HbA1c) NA

(4.0 – 6.0 HbA1c) 1.1F0.1

(NS;HbA1c) NS

0

CT:~1.0

(MDI:~18)c

NS

0

IT:~3.0 CT:~ NS

(IIP:~ 0.35) NS

20F2 CT: 9.4F1.5 IT: 7.1F1.1 (4.8 – 6.4; HbA1c) 22F24 Ag/24hrb

2.3

1

8F7

0

20

0

NS

IT:~ NS Abbreviations. SH: severe hypoglycemia; DM: diabetes mellitus; RCT: randomised controlled trial; CT: conventional therapy; IT: intensive therapy; MDI: Multiple daily insulin therapy, IIP: Implantable insulin pump, NS: not specified; OHA: Oral hypoglycaemic agents, Data are meanFSD (or SEM as indicated), and median and range. a IU/24hr. b Urinary C-peptide. c Definite and suspected SH added.

K. Akram et al. / Journal of Diabetes and Its Complications 20 (2006) 402–408

(mean duration approximately 10 years) compared to the patients included in the retrospective studies (mean duration approximately 13 years) (Gu¨rlek et al., 1999; Henderson et al., 2003; Hepburn et al., 1993). Exposure to insulin therapy, if stated, was approximately 4 years in the retrospective studies (Hepburn et al., 1993; Henderson et al., 2003), meaning that insulin therapy was initiated on average after 9 years with diagnosed type 2 diabetes. In contrast, insulin therapy was initiated after a 3-month runin period following the diagnosis of type 2 diabetes in the UKPDS (UK Prospective Study Group, 1998).

4. Risk factors of severe hypoglycemia Six of the studies (Henderson et al., 2003; Hepburn et al., 1993; Miller et al., 2001; Ohkubo et al., 1995; Saudek et al., 1996; UK Prospective Study Group, 1998) reported possible risk factors for severe hypoglycemia, including two retrospective studies giving more detailed information (Henderson et al., 2003; Miller et al., 2001): age (Henderson et al., 2003; Miller et al., 2001), sex (Miller et al., 2001), (Miller et al., 2001) BMI, duration of diabetes (Henderson et al., 2003; Miller et al., 2001), duration of insulin therapy (Henderson et al., 2003; Hepburn et al., 1993), insulin dose (Henderson et al., 2003), intensive insulin therapy (Ohkubo et al., 1995; Saudek et al., 1996; UK Prospective Study Group, 1998), HbA1c (Henderson et al., 2003; Miller et al., 2001), hypoglycemia unawareness (Henderson et al., 2003; Hepburn et al., 1993), and previous history of severe hypoglycemia (Miller et al., 2001). The study by Henderson and co-workers (Henderson et al., 2003) that illuminated in details relevant risk factors identified increased rates of severe hypoglycemia with increasing age, long diabetes duration and duration of insulin therapy, and impaired hypoglycemia awareness, while they did not find any association to high insulin dose or HbA1c. Miller and co-workers (Miller et al., 2001) did not find any relation between occurrence of severe hypoglycemia and age, sex, BMI, diabetes duration, antecedent hypoglycemia, follow-up plasma glucose level, follow-up HbA1c, type of diabetes therapy, or increased diabetic medication. Shorter observation period and the small number of patients with severe hypoglycemia episodes (5 patients experienced severe hypoglycemia in 7 months) in the latter study (Miller et al., 2001) makes it difficult to compare its results with the former study (32 encountered 60 episodes of severe hypoglycemia in one year) (Henderson et al., 2003; Miller et al., 2001). In the study by Hepburn et al. (Hepburn et al., 1993), similar rates of severe hypoglycemia were observed in type 1 and type 2 diabetes with normal hypoglycemia awareness (4%). In this study participants were divided into three categories (normal, partial and absent awareness) according to their state of awareness of the onset of hypoglycemia in the preceding year. The effect of impairment in hypoglyce-

405

mia awareness was increased rates in both groups; in type 2 diabetes all those who experienced severe hypoglycemia in the preceding year were categorized bpartial aware.Q In the study by Henderson et al. (Henderson et al., 2003), hypoglycemia awareness was scored on 7-point scale (1=always aware, 7=never aware). The impact of impaired hypoglycemia awareness on the rate of severe hypoglycemia was a 9-fold higher risk compared to normal hypoglycemia awareness. Impairment of hypoglycemia awareness was not associated with age, diabetes and insulin duration. In the retrospective studies, no association was found between HbA1c and the rate of severe hypoglycemia (Henderson et al., 2003; Miller et al., 2001). In the prospective studies aiming to achieve near-normal glycemia (and lower HbA1c) with intensive insulin therapy (Saudek et al., 1996; UK Prospective Study Group, 1998), no data are given on an association with the level of HbA1c. No association between the frequency of antecedent hypoglycemia at baseline and severe hypoglycemia was found (Miller et al., 2001). No study has so far analyzed the possible relationship between the magnitude of residual beta-cell function and the occurrence of severe hypoglycemia in insulin-treated type 2 diabetes.

5. Discussion In the limited literature available regarding severe hypoglycemia in insulin-treated type 2 diabetes the reported incidence rates are very diverse ranging from zero to 73 episodes per 100 patient-years (Abraira et al., 1995; Gu¨rlek et al., 1999; Henderson et al., 2003; MacLeod et al., 1993; Murata et al., 2005; Ohkubo et al., 1995; Saudek et al., 1996; Yki-Jarvinen et al., 1999). This is lower than incidence rates in type 1 diabetes of 100-160 episodes per 100 patientyears (MacLeod et al., 1993; Pedersen-Bjergaard et al., 2004; Pramming et al., 1991; Ter Braak et al., 2000). Studies included in this survey defined severe hypoglycemia as an episode requiring assistance from others to restore the blood glucose level. A retrospective populationbased study of severe hypoglycemia using the more restrictive definition of severe hypoglycemia as an episode requiring emergency treatment with glucagon or intravenous glucose (episodes of hypoglycemia treated either at home or in the workplace, by family or friends, were not recorded) reported similar frequencies (approximately 12 episodes per 100 patient-years) in type 1 diabetes and type 2 diabetes treated with insulin (Leese et al., 2003). Using a similar definition for severe hypoglycemia Holstein et al. reported an incidence of severe hypoglycemia of 1.5 episodes per 100 patient-years in type 2 diabetes in a 4-year prospective study (Holstein, Plaschke, & Egberts, 2003). This suggests that more episodes of severe hypoglycemia are managed outside hospitals in type 1 than in type 2 diabetes and shows that assessing only a fraction of episodes may lead to different conclusions.

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In the retrospective studies, the lowest incidence of severe hypoglycemia was reported in the study using medical records (Gu¨rlek et al., 1999), a data source probably less accurate in reporting frequency of hypoglycemia. In contrast, the highest incidence was recorded in the study with the smallest number of patients who had required insulin therapy following secondary failure of oral hypoglycemic agents (MacLeod et al., 1993). One study reported the prevalence of hypoglycemia predominantly in a minority population (Afro-Americans) with high ratio of female participants (Miller et al., 2001). In the prospective studies (Abraira et al., 1995; Ohkubo et al., 1995; Saudek et al., 1996; UK Prospective Study Group, 1998; Yki-Jarvinen et al., 1999), rates of severe hypoglycemia are comparatively lower. These studies are, however, controlled clinical trials in selected populations that may have excluded high-risk individuals and consequently they may well underestimate the rate of severe hypoglycemia as apparent in the general population of patients with insulin-treated type 2 diabetes. Thus, in one study patients with a history of hypoglycemia unawareness were specifically excluded (Saudek et al., 1996) and, consequently, reported hypoglycemia rates may have been underestimated. Younger age, shorter disease duration, hence a shorter exposure to insulin therapy, could also be the underlying reasons for reporting lower rates in prospective studies. In the latest prospective trial (Murata et al., 2005) where participants had higher age as well as longer duration of diabetes and insulin therapy than in earlier prospective studies, a higher incidence of severe hypoglycemia was observed. Finally, severe hypoglycemia was not an absolute aim in most prospective trials and was observed along with other endpoints. The two studies without any severe hypoglycemic events were also the studies with least details about their data collection in relation to the events (Ohkubo et al., 1995; Yki-Jarvinen et al., 1999). The frequency of severe hypoglycemia observed so diversely may be attributed to differences in clinical characteristics such as age classes, duration of diabetes and insulin therapy, type of insulin regimen and intensity of treatment, and risk factor profiles. The distribution of episodes of severe hypoglycemia is very skewed in both type 1 (Pedersen-Bjergaard et al., 2004) and type 2 (Henderson et al., 2003; Murata et al., 2005) diabetes with a small proportion of patients accounting for the majority of events, and exclusion of only a few high-risk patients would reduce the incidence of severe hypoglycemia markedly (Pedersen-Bjergaard et al., 2004). Such differences in selection of subjects may well account for some of the differences between retrospective studies and prospective trials of insulin-treated type 2 diabetes. Furthermore, in the retrospective studies the diagnosis of type 2 diabetes was clinical and no information about C-peptide levels are available in these studies. Thus, the inclusion of other types of diabetes cannot be excluded. Finally, in the retrospective studies (Gu¨rlek et al., 1999; Hepburn et al., 1993; MacLeod

et al., 1993; Miller et al., 2001; Henderson et al., 2003) - and to a lesser extent in the prospective studies - the frequency of severe hypoglycemia is based upon patients’ recall of such episodes. However, in type 1 diabetes recall of severe hypoglycemia has been demonstrated to be a robust measure (Pedersen-Bjergaard, Pramming, & Thorsteinsson, 2003) and preliminary data from our group indicate that recall of severe hypoglycemia is also well-preserved in patients with insulin-treated type 2 diabetes (Akram, Pedersen-Bjergaard, Borch-Johnsen, & Thorsteinsson, 2003). The protective hormonal counter-regulatory responses to hypoglycemia that are intact at early stages of disease are diminished in long-standing type 2 diabetes with secondary beta-cell failure just as in type 1 diabetes (Bolli et al., 1983). Recently, a highly compromised hormonal counter-regulatory response during hyperinsulinaemic hypoglycemic clamp was demonstrated in the insulin-deficient end of the spectrum of type 2 diabetes (Segel, Paramore, & Cryer, 2002). Preserved beta-cell residual function is associated with adequate hormonal counter-regulation with glucagon (probably via a paracrine interaction between the beta- and alpha-cells in the islets of Langerhans) in early phase of disease while the risk of severe hypoglycemia increases with deterioration of beta-cell function - and thereby the glucagon response - in the later years, as it has been observed in type 1 diabetes (Pedersen-Bjergaard, AgerholmLarsen, Pramming, Hougaard, & Thorsteinsson, 2001). However, the association between residual beta-cell function and risk of severe hypoglycemia in type 2 diabetes remains to be assessed formally. During tight metabolic control diminished response of counter-regulatory hormones has been observed in type 1 diabetes (Amiel, Sherwin, Simonson, & Tamborlane, 1988). A similar reduced response to provoked hypoglycemia has been described in insulin-treated type 2 diabetes (Bolli, Tsalikian, Haymond, Cryer, & Gerich, 1984; Polonsky et al., 1984; KorzonBurakowska et al., 1998). Failure to recognize the impending event of hypoglycemia (hypoglycemia unawareness) is a well-known risk factor in insulin-treated diabetes (Pedersen-Bjergaard et al., 2001; Pedersen-Bjergaard et al., 2004; Pramming et al., 1991). Lack of agreement in definitions of hypoglycemia unawareness makes it difficult to find precise estimates of prevalence and compare rates in different study populations. The prevalence of impaired hypoglycemia awareness is lower in insulin-treated type 2 diabetes (7-8%) (Henderson et al., 2003; Hepburn et al., 1993) compared to type 1 diabetes (20-50%) (Pedersen-Bjergaard et al., 2004; Pramming et al., 1991), but when present its impact in terms of relative increase in risk of severe hypoglycemia is comparable to that in type 1 diabetes (Henderson et al., 2003; Pedersen-Bjergaard et al., 2004). This suggests that impaired hypoglycemia awareness may be the most important risk factor of severe hypoglycemia in insulintreated type 2 diabetes as is the case in type 1 diabetes (Pedersen-Bjergaard et al., 2004; Ter Braak et al., 2000).

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Two retrospective studies compared level of glycated hemoglobin and risk of severe hypoglycemia and found no association (Henderson et al., 2003; Miller et al., 2001). However, the studies only had a total of 37 events and thereby may have lacked the power to detect differences. The clinical consequence of this lack of relationship, if true, is important considering the fact that near-normal glucose level is the generally accepted glycemic target in the treatment of type 2 diabetes today (De Backer et al., 2003). This aspect needs to be examined in type 2 diabetes in future studies. In most studies of unselected populations with type 1 diabetes a similar lack of association between risk of severe hypoglycemia and level of glycated hemoglobin have been reported (MacLeod et al., 1993; PedersenBjergaard et al., 2001; Pedersen-Bjergaard et al., 2004; Ter Braak et al., 2000). In conclusion, severe hypoglycemia appears to be less frequent in insulin-treated type 2 diabetes compared with type 1 diabetes. The lower rate may be explained by several factors including insulin resistance, residual endogenous insulin production, intact or better preserved counterregulatory hormonal response, and lower prevalence of impaired hypoglycemia awareness compared to type 1 diabetes. However, many important questions remain unanswered, and the studies have given inconsistent answers to other questions. The paucity of data and the heterogeneity of the few studies in the area that set the limits of this literature survey and the rapidly growing use of insulin treatment in type 2 diabetes stresses the need for large and long-lasting studies with severe hypoglycemia as primary endpoint in order to further clarify the occurrence of severe hypoglycemia and the influence of related risk factors in unselected populations of insulin-treated type 2 diabetic patients.

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