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Impaired glucose tolerance and role of voglibose: an observational study.

INTRODUCTION: Metabolic disorders with a predisposition towards impaired glucose intolerance and ultimately leading to type 2 diabetes mellitus is the major health problem. Although type 2 diabetes has a genetic basis, evidence supports a key part played by modifiable behavioural risk factors such as obesity and physical inactivity. Disorders such as impaired glucose intolerance and metabolic syndrome seem to be intermediate stages between normal glucose tolerance and overt diabetes, and greatly increase the risk of type 2 diabetes and its attendant macroangiopathy. The International Diabetes Federation Taskforce on Prevention and Epidemiology convened a consensus workshop in Lisbon, (1) Portugal, and recommended a three-step approach-identification of those at risk, measurement of the risk, and appropriate intervention-to prevent or delay the development of type 2 diabetes. At the core of this strategy is lifestyle modification-ie, dietary control and increased exercise, but the International Diabetes Federation recognises that pharmacotherapy might be needed in some individuals who cannot maintain such behavioural changes.

The European DECODE study, (2) a meta-analysis of 13 prospective cohort studies, some in Asian individuals, reported that impaired glucose tolerance is a prognostic factor for both all-cause and cardiovascular death. Thus, impaired glucose tolerance not only increases the likelihood of developing diabetes, but also exacerbates macrovascular pathological changes. Treatment strategies designed to slow or delay the progression of impaired glucose tolerance therefore have the potential to reduce cardiovascular morbidity and mortality, and some of the burden on health-care resources. Indeed, results of large, well designed trials have suggested that intensive diet and exercise programmes, and pharmacological intervention, help prevent or delay the development of diabetes in high-risk individuals with impaired glucose tolerance. (3)

Diabetes is a global problem, and its prevalence in Asia is predicted to increase substantially over the next 25 years. Studies specifically involving Asian people include the Da Qing study in China, the Indian Diabetes Prevention Programme, and a Japanese lifestyle intervention trial. Until now, no active drug intervention trial in Japanese individuals with impaired glucose tolerance has been reported. (4,5) We therefore investigated the effectiveness of voglibose, an [alpha]-glucosidase inhibitor that reduces diurnal insulin secretion, for prevention of the development of type 2 diabetes in Japanese patients with impaired glucose tolerance. (5)

METHODS:

STUDY DESIGN: This study was an observational study comprising of voglibose and placebo in individuals with impaired glucose tolerance. From October, 2012, we aimed to treat people until type 2 diabetes or normoglycaemia was diagnosed, or for at least 2 years.

PROCEDURE: We recruited individuals from all socio-economic status, mainly through assessment of high-risk populations, and in particular from first-degree relatives of patients with type 1 or 2 diabetes. We screened 540 men and women aged 30-70 years, with suspected impaired glucose tolerance for family history, blood pressure, body weight, body-mass index, routine blood chemistry (including lipid concentrations), fasting plasma glucose concentrations, and HbA1c, and did an oral glucose (75 mg) tolerance test (OGTT) during a 4-week observation. Individuals were eligible, if they had a fasting plasma glucose concentration of less than 6.9 mmol/L, a 2 h plasma glucose concentration during OGTT (2hPG) of between 7.8 mmol/L and 11.0 mmol/L, [HbA.sub.1c] less than 6.5%, and at least one of the following risk factors for type 2 diabetes: high normal blood pressure (systolic [greater than or equal to]130 mmHg or diastolic [greater than or equal to]85 mmHg) or were being treated for hypertension; dyslipidaemia (concentrations of total cholesterol [greater than or equal to]5.7 mmol/L, triglyceride [greater than or equal to]1.7 mmol/L, or HDL cholesterol <1.04 mmol/L); obesity (body-mass index [greater than or equal to]25 kg/[m.sup.2]); and a family history of diabetes (in a first-degree or second-degree relative). We excluded patients with diabetes or a disease likely to impair glucose tolerance. The patient who were fitting into the inclusion criteria were only 126.

After 4 weeks, eligible individuals were randomly allocated to voglibose 0.2 mg or an identical-looking placebo three times a day before meals. Randomisation was done with a stratified allocation procedure designed to balance the two treatment groups with respect to the number of risk factors ([less than or equal to]2 or [greater than or equal to]3), which were hypertension or high normal blood pressure, dyslipidaemia, obesity, a family history of diabetes, and a 2hPG greater than 9.4 mmol/L (a concentration associated with an increased risk of developing type 2 diabetes) to 11.0 mmol/L.

4-8 weeks before the start of treatment, each person was given advice about appropriate nutrition and exercise programmes (interview, survey of lifestyle, and individualised guidance on future lifestyle habits based on intensity of daily activity categories) and adherence to these was assessed at each visit. The primary endpoint was the development of type 2 diabetes, which was defined as an [HbA.sub.1c] level of at least 6-5%, and, on two separate occasions, at least one of the following: a 2hPG of at least 11.1 mmol/L, fasting plasma glucose concentration of at least 7-0 mmol/L, or random plasma glucose concentration of at least 11.1 mmol/L. The secondary endpoint was the number of people who achieved normoglycaemia (ie, 2hPG <7.8 mmol/L and a fasting plasma glucose concentration <6.1 mmol/L). Once the primary or secondary endpoint was achieved, patients discontinued their medication (those who achieved normoglycaemia are being followed up until study completion, when their responses will be analysed).

Every 12 weeks, we measured the concentrations of fasting blood glucose, [HbA.sub.1c], and blood lipids (triglycerides, total cholesterol, HDL cholesterol, and free fatty acids), did clinical laboratory tests (chemistry, haematology, and urinalysis), measured blood pressure and body weight, did compliance checks (returned tablet counts), and questioned patients about adverse effects. We did an OGTT every 24 weeks. All blood and urinary analytical tests were done at a central laboratory with standard methods.

RESULTS: In the final analysis, 126 registered individuals fulfilled the inclusion criteria: 66 were randomly assigned to receive voglibose and 60 placebos (two participants in the placebo group did not take their medication and were excluded). The mean duration of treatment was 48.2 weeks (SD 36.2)-ie, 45.1 weeks (34.6) for voglibose and 51.4 weeks (37.7) for placebo. Compliance with treatment was similarly high in the two treatment groups.

In the analysis, we found that voglibose was better than placebo (p=0.0026) in individuals treated for an average of 48.2 weeks (SD 36.2). Patients treated with voglibose had a lower risk of progression to type 2 diabetes than did those on placebo. More people in the voglibose group achieved normoglycaemia than did those in the placebo group. Serious adverse events (all one each) in the voglibose group were cholecystitis, colonic polyp, rectal neoplasm, inguinal hernia, liver dysfunction, and subarachnoid haemorrhage, and in the placebo group were cerebral infarction and cholecystitis.
      Manifestation          Voglibose   Placebo   p value

Gastrointestinal symptoms:
Flatulence                    11(17%)     4(7%)    <0.0001
Abdominal distension          8 (13%)     3(5%)    <0.0001
Diarrhoea                     8(13%)      3(5%)    <00001
Abnormal bowel sounds          2(4%)      1(2%)    <0.0001


DISCUSSION: In our study, even though we reinforced diet and exercise programmes, individuals remained at risk of developing diabetes. Voglibose significantly reduced the risk of individuals with impaired glucose tolerance developing type 2 diabetes and significantly increased the proportion of people who achieved normoglycaemia compared with placebo. Thus, the clinically important benefits associated with voglibose were achieved in a short time, particularly in the high-risk group ([greater than or equal to]3 risk factors). Similarly, in terms of achieving normoglycaemia, improvement in high-risk individuals was significant. These results are encouraging and emphasise the benefits of voglibose for people at increased risk of developing type 2 diabetes, and are in line with recommendations made at the International Diabetes Federation Taskforce on Prevention and Epidemiology consensus workshop convened in Lisbon.

One of the potential benefits of a reduction in the progression of impaired glucose tolerance to type 2 diabetes might be a reduction in cardiovascular risk. However, a 20-year follow-up from the original Da Qing Diabetes Prevention Study (6,7) showed that, although lifestyle changes could produce a long-lasting reduction in the incidence of type 2 diabetes, the effect on cardiovascular events was at best modest.

In the past decade, several studies have drawn attention to the benefits of strict and individualised diet and exercise programmes in delaying the progression to type 2 diabetes. In these studies, lifestyle modification reduced the risk of type 2 diabetes by 42% over 6 years (p<0.005) in a Chinese cohort, by 58% over 4 years (p<0.001) in Finnish patients, and by 58% over 2.8 years in a US study. Lifestyle modification thus represents a mainstay of medical care for individuals with impaired glucose tolerance. (8,9) Pharmacological approaches have also been investigated as a means of delaying the onset of type 2 diabetes and drugs such as metformin, acarbose, orlistat, troglitazone, and rosiglitazone have all shown some ability to delay or prevent the progression of impaired glucose tolerance to type 2 diabetes. (9,10) For example, in the Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), (11) the [alpha]-glucosidase inhibitor acarbose reduced the risk of progression to diabetes by 25% over 3-3 years compared with placebo. This result was achieved in people with impaired glucose tolerance that was given advice on diet and exercise. Similarly, the Diabetes Prevention Program Research Group reported (12) that metformin reduced the relative risk of people with impaired glucose tolerance developing diabetes by 31% over 2-8 years. Thus, current best practice indicates a primary role for diet and exercise programmes in the management of impaired glucose tolerance, with drug treatment reserved for those unable to achieve glycaemic control, at high risk of progression to type 2 diabetes, and unable to adequately exercise.

Defects in the action or secretion of insulin, or both, are the two main abnormalities leading to the development of type 2 diabetes, and any intervention that reduces insulin resistance or protects the pancreatic [beta] cells could help to prevent or delay the progression of the disease. Results with voglibose show that it reduces diurnal insulin secretion through improvement of postprandial hyperglycaemia, and these changes should reduce the stress on overworked [beta] cells. (13,16) In our study, 2hPG concentrations fluctuated at a lower level in the voglibose group than in the placebo group between 24 weeks and 96 weeks as indicated by lower [HbA.sub.1c] levels during this period. Assessments beyond this time point are not meaningful because of the small numbers of patients.

Voglibose significantly improved glucose tolerance, in terms of delayed disease progression and in the number of patients who achieved normoglycaemia. (17) Thus, long-term prophylaxis with this a-glucosidase inhibitor in high-risk individuals with impaired glucose tolerance could provide a pharmacological option, along with lifestyle modification, to help reduce the burden of type 2 diabetes.

DOI: 10.14260/jemds/2015/35

ACKNOWLEDGEMENT: We would like to thank the management and all the doctors of Esani Diabetes and Multispeciality Centre in helping to collect the data and follow-up the patient for 2 years.

REFERENCES:

(1.) International Diabetes Federation. Diabetes facts and figures. http://www.idf.org (accessed December 10, 2014).

(2.) The DECODE Study Group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet 1999; 354: 617-21.

(3.) Alberti KGMM. The clinical implications of impaired glucose tolerance. Diabet Med 1996; 13: 927-37.

(4.) Ramachandran A, Snehalatha C, Mary S, et al. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006; 49: 289-97.

(5.) Kosaka K, Noda M, Kuzuya T. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract 2005; 67: 152-62.

(6.) Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008; 371: 1783-89.

(7.) Pan X-R, Li G-W, Hu Y-H, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 53744.

(8.) Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365: 1415-28.

(9.) Alberti KGMM, Zimmet P, Shaw J. International Diabetes Federation: a consensus on type 2 diabetes prevention. Diabet Med 2007; 24: 451-63.

(10.) Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343-50.

(11.) Chiasson J-L, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359: 2072-77.

(12.) Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403.

(13.) Scheen AJ. Is there a role for [alpha]-glucosidase inhibitors in the prevention of type 2 diabetes mellitus? Drugs 2003; 63: 933-51.

(14.) Van De Laar FA, Lucassen PL, Akkermans RP, et al. [alpha]-Glucosidase inhibitors for patients with type 2 diabetes. Diabetes Care 2005; 28: 154-63.

(15.) Matsumoto K, Yano M, Miyake S, et al. Effects of voglibose on glycemic excursions, insulin secretion, and insulin sensitivity in non-insulin-treated NIDDM patients. Diabetes Care 1998; 21: 256-60.

(16.) Matsumoto K, Sera Y, Abe Y, et al. Combination therapy of alpha-glucosidase inhibitor and a sulfonylurea compound prolongs the duration of good glycemic control. Metabolism 2002; 51: 1548-52.

(17.) Fujisawa T, Ikegami H, Inoue K, et al. Effect of two [alpha]-glucosidase inhibitors, voglibose and acarbose, on postprandial hyperglycemia correlates with subjective abdominal symptoms. Metabolism Clin Exp 2005; 54: 387-90.

Mohammed Riyaz [1], Imran [2], Rinu Manuel [3]

AUTHORS:

[1.] Mohammed Riyaz

[2.] Imran

[3.] Rinu Manuel

PARTICULARS OF CONTRIBUTORS:

[1.] Associate Professor, Department of General Medicine, MNR Medical College, Sangareddy, Telangana

[2.] Consultant Diabetologist, Esani Diabetes & Multispeciality Centre, Tolichowki Hyderabad, Telangana.

[3.] Senior Diabetic Educator Nurse, Esani Diabetes & Multispeciality Centre, Tolichowki Hyderabad, Telangana.

NAME ADDRESS EMAIL ID OF THE CORRESPONDING AUTHOR:

Dr. Mohammed Riyaz, # 11-5-337/2 Red Hills, Hyderabad, Telangana-500004. E-mail: riyazesani@hotmail.com

Date of Submission: 20/12/2014.

Date of Peer Review: 22/12/2014.

Date of Acceptance: 29/12/2014.

Date of Publishing: 03/01/2015.
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Title Annotation:ORIGINAL ARTICLE
Author:Riyaz, Mohammed; Imran; Manuel, Rinu
Publication:Journal of Evolution of Medical and Dental Sciences
Article Type:Report
Date:Jan 5, 2015
Words:2415
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