ABSTRACT
BACKGROUND The burden of diabetes mellitus has become an important issue of public concern. An epidemic of Type2 Diabetes Mellitus (T2DM) and its morbidities is under way worldwide with developing countries being disproportionately affected. This poses great challenges in the management of T2DM patients particularly in developing countries like Nigeria. Secondary oral hypoglycaemic agent (OHA) failure is one of the many challenges of diabetes management, the consequence of which is poor diabetes control and early development of chronic complications. Prospective studies on secondary OHA failure have not been done in Northern Nigeria. The aim of this study was to determine the prevalence and risk factors associated with development of secondary failure of OHA among T2DM subjects.
METHODS A total of 200 hundred consecutive T2DM patients were studied over a 10 months period. Parameters studied included age, sex, BMI, WC, FPG, 2hrPPG, lipids profile, glycated haemoglobin and GAD autoantibody positivity. The prevalence of OHA failure was determined using simple percentage and risk factors were determined by comparing the clinical and laboratory parameters between subjects with OHA failure and those without OHA failure. The relative risk was estimated by calculating the odds ratio (O.R).
RESULTS The mean (SD) age of the subjects was 53.2(8.9) years (range 34-75 years). The prevalence rate of secondary OHA failure was 36% with a female preponderance 46(63.9%); males were 26(36.1%).Fifty four (75%) of them belonged to low social class. The mean(SD) BMI [22.9(5.4) kg/m
] and mean (SD) WC for both males and females [87.7(11.3)cm and 90.3(7.9)cm] were significantly lower in subjects with OHA failure than those without OHA failure [27.2(4.8)kg/m
, 93.5(10)cm and 95.7(6.8)cm respectively], p<0.05. The mean (SD) FPG [11.7(2.6) mmol/L], 2hr PPG [14.5(3.7) mmol/L] and HbAlc [8.3(1.42)%] of those with OHA failure indicating poor glycaemic control were significantly higher than in those without OHA failure [5.7 (1.5)mmol/L, 11.1 (2.8)mmol/L and 7.0(2.07)% respectively], p<0.05. The mean (SD) TC, LDL-C and TG [4.89(0.90) mmol/L, 3.8(0.9) mmol/L and 0.95 (0.34) mmol/L] in subjects with OHA failure were lower than in subjects without OHA failure, though not significant p>0.05. The prevalence of anti-GAD positivity generally among the study subjects was 14.5% while in those with and without OHA failure were found to be 31.4% and 3.1% respectively. Risk factors that were associated with secondary OHA failure included early age at diagnosis of diabetes, duration of diabetes, WC, BMI, FPG, 2hr PPG, TG and HbA1c.
CONLCUSION The prevalence of secondary OHA failure appears to be high among T2DM patients in the Northern part of Nigeria. Low BMI, WC and duration of diabetes have been found to be risk factors. The consequence of secondary OHA failure is early development of chronic diabetes complications. The burden of the morbidity and mortality from these complications is enormous particularly in a developing country like Nigeria. Therefore improved diabetes education and routine screening of T2DM patients for secondary OHA failure risk factors are recommended for early detection and prompt management, in order to reduce the rate of chronic complications.
CHAPTER ONE
1.0 INTRODUCTION
Page 1 of 5
1.1 DEFINITION OF DIABETES MELLITUS
Diabetes mellitus is a group of metabolic diseases characterised by chronic hyperglycaemia resulting from an absolute deficiency of insulin secretion or a reduction in the biologic effectiveness of insulin (or both).
It manifests with symptoms like polyuria, excessive thirst, weight loss and sometimes blurring of vision. It is associated with acute complications such as ketoacidosis, hyperosmolar state and hypoglycaemia, as well as long-term complications affecting the eyes, kidneys, feet, nerves, brain, heart and blood vessels. 1,2
1.2 CLASSIFICATION OF DIABETES MILLETUS
Diabetes mellitus has been classified, according to American Diabetes Association/World Health Organization (ADA/WHO) into four types 1,2 . These include: type 1 diabetes (formerly known as insulin dependent diabetes or IDDM), type 2 diabetes (formerly non-insulin dependent diabetes or NIDDM), other specific types and gestational diabetes. 1,2
Type 1 diabetes (T1DM): This occurs as a result of absolute insulin deficiency following autoimmune pancreatic β-cell destruction. A small fraction (5%) of T1DM may be idiopathic with no evidence of autoimmunity.
It occurs commonly in the younger age group, with low BMI and they are ketosis prone. It is characterised by the presence of several distinct circulating
autoantibodies including autoantibodies to glutamic acid decarboxylase (GAD), islet cell and tyrosine phosphatase (IA-2/ICA512) and absent connecting peptide (C-peptide).
Type 2 diabetes (T2DM): It is the predominant form of diabetes accounting for greater than 90% of diabetes worldwide.
It is due to relative insulin deficiency and or insulin resistance (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance).
It commonly affects older age groups, more females than males, with a strong association with obesity, sedentary lifestyle, urban living, family history, alcohol, multiparity, genetic predisposition and high blood pressure. 2. There are usually no distinct circulating autoantibodies but relative presence of C- peptide and dyslipidaemia is a common feature.
Other specific types: These occur as a result of specific defect or disease entity and include; A. Genetic defects of β cell function e.g maturity onset diabetes of the young, (MODY 1-6), mitochondrial DNA defect. B. Genetic defects in insulin sensitivity e.g type A insulin resistance, leprechaunism. C. Diseases of the exocrine pancreas e.g pancreatitis, pancreatectomy, neoplasia, trauma, heamochromatosis, cystic fibrosis.
D. Endocrinopathies e.g acromegaly, Cushing’s syndrome, glucagonoma, hypothyroidism. E. Drug or chemical induced e.g vacor, glucocorticoids, thyroid hormone, β- adrenergic agonists, thiazides, phenytoin, phentamidine, nicotinic acid. F. Infections e.g congenital rubella, CMV etc. G. Uncommon forms of immune-mediated diabetes e.g Stiff-man syndrome, anti- insulin receptor antibodies. H. Other genetic syndromes sometimes associated with diabetes e,g Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, Wolfram syndrome, Prader-Willi syndrome etc. Gestational diabetes mellitus: This is defined as any form of glucose intolerance discovered for the first time during pregnancy with resolution at the end of pregnancy. However, there is a considerable risk (5%) of developing T2DM later.
Page 2 of 5
It occurs commonly in otherwise healthy pregnant women with BMI > 25kg/m
, previous history of GDM, or large baby (birth weight>4kg), poor obstetric history, multiparity, family history of diabetes, history of impaired glucose tolerance and glycosuria. 6,7
1.3 EPIDEMIOLOGY OF TYPE 2 DIABETES MELLITUS (T2DM)
Type 2 Diabetes Mellitus (T2DM) is the predominant form of diabetes worldwide, accounting for 90% of cases globally. 8,9 An epidemic of T2DM is underway worldwide with developing countries disproportionately affected.
Globally, the number of people with diabetes is expected to rise from the current estimate of 194 million to 250 million in 2010 and 333 million in 2025 and about 70% of this is expected to be in developing countries.
The prevalence of T2DM varies according to racial/ethnic and environmental influences. The highest rate of about 40% is seen among adults of the Pacific Island of Nauru and Pima Indians while the lowest rate is found among the natives of Papua New Guinea.
The prevalence of T2DM among blacks in the United States and Caribbean Islands is said to be 11% and 9% respectively and a rate of 30% is found among Asian immigrants in Britain. 10,11
In Nigeria, the national survey of 1992 reported (in 1997) an age adjusted prevalence of 2.2%.
Recent studies in Port Harcourt and Zaria showed a prevalence of 7.9% and 5% respectively. 13,14
1.4 PATHOGENESIS OF TYPE 2 DIABETES MELLITUS
The maintenance of normal glucose homeostasis is largely dependent on three factors: normal insulin secretion by pancreatic β-cells in response to glycaemic stimulus, ability of the insulin to promote peripheral utilisation of glucose and to inhibit endogenous hepatic glucose production (insulin sensitivity) and to some extent the ability of the glucose to independently suppress hepatic glucose output (glucose sensitivity).
Central to the development of T2DM is the disturbance of glucose homeostasis by insulin resistance and/or abnormal insulin secretion (defective - cell function). Although controversy remains regarding the primary defect, most
studies among Caucasians and African Americans support the view that insulin resistance precedes insulin secretory defect. 15,16 However, Bakari et al
in Northern Nigeria, in their work have found significant (60%) pancreatic β cell dysfunction among T2DM patients.
1.5 ORAL HYPOGLYCAEMIC AGENTS FAILURE
A drug failure is said to occur when a therapeutic agent, in appropriate dose, loses its capacity to produce a desired maximal therapeutic effect after administration.
Reasons are varied as to why drugs fail in some patients and not in others. This will include both intrinsic and extrinsic factors in the host assuming the efficacy of the therapeutic agent is uncompromised.
Page 3 of 5
Secondary oral hypoglycaemic agent failure is common among T2DM patients taking oral agents particularly late into the disease, with about 30% failure rate 5-6 years after initiation of therapy. 20,21
The rapidity with which the secretory function of pancreatic β-cells deteriorates to such a point when OHAs fail to either induce or optimise insulin among T2DM patients depends on some host factors. These include factors such as genetic predisposition, β-cell function, low BMI, lipotoxicity, chronic hyperglycaemia and anti-GAD positivity. 19,22 In other words, insulin therapy will be required, at varying times, for optimal management of people with T2DM.
1.6 EPIDEMIOLOGY OF OHA FAILURE
The prevalence of secondary failure to oral hypoglycaemic agents in
T2DM patients among Caucasians, Hispanics and African Americans on sulphonylurea and metformin was shown to be 3 – 10% per annum and as much as 20–30% in 4 – 6 years after diagnosis of diabetes. 20-23 As the incidence of T2DM continues to rise so also that of secondary failure to OHA.
The literature available on secondary failure of oral hypoglycaemic agents among T2DM patients is scanty in Africans particularly in Nigeria. However, a prevalence of 9.7% was recorded in Lagos by Fasanmade and co-workers (unpublished data).
1.7 JUSTIFICATION FOR THE STUDY
Type 2 diabetes mellitus is the predominant form of diabetes worldwide. By 2025, it is estimated that about 333 million people will be affected. 1,2, This global epidemic is disproportionate with over 70% expected to affect the developing countries including Nigeria.
Thus T2DM has become an important public health problem of concern to both the developed and developing countries. As the prevalence of T2DM is rising in Nigeria, it is also expected that chronic complications will increase as well 8,9 . The consequence of poorly managed T2DM is early development of chronic complications and this poses a lot of management challenges. The resources needed to manage these complications are usually enormous and scarce especially in Nigeria where we have a double burden posed by infections such as malaria and human immunodeficiency virus/acquired immune deficiency syndrome and non
communicable diseases like hypertension. Consequently, the morbidity and mortality from this disease will increase, especially in the setting of poor control. Solagberu
in Ilorin and Ogunlade et al
in Ibadan showed that diabetes is the second leading cause of amputations after trauma, responsible for 29% and 26% respectively. Akinsola et al
in Ife, found that diabetes is the fourth leading cause of chronic renal failure among Nigerians while Nwosu
in Nnewi, reported that T2DM is responsible for bilateral blindness in 18% of diabetic patients attending the eye clinic. Having recognised some of the consequences of poor diabetes control among Nigerian patients, it is therefore very important in the management of these patients to identify those T2DM patients at risk of developing secondary failure to OHA early enough so as to institute a rational approach to their management to prevent these devastating chronic complications. There is very scanty data in Nigeria on OHA failure in T2DM patients. There has not been any study in Northern Nigeria. The purpose of this study therefore was to determine the prevalence and risk factors for the development of secondary failure to OHA among T2DM patients in Zaria, Nigeria.
Page 4 of 5
1.8 GENERAL AIM AND OBJECTIVE
The general aim of this study is to estimate the prevalence and identify risks factors associated with secondary failure to oral hypoglycaemic agents (OHA) among T2DM patients in Ahmadu Bello University Teaching Hospital (ABUTH) Zaria.
SPECIFIC OBJECTIVES The specific objectives of this study are: i. To determine the prevalence of secondary failure of OHA among T2DM patients attending the Diabetes clinic of ABUTH Zaria. ii. To identify the risk factors associated with secondary failure to OHA. iii. To determine glutamic acid decarboxylase (GAD) antibody positivity among patients with secondary failure.
Page 5 of 5
