Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73

Article Outline

• Abstract
• 1. Introduction
• 2. Research design and methods
  • 2.1. Patients
  • 2.2. Therapies
  • 2.3. Hypoglycemia
  • 2.4. Statistical analysis
• 3. Results
  • 3.1. Therapy and previous HbA1c
• 4. Discussion
• Acknowledgments
• References
• Copyright

Abstract 

The UK Prospective Diabetes Study (UKPDS) showed that a more intensive glucose control policy reduced risk of diabetic complications. As hypoglycemia is a barrier to achieving glycemic targets, we examined its occurrence and contributing factors in UKPDS patients randomized to and remaining for 6 years on diet, sulfonylurea, metformin (overweight subjects only), or insulin monotherapy from diagnosis of Type 2 diabetes. Self-reported hypoglycemic episodes were categorized as (1) transient, (2) temporarily incapacitated, (3) requiring third-party assistance, and (4) requiring medical attention, recording the most severe episode each quarter. Proportions of patients reporting at least one episode per year were calculated in relation to therapy, HbA_1c, and clinical characteristics. In 5063 patients aged 25–65 years, only 2.5% per year reported substantive hypoglycemia (Grades 2–4) and 0.55% major hypoglycemia (Grade 3 or 4). Hypoglycemia was more frequent in younger (4.0% <45 years vs. 2.2% ≥45 years), female (3.0% vs. 2.2% male), normal weight (3.6% body mass index <25 kg/m² vs. 1.9% ≥25 kg/m²), less hyperglycemic (5.2% HbA_1c <7% vs. 2.3% ≥7%), or islet autoantibody-positive patients (4.3% vs. 2.1% negative) (all P<.0001). More on basal insulin reported hypoglycemia (3.8% per year) than diet (0.1%), sulfonylurea (1.2%), or metformin (0.3%) therapy, but less than on basal and prandial insulin (5.3%) (all P<.0001). Low hypoglycemia rates seen during the first 6 years of intensive glucose lowering therapy in Type 2 diabetes are unlikely to have a major impact on attempts to achieve guideline glycemic targets when sulfonylurea, metformin, or insulin are used as monotherapy.

Keywords: UKPDS, Hypoglycemia, Type 2 diabetes

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1. Introduction 

Intensive blood glucose control improves clinical outcomes in diabetes (DCCT Research Group, 1993, UKPDS Group, 1998), but most treatment regimens increase weight gain and risk of hypoglycemia. Information about hypoglycemia in diabetes is largely confined to Type 1 diabetes (Cryer, 2001) and insulin requiring Type 2 diabetes, where fear of hypoglycemia is often cited as a factor-limiting attempts to intensify therapy (Cryer, 2002). Severe hypoglycemia rates (episodes requiring third-party assistance) for people with Type 1 diabetes in the Diabetes Control and Complications Trial (DCCT) (DCCT Group, 1997) were approximately threefold greater in the intensive treatment group [61.2/100 person-years (pyrs)] than the conventional treatment group (18.7/100 pyrs). Although hypoglycemia is a concern also in Type 2 diabetes (Jennings, Wilson, & Ward, 1989), occurrence is much lower with rates of one or more episodes per year reported by the UK Prospective Diabetes Study (UKPDS) of 0.4% patients on chlorpropamide, 0.6% on glibenclamide (glibenclamide), and 2.3% on insulin (UKPDS Group, 1998), confirming an earlier report on a smaller subset of patients (UKPDS Group, 1995).

We have analyzed self-reported hypoglycemia in UKPDS patients according to their allocated monotherapy over 6 years from diagnosis of Type 2 diabetes and examined factors that might be associated with higher rates of hypoglycemia.

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2. Research design and methods 

2.1. Patients 

The UKPDS recruitment process and protocol have been reported previously (UKPDS Group, 1991). The study received ethical committee approval in 23 clinical centers and conformed to the guidelines of the Declarations of Helsinki (1975 and 1983). Briefly, 5102 of 7616 patients referred entered the study between 1977 and 1991. They gave informed consent, were aged 25–65 years, and had fasting plasma glucose (FPG) levels >6.0 mmol/l on two occasions after being diagnosed diabetic. Of the 5102, 81% were self-reported White Caucasian, 10% Asian Indian, and 9% Afro-Caribbean. The 2514 excluded were because of (1) ketonuria >3.0 mmol/l, (2) serum creatinine >175μmol/l, or (3) severe previous illness that would limit life or require extensive systemic treatment.

After a 3-month dietary run-in period, patients achieving FPG levels ≥6.0 but ≤15.0 mmol/l were randomized to a conventional glucose control policy, primarily with diet alone, or to an intensive glucose control policy, primarily with sulfonylurea, metformin (overweight subjects only), or insulin therapy, and followed at quarterly clinic visits. Those with post run-in FPG levels >15.0 mmol/l or with persistent hyperglycemic symptoms were randomized only to intensive glucose control policy therapies. Patients with post run-in FPG levels <6.0 mmol/l were maintained on diet alone unless FPG levels subsequently became >6.0 mmol/l, when they were randomized to conventional or intensive glucose control as above.

Of the 5102 patients, 5063 White Caucasians, Indian Asians, or Afro-Caribbeans were included in this analysis and 39 of mixed ethnicity were excluded. Of the 5063 patients, 4191 were allocated to diet (949), sulfonylurea (1687), metformin (336), or insulin (1219) therapy, and only 3538 of whom remained on their allocated therapy over 6 years and could be included in analyses by therapy. The 872 patients with post run-in FPG <6.0 mmol/l are included in the analysis of baseline contributing factors.

2.2. Therapies 

The conventional glucose control policy aimed to achieve the best possible FPG <15 mmol/l and to avoid hyperglycemic symptoms. The intensive glucose control policy aimed to maintain FPG <6 mmol/l if at all possible using computer-assisted checking to ensure that the monotherapy doses were increased as necessary on a visit by visit basis to a maximum of glibenclamide 20 mg/day, chlorpropamide 500 mg/day, glipizide 40 mg/day, or metformin 2550 mg/day. Basal insulin (ultralente or isophane) was increased similarly with no upper dose limits, but if weight-corrected doses were >14 units/day, or premeal or bedtime home blood glucose measurements were >7 mmol/l, short-acting insulin was added aiming to maintain premeal blood glucoses between 4 and 7 mmol/l. A modified protocol was used in eight centers for 389 of the 1687 patients allocated to sulfonylurea therapy, which required basal insulin be added if the FPG became >6 mmol/l despite maximum sulfonylurea doses (Wright, Burden, Paisey, Cull, & Holman, 2002).

Plasma glucose was measured quarterly after an overnight fast from 2200 h and HbA_1c annually by high-performance liquid chromatography (Biorad Diamat, Automated Glycosylated Haemoglobin Analyser, Hemel Hempstead, UK), as reported previously (UKPDS Group, 1994).

2.3. Hypoglycemia 

Patients were asked specifically about hypoglycemic symptoms at every visit, which physicians graded on a four-point scale: (1) transitory symptoms not affecting normal activity, (2) temporarily incapacitated but patient able to control symptoms without help, (3) incapacitated and required assistance to control symptoms, and (4) required medical attention or glucagon injection. Only the most severe episode to occur during the preceding 3-month period was recorded. For Grade 2 episodes, patients were asked to confirm that remedial action had been taken and was successful in reversing symptoms. Clinical trial notes were scrutinized in relation to all Grade 3 episodes, and general practice and/or hospital admission notes were checked to confirm the severity of Grade 4 or recurrent episodes. The analyses presented here examine the occurrence of any hypoglycemia (Grades 1–4), substantive hypoglycemia (Grades 2–4), and major hypoglycemia (Grade 3 or 4).

2.4. Statistical analysis 

Analyses were performed using SAS version 8.2 (SAS Institute, Cary, SC, USA). As the highest-grade hypoglycemic episode, rather than the number of individual occurrences, was recorded each quarter, the annual percentage of patients with at least one episode was modeled using a binomial distribution with each quarter taken as a “binomial trial.” The number of patients reporting episodes of each grade in more than one quarter per year was determined also. Main analyses are limited to substantive hypoglycemia (Grades 2–4), as recall and diagnosis are more certain than for Grade 1 (Pramming, Thorsteinsson, Bendtson, & Binder, 1991). Proportions of patients reporting hypoglycemic episodes were examined in relation to their most recent HbA_1c values, but because these measurements were undertaken annually, results used could be up to 12 months before any particular episode. HbA_1c was included in statistical models either as a continuous variable or as quintiles of the distribution. Baseline variables used were those measured following the dietary run-in period. For patients allocated to insulin, separate analyses were undertaken for those remaining on basal therapy alone and those requiring additional soluble insulin. Data are presented as mean (S.D.), median (IQR), or geometric mean (1 S.D. interval).

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3. Results 

Baseline characteristics, post-dietary run-in, for 5063 patients are listed in Table 1. The overall proportion of patients reporting at least one Grades 1–4 hypoglycemic episode (95% CI) per year was 11.0% (10.7 to 11.2), for a Grades 2–4 episode 2.5% (2.4 to 2.7), and for a Grade 3 or 4 episode 0.55% (0.50 to 0.60).

Table 1. Baseline characteristics postdietary run-in

N	5063
Male	2985 (59%)
Ethnicity
White Caucasian	4180 (83%)
Afro-Caribbean	387 (8%)
Indian Asian	496 (9%)
Age (years)+	52.4 (8.8)
BMI (kg m2)+	27.5 (5.4)
Fasting plasma glucose (mmol/l)*	8.2 (6.8 to 11.0)
HbA1c (%)*	6.9 (5.9 to 8.1)
ICA and/or GADA +ve	552 (11%)
Allocated therapy
Diet alone	949 (19%)
Sulfonylurea	1687 (33%)
Metformin	336 (7%)
Insulin	1219 (24%)
Not allocateda	872 (17%)

N (%) except ⁺mean (S.D.), *median (IQR).

Table 2 shows annual percentages of patients reporting hypoglycemia, irrespective of current therapy or glycemic control, according to age, sex, ethnicity, body mass index (BMI), islet autoantibody status, and glycemia at diagnosis. Patients who were younger (4.0% <45 years vs. 2.2% ≥45 years), female (3.0% vs. 2.2% male), normal weight (3.6% BMI <25 kg/m² vs. 1.9% ≥25 kg/m²), less hyperglycemic (5.2% HbA_1c <7% vs. 2.3% ≥7%), or islet autoantibody-positive patients (4.3% vs. 2.1% negative) were more likely to report hypoglycemia than patients who were older, overweight, or male (all P<.0001). Both Afro-Caribbean (1.5%) and Indian Asian (1.1%) patients were significantly less likely to report hypoglycemia than White Caucasians (2.8%). Patients in the lower third of the FPG distribution <7.3 mmol/l) and those with HbA_1c values <7% at randomization were significantly more likely to report hypoglycemia than those with higher values, as were islet autoantibody-positive (ICA and/or GADA, 4.3%) than autoantibody-negative patients (2.1%). Hypoglycemia reporting rates did not differ significantly (P=.43) between patients who took ACE inhibitors [2.7 (2.2 to 3.4)%] and those who did not [2.6 (2.3 to 2.9)%].

Table 2. Annual percentage (95% CI) of patients reporting at least one hypoglycemic episode in relation to demographic characteristics and therapy

For all variables, the significance of differences between levels is P<.0001.

3.1. Therapy and previous HbA_1c 

Hypoglycemia rates for the 3538 patients remaining on allocated treatment over 6 years, irrespective of achieved glycemic control, are shown in Table 2. For Grades 2–4 episodes, these were lowest in those on diet (0.1%) and metformin (0.3%), higher on sulfonylurea (1.2%), and highest on insulin. A higher but not statistically significant proportion of patients taking basal plus soluble insulin reported Grades 2–4 hypoglycemic episodes [5.5 (2.0 to 14.0)%] than those on basal insulin alone [3.8 (1.2 to 11.1)%], irrespective of achieved glycemic control.

The proportion of patients reporting Grades 1–4 hypoglycemia decreased with increasing values of most recent HbA_1c for those treated with diet, sulfonylurea, or metformin, but appeared to increase with increasing HbA_1c in insulin-treated patients (Fig. 1, upper panel). Similar relationships were seen for Grades 2–4 hypoglycemia in sulfonylurea and insulin-treated patients (Fig. 1, lower panel). The trend for more insulin-treated patients to report hypoglycemia with increasing HbA_1c persisted after adjustment for their concurrent daily insulin dose (data not shown). However, fewer patients on a low total daily insulin dose (<0.5 U/kg) reported Grades 2–4 hypoglycemia [5.0 (4.4 to 5.6)%] than on higher doses [7.7 (5.6 to 10.5)%], irrespective of achieved glycemic control.

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• Fig. 1. 

  Annual percentages of patients (closed diamond) with 95% CI (solid lines) reporting one or more hypoglycemic episodes in relation to most recently measured HbA_1c for patients remaining on their allocated therapy for 6 years. The dashed line indicates the relationship calculated for HbA_1c as a continuous variable. Top panel: Grades 1–4 hypoglycemic episodes for patients allocated to diet, sulfonylurea, or metformin (left) or insulin (right). Bottom panel: Grades 2–4 hypoglycemic episodes for patients allocated to sulfonylurea (left) or insulin (right).

Recurrent Grades 2–4 hypoglycemia was infrequent, being reported only by 30 (3%) insulin-treated and 2 (0.1%) glibenclamide-treated patients. Of these, 4 insulin-treated patients experienced at least four episodes in 1 year, 6 insulin-treated patients at least three episodes over 2 years, and 20 insulin-treated patients at least two episodes within a 4-year period. Both of the glibenclamide-treated patents reported two episodes within a 2-year period.

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4. Discussion 

This evaluation of self-reported hypoglycemia over 6 years from diagnosis of Type 2 diabetes during the UKPDS trial emphasizes that compared with Type 1 diabetic patients (DCCT Research Group, 1991), the proportion of patients reporting hypoglycemia is substantially less, even in those allocated to intensive glucose monotherapies. The occurrence of major hypoglycemic episodes, requiring third-party or medical assistance, was especially low, and only one hypoglycemia-related fatality occurred (UKPDS Group, 1998). The relative infrequency of hypoglycemia suggests that it is unlikely to inhibit attempts to achieve recommended glycemic targets with intensive sulfonylurea, metformin, or insulin monotherapy to any great extent.

Strict ascertainment of hypoglycemia is difficult in large-scale studies, particularly here, where confirmatory blood glucose measurements are not available. Hypoglycemic episodes categorized as Grade 1 in this study may or may not reflect low blood sugar values, and results including these data may be less dependable, as has been seen in patients with Type 1 diabetes (Pramming et al., 1991). Hypoglycemia reported by patients on diet alone or metformin was almost exclusively Grade 1 and unsupported by biochemical evidence. There is no obvious explanation for the slightly higher rates seen in those on metformin. Grades 2–4 hypoglycemia reports are more dependable, but similar patterns of occurrence were observed whether analyses were for all grades or limited to Grades 2–4. Major hypoglycemia episodes (Grades 3–4) were not examined separately because too few were reported for valid statistical analysis.

Proportions of patients reporting at least one episode of hypoglycemia per year are reported here, rather than absolute rates of hypoglycemia, due to the limitations in the way the data were collected. Actual hypoglycemia rates could be higher, particularly if many patients had recurrent hypoglycemia, as previous hypoglycemia has been shown to predict subsequent episodes in Type 1 diabetes (DCCT Research Group, 1991). Few UKPDS patients, however, reported recurrent hypoglycemia (0.6% overall). Analyses presented here focus primarily on Grades 2–4 hypoglycemia as Grade 1 episodes may be underreported, given that only the highest-grade episode reported each quarter was recorded. Higher rates of hypoglycemia have been reported in Type 2 diabetes in a study of 173 patients (16.37 episodes per patient per year), but these had been on long-term insulin therapy with a mean diabetes duration of 14.4 years (Donnelly et al., 2005).

The lower proportion of patients reporting hypoglycemia in patients ≥45 years old is reassuring because they may be at higher risk of complications, and hypoglycemia may be an added risk factor. It is uncertain whether this finding applies to the elderly as patients over 65 years old were not recruited. In a study of severe hypoglycemia in older Type 2 diabetic patients treated with multiple insulin (mean age, 68 years), there was an association with increasing age (Henderson, Deary, & Frier, 2003), but there is no UKPDS evidence that hypoglycemia occurrence increases with duration of diabetes (UKPDS Group, 1998). Hepburn, Macleod, Scougal, and Frier (1993) found that severe hypoglycemia was directly correlated with longer duration of insulin therapy (range, 1–22 years) in Type 2 diabetes. Henderson et al. (2003) reported a similar finding in a retrospective study of 157 Type 2 diabetic patients treated with multiple or mixed insulin. Over 1 year, rates of severe hypoglycemia requiring emergency treatment in insulin-treated patients with Type 2 diabetes (66/901, 7.3%) were comparable to those in Type 1 diabetes (69/977, 7.1%) (Leese et al., 2003).

The higher percentages of women reporting hypoglycemic episodes in this study may reflect differential reporting of symptoms by gender as women were also three to four times more likely to report drug-related symptoms of any kind than men (UKPDS, unpublished observation) and have been noted to report more symptoms than men in other conditions (Almeida et al., 1999, Devnes et al., 1999). A lower rate of hypoglycemia requiring assistance was noted in men compared with women in conventionally but not intensively managed DCCT patients (DCCT Research Group, 1991). A study of plasma glucose thresholds for counter-regulatory hormone release in Type 1 diabetes showed that although men responded to epinephrine and glucagon at higher plasma glucose levels than women, plasma glucose levels for initial perception of either autonomic or neuroglycopenic symptoms or for total symptom score did not differ (Cox, Gonder-Frederick, Julian, & Clarke, 1996).

Hypoglycemia was reported more frequently by White Caucasian patients than other ethnic groups despite similar levels of glycemic control. It is not clear whether this reflects cultural differences in acknowledging side effects of diabetic therapies, or is associated with other differences between the ethnic groups, including underlying disease pathology. The percentage of patients reporting hypoglycemic episodes was greater in nonobese and islet autoantibody-positive patients, characteristics of those referred to as latent autoimmune diabetes in adults (LADA). This suggests that identification of patients with LADA (Pozzilli & Di-Mario, 2001) might be worthwhile, because of their need for earlier insulin therapy (UK Prospective Diabetes Study Group, 1997, Davis et al., 2005) and proactive management of hypoglycemia.

A higher proportion of patients reported hypoglycemic episodes on basal insulin therapy than those on a sulfonylurea, but only marginally greater in patients on metformin therapy than those on diet alone. The highest percentage of patients reporting hypoglycemic episodes was seen in patients on a basal plus prandial insulin regimen. The sulfonylurea-related percentage of patients reporting hypoglycemic episodes of Grades 1–4 hypoglycemia is similar to that published by Jennings et al. (1989) who reported confirmed hypoglycemia using stringent diagnostic criteria with chlorpropamide and glibenclamide in 13.6% and 31.5% of patients, respectively, a differential rate noted previously (Clarke & Campbell, 1975, UKPDS Group, 1998). The increased percentage of patients reporting hypoglycemic episodes at lower HbA_1c levels reported here may be a limiting factor for sulfonylurea dose increases, but the proportion of patients reporting hypoglycemia fell over time as glycemic control tended to deteriorate. Although elderly patients and those with impaired renal function are known to be at higher risk of hypoglycemia on sulfonylurea therapy (Asplund, Wiholm, & Lithner, 1983), it was not possible to examine this aspect as impaired renal function was a UKPDS exclusion criterion.

The unexpected finding of an increased percentage of patients reporting hypoglycemic episodes at higher HbA_1c values in insulin-treated patients differs from that found in the DCCT for Type 1 diabetes (DCCT Research Group, 1991), where the risk of hypoglycemia was greatest in those with the lowest HbA_1c. Henderson et al. (2003) report a finding similar to the DCCT although not for severe hypoglycemia. Our ability to relate percentage of patients reporting hypoglycemic episodes to HbA_1c levels was limited, as these were measured only on an annual basis and may not adequately reflect glycemic control at the time of any hypoglycemic episode. Also, UKPDS therapy adjustment was based on current FPG, not HbA_1c values. Symptoms of hypoglycemia may be experienced more frequently in poorly controlled patients with higher ambient blood glucose concentrations, as shown in paired clamp studies (Korzon-Burakowska et al., 1998). The effect could not be attributed to patients who were islet autoantibody positive because the proportions were not different in those allocated to insulin and sulfonylurea (13% vs. 13%), nor to other factors also not significantly different between allocated therapies (UKPDS Group, 1998). The low overall occurrence of hypoglycemia reported by patients on insulin in this study cannot necessarily be extrapolated to other insulin regimens, or when insulin is used with different glycemic targets, or in patients requiring insulin therapy following oral agent failure, or with longer duration of diabetes, which may contribute to the differences with the report from Donnelly et al. (2005), but it is encouraging to note lower rates when insulin is used in combination with sulfonylurea (Wright et al., 2002) and that rates can be reduced by using glargine rather than isophane insulin in such combination therapy (Riddle, Rosenstock, & Gerich, 2003).

Our study did not address all possible reasons why hypoglycemia is less commonly reported in insulin-treated Type 2 diabetes compared with Type 1 diabetes. Counter-regulatory hormone responses to hypoglycemia usually remain intact in patients with Type 2 diabetes (De Galen & Hoekstra, 2000, Heller et al., 1987), except for a blunting of glucagon responses in the very elderly (Meneilly, Cheung, & H.T. 2000) and patients with long duration of diabetes approaching insulin deficiency (Segel, Paramore, & Cryer, 2002). Insulin-treated patients with Type 2 diabetes do not have substantial impairment in counter-regulatory responses compared with sulfonylurea-treated patients, even when glycemic control is good (Peacey et al., 2000). It has been suggested that the counter-regulatory response to hypoglycemia is initiated at relatively normal (Spyer, Hattersley, Macdonald, Amiel, & MacLeod, 2000) or higher glucose concentrations (Korzon-Burakowska et al., 1998, Levy & Kinsley, 1998) in Type 2 diabetes than in controls. However, the increasing insulin resistance, as indicated by increasing body mass, and the additional ability to suppress endogenous residual β-cell function are possible mechanisms contributing to a reduction in hypoglycemia occurrence in patients with Type 2 diabetes. Studies in Type 1 diabetes have shown that ACE genotype and ACE activity are strong independent markers of risk of severe hypoglycemia (Pedersen, Agerholm, Pramming, Hougaard, & Thorsteinsson, 2001), and there are controversial reports of increased risk in ACE inhibitor-treated patients (EUCLID Study Group, 1997, Herings et al., 1995). Our limited results did not find an increased occurrence of hypoglycemia in patients taking an ACE inhibitor compared with those not taking one.

These results confirm that hypoglycemia is relatively uncommon with intensive glycemic lowering therapy over the first 6 years from diagnosis of Type 2 diabetes, when sulfonylurea, metformin, or even insulin are used as monotherapy. Modestly higher rates were seen in patients on sulfonylurea and patients who were less hyperglycemic, younger, normal weight, and with islet autoantibodies. In such patients, more extensive education and blood glucose monitoring may be advisable to allow a more intensive glycemic control policy to be pursued more safely.

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Acknowledgments 

The cooperation of patients and many NHS and non-NHS staff at the centers is much appreciated. The major grants for this study were from the UK Medical Research Council, British Diabetic Association, the UK Department of Health, The National Eye Institute and The National Institute of Digestive, Diabetes and Kidney Disease in the National Institutes of Health, USA, The British Heart Foundation, Novo-Nordisk, Bayer, Bristol Myers Squibb, Hoechst, Lilly, Lipha and Farmitalia Carlo Erba. Other funding companies and agencies, the supervising committees, and all participating staff are listed in an earlier paper (UKPDS Group, 1998). Dr Roger J. Owen is thanked for helpful discussion on statistical methods.

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