A Dash, T Kumar, N Agarwal
A Dash, T Kumar, N Agarwal. Diabetes :A Paradigm and its Prevention. The Internet Journal of Pharmacology. 2008 Volume 7 Number 1.
Diabetes is a progressive disease with acute and chronic morbidities and high mortality. At present there are 171 million diabetic patients in the world with India accounting for 31.7 million. Prevalence in India is expected to increase to 79.4 million by the year 2030. Approximately 85 -90% of these people have type 2 diabetes mellitus. The illness is best managed by combining patient education and long-term medical care to prevent or to reduce the risk of long-term complications. Diabetes is associated with serious health consequences. It has been the leading cause of coronary heart disease (CHD), stroke and chronic renal failure, hypertension, atherosclerosis, endothelial dysfunction. Management of diabetes is intricate and requires many issues be addressed beyond glycemic control alone. According to American Diabetic Associtaion (2002), the cost related to diabetes for hospitalization and complications was $132 billion  and formed 34% of the medical budget. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. The studies like UKPDS [4-6], DCCT [7, 8] and Kumamoto  have shown a significant decrease in cost and complications with an intensive glycemic and blood pressure control.Diabetes is a chronic disease treated for long with goal of ‘s
Diabetes As An Epidemic
It is believed that diabetes presently affects 1 in 20 adults across the world and projections estimate that there will be estimated 300 million cases worldwide by 2025. Over the last few decades, the mean age of onset of diabetes has decreased to affect younger people. In a study of 3010 diabetics by Ramachandran. A,the prevalence of microvascular complications was: retinopathy 23.7%, Nephropathy 5.5%, Neuropathy – 27.5% & prevalence of CHD 11.4 % & PVD was 4%. Although effective treatment of diabetes can reduce the incidence of its complications, type 2 diabetes is more often than not an asymptomatic condition. Many people with type 2 diabetes may have had the condition for 9–12 years before diagnosis. This means that many of its sufferers have macrovascular and microvascular complications by the time their condition is diagnosed.
The Metabolic Syndrome
A study looking at an older British, predominantly white, socially representative cohort of patients enrolled in heart disease studies showed a prevalence of 20% (i.e. 1 in 5 patients) with impaired fasting plasma glucose.indicating that there is a significant minority of patients in the at-risk group who have impaired glucose levels and the significant cohort is considered to be suffering from 'pre-diabetes' and the features of the metabolic syndrome (an overlapping constellation of risk factors comprising obesity, hypertension, insulin resistance and dyslipidaemia), and therefore at a significantly increased risk of developing type 2 diabetes and its vascular complications.
There has been evidence suggesting that preliminary identification of these patients and modification in lifestyle, manipulation of renin-angiotensin-aldosterone system (RAAS) and with thiazolidindiones treatment there is a decrease in the incidence of progression to type 2 diabetes in this group 
Diabetes a new Paradigm
Diabetes meets all criteria to justify the shift in paradigm to primary prevention because it is an important public health problem, a clear understanding about its natural history and the role of risk factors like obesity, physical inactivity, and the dietary factors in its pathogenesis is established and has been clearly showed that impaired glucose regulation is one of strongest predictors of a progression to diabetes. Most importantly this condition can easily be identified by simple test like the oral glucose tolerance test (OGTT) and fasting plasma sugar (FPG) and the tests are cost effective and easily accesible. Many studies like the Finnish diabetes prevention study (DPS) and the Diabetes prevention program (DPP) that have demonstrated the efficacy and benefits of some of the proposed interventions  been shown to be safe and acceptable. Given these facts, it is not surprising that increasingly the primary prevention of diabetes is being considered as an important approach and must be a cost effective approach looking at the risks associated with it.
Identifification of patients at risk of 'pre-diabetes' in primary care
Most studies use the following criteria to identify the population that may benefit from the detection of frank type 2 diabetes or 'pre-diabetes'.
Age above 45–50 years
Body mass index (BMI; calculated as weight in Kg divided by square of height in m) above 27–30 kg/m 2
High-risk ethnic group for Type 2 diabetes, eg UK-based African-Caribbean- or Asian-origin populations[
Family history of Type 2 diabetes[
those with cardiovascular disease,
A history of gestational diabetes,
obese women with polycystic ovary syndrome and
.previous evidence of impaired glucose tolerance.
Screening on the basis of age alone has been shown to have a low yield.[
The Modifiable Risk Factors
The diabetes as an epidemic is a result of the interrelation between genetic predisposition and environmental and behavioral factors. Obesity has unequivocally been shown to be associated with diabetes with studies suggesting that an increase in the mean weight of the population by one kilogram would increase the risk of diabetes by 9  and female population with a BMI (body mass index) of more than 35 kg /m 2 have 93 times the risk of developing diabetes as compared to females with a BMI below 21kg/m 2 . This has been concordant with a dramatic rise in the prevalence of diabetes. It has been well documented that obesity is strongly associated with physical inactivity which therefore can be a risk factor in the development of diabetes  and both obesity and physical inactivity have been identified as the main modifiable risk factors for progression to diabetes .
According to British Regional heart study, men who were physically active had lower risk for diabetes in comparison to men with less physical activity even after controlling for BMI and age . Other studies have showed that physical inactivity has been a strong predictor for progression to diabetes. In a study by Wei et al, a person who is overweight but is physically active may be as likely or less likely to develop diabetes as compared to a person who is physically inactive with normal or low weight .
Dietary factors are also one the important risk factors for diabetes, although their association with progression to diabetes has not been clearly demonstrated. EPIC-Norfolk study has shown an inverse association between the intake of fruits and vegetables with the levels of glycosylated hemoglobin . Increased fat intake has been reported as a risk factor for obesity and diabetes, although the relationship becomes tenuous when calorie intake is taken into consideration, as fat is energy dense . Probably, the type of fat is also important e.g. Japanese and Eskimo’s have a lower prevalence of diabetes in spite of having a high fat intake. This is mainly ascribed to the fact that the main component of fat in their diets is omega 3 poly unsaturated fatty acids . Another observational study reported that individuals with the lowest level of emotional support had an increased risk for diabetes as compared to individuals with higher emotional support  showing that stress also playing an important role in diabetes.
Primary Prevention of Diabetes- The Evidence So Far
There have been a number of studies to determine the feasibility, and benefits of the various strategies and interventions for primary prevention of diabetes. Some of these studies are discussed below.
Lifestyle interventional study
The various clinical trails done to study the role of lifestyle interventions in the primary prevention of diabetes mainly studied body weight, diet and physical inactivity one of the earliest trial being the Malmohus study . This comprised 267 subjects (mean age 54.1 years and mean weight 76 Kg) with impaired glucose tolerance, who were divided into five groups. The study concluded that the men randomized to the treatment group (diet only or diet plus drug/placebo) had significantly less incidence of diabetes over the 10 year study period as compared to those who didn’t receive any treatment. The intervention in the study, however, was not properly described, and adherence to intervention was at best modest. In spite of these weaknesses in the study design, the Malmohus study suggested a probable way to prevent development of diabetes. This trial in essence suggested a few effective lifestyle interventions.
Malmo Study 
Altogether 217 men (mean age 48 years, mean BMI 26 kg/m 2 ) were recruited with impaired glucose tolerance and were divided into an intervention group or a control group according to their choice. They were followed up for 6 years for the development of diabetes. The men in the intervention group received intervention in the form of either dietary advice, exercise advice or both. Though there was no difference in incidence of diabetes seen between the three intervention groups but a relative risk reduction of 59% was seen in incidence of diabetes was seen in interventional group in comparison to control. Study subjects had chosen to be either in the intervention or the control group. Thus there was a potential bias in favor of the intervention groups, as the subjects were likely to be more motivated and amenable to take up the intervention. In spite of this criticism, this study showed that it is possible to delay or prevent type 2 diabetes in motivated high risk individuals.
Da-Qing Study 
A cluster randomized trial carried in the Da-Qing province of China. Using World Health Organization criteria, 577 individuals (mean age 45 years, mean BMI 25.6 kg/m 2 ) were classified as those with impaired glucose tolerance after screening 110,660 people. They were randomized either to a control group or to one of three active treatment groups : diet only, exercise only, or both and were followed for 6 years. After controlling for baseline BMI and the fasting glucose level, the net reduction in incidence per group was 31% with diet, 46% with exercise and 42% with both. This study suggested that diet and exercise interventions are successful in preventing or delaying the onset of diabetes in a South Asian population. This is a significant finding since the study population had a mean BMI of 25.6kg/m 2 and a mean age of 45 years both of which are considerably lower than that seen in Caucasian or western populations. In this study, there was no significant change in the mean weight in the intervention group and the control group. Significant weight loss of 1kg could be demonstrated only in people with a BMI above 25kg/m 2 . In this group, those who exercised had a significantly lower risk of developing diabetes indicating physical activity as an important factor in the population. In summary, this study emphasized the importance of exercise and the qualitative change in diet even without the weight loss, especially in the leaner populations. However, the results of the Da-Qing study may or could not be generalized for Caucasian populations.
Finnish Diabetes Prevention Study (DPS) 
The DPS was one of the first randomized control trials where subjects were randomized at the individual level. Five hundred twenty two subjects (mean age 557 years, mean BMI 31.4kg/m 2 ) with impaired glucose tolerance were randomly allocated either to the usual care group or to the lifestyle intervention group. The intervention was in the form of intensive advice in the primary care setting regarding exercise and diet. Each individual was given a set of three goals : (i) reducing weight > 5%, (ii) total fat intake of <30%; with saturated fat being <10% of total calorie intake, (iii) increasing fiber intake of >15 mg /1000 Kcal and (iv) physical activity of 30 min every day or 150 min / week. Approximately 86% of the subjects managed to achieve the exercise goal whereas only 43% decreased their weight by 5% or more during the follow-up. The intervention group showed improvement in weight, measures of glycaemia and lipid levels. After an average follow-up of 3.2 years, reduction in the incidence of diabetes in the intervention group was 58%. These results provided a convincing argument that diabetes could be prevented or delayed by lifestyle changes.
Diabetes Prevention Program (DPP) 
DPP was a large multicentric randomized trial in which the intervention group was provided with intensive lifestyle education and support. From 27 different centers, 3234 subjects (
Drug trials interventional study
Lifestyle intervention trials lead to an appreciation of the fact that not all individuals could achieve the modest goals / targets for lifestyle changes. There is a genuine concern about long-term adherence and feasibility of these lifestyle modifications in a routine clinical setting. This has led to certain trails investigating the efficacy of various pharmacological agents in diabetes prevention.
Oral Hypoglycemic agents
DPP was one of the largest trials exploring the efficacy of metformin in the prevention of diabetes in people with impaired glucose tolerance. 1073 subjects were randomized to a metformin group and 1043 were randomized to a placebo group. Metformin was associated with a 2 kg mean weight reduction and a 31% diabetes risk reduction as compared to the placebo group. However, the reduction in the lifestyle modification arm was significantly more than that in the Metformin arm (NNT for lifestyle intervention was 7 and for metformin was 14). In post-hoc analysis, metformin was fond to be considerably more efficacious in obese (35 kg/m 2 ) and younger adults. Further, the protective effects of metformin lasted even after the drug was discontinued.
Other studies on biguanides have produced mixed results; Jarrett et al used phenformin on 204 male patients for a period of 5 years but there was no significant reduction in incidence of diabetes though they were mostly underpowered due to small sample sizes or a low incidence of diabetes in their study populations .
The Malmohus study  showed that there is a likelihood of some beneficial effects of tolbutamide in individuals with high risk. However, the intention to treat analysis of the same data did not show any significant difference between those treated with tolbutamide and those treated with the placebo. Other similar study by Keen et al  also showed no effect of tolbutamide on the progression to diabetes after 10 year of follow-up. These studies had small sample size and underpowered.
In the Fasting Hyperglycemia study  II (FHS), 227 subjects with fasting hyperglycemia (entry criteria based on fasting plasma glucose level) were randomized to basic lifestyle advice (advice at initial visit) or reinforced healthy living advice (every 3 months). They were further randomized to either a control group or a sulphonylurea group (gliclazide) in the form of a 2 X 2 factorial design. The initial results suggest that there was no changed in weight in the two groups, and healthy lifestyle advice does not seem to have any effect of the progression to diabetes in subjects with fasting hyperglycemia. The study is ongoing and results regarding the efficacy of sulfonylurea are awaited.
Initial studies  have examined the effect of Troglitazone, which now has been withdrawn due to associated liver toxicity. In DPP, treatment with troglitazone was one of the intervention arms. While troglitazone was given, there was significantly less progression to diabetes in this groups as compared to the other groups, i.e., placebo, intensive lifestyle and metformin groups . But when the drug was withdrawn, the protective effect also did not continue. This study, although terminated earlier, suggests the potential of thiazolidinediones in the primary prevention of diabetes. However, it remains to be seen whether the protective effects of thiazolidinediones persist after the discontinuation of therapy.
The TRIPOD (Troglitazone in prevention of Diabetes) was conducted with Hispanic women with a history of gestational diabetes with a follow up time of 30 months. There was a reduction in the incidence of diabetes in the intervention arm by 55% in comparison to control arm. In this study, the protective effect remained even after stopping the drug.
The Durbin a cohort study  with 172 patients with impaired glucose tolerance, the subjects in the treatment arm were initially given troglitazone followed by rosiglitazone or pioglitazone. The subjects were followed up for 3 years and showed a significant decrease in incidence. It showed that Thiazolidinediones improve insulin sensitivity and are potentially ideal drugs to delay the progression of diabetes.
In the STOP-NIDDM  (study to prevent non insulin dependent diabetes) trial, acarbose was found to be an effective drug in risk reduction of incidence of diabetes by 25%. The study was conducted with 1429 subjects with a minimum follow-up of 3 years. Nearly 25% of the subjects on acarbose discontinued the drug early because of gastrointestinal adverse effects. Another significant finding of this trial was a reduction of cardiovascular events (NNT =40) and the incidence of hypertension (NNT =19).
In the Xendos study , (Xenical in the prevention of Diabetes in Obese Subjects), 3305 obese subjects (BMI = 30 Kg /m 2 ) were randomized into: lifestyle advice plus placebo or lifestyle advice plus orlistat. 21% of the subjects had impaired glucose tolerance. The primary outcomes of the study were weight loss and time to development of diabetes. After a 4 year of follow-up, orlistat reduced the incidence of diabetes by 37% in comparison to the placebo group. However, there was a 57% attrition rate and 91% of orlistat treated patient’s experienced GI side effects in the first year of therapy. Another study by Heymsfield et al  that pooled analysis of three small trials, reported that orlistat addition may also reduce the incidence of type 2 diabetes.
Trials with prevention of diabetes as the secondary objective
There have been trials where the incidence of diabetes has been studied as either a secondary or tertiary objective.
The heart outcome prevention evaluation (HOPE) trial studied the effect of ramipril on the prevention of cardiovascular events. 5720 patients were randomized in this trial. A new diagnosis of diabetes was seen to be significantly reduced in the ramipril group (relative risk reduction of 34%). This was a post-hoc analysis and the determination of diabetes was done on self reporting, thus the results need to be evaluated with caution .The Captopril prevention project (CPP) reported that 6.5% of people on captopril developed diabetes as compared to 7.2% in the control group (p< 0.05). The recently concluded DREAM Trial in which Ramipril 15 mg daily with median follow up of 3 years had a modest benefit on regression to normoglycemia. .
In the losartan intervention for the endpoint (LIFE) study treatment with losartan was associated with a reduced risk of developing diabetes as compared to those on atenolol. Use of candesartan in the CHARM  (candersartan in heart failure assessment of reduction in mortality and morbidity) study and SCOPE  (study of cognition and prognosis in elderly) study resulted in a lowering in the incidence of diabetes. Another study (VALUE Trial) valsartan also reported a decrease in the incidence of diabetes from 16% to 13% compared with an amlodipine based regimen.
Several trials on the role of statins in diabetes prevention have been post-hoc analysis studies and have reported conflicting results . In WOSCOPS (west of Scotland coronary prevention study) the diabetes incidence was lowered by 30% whereas in ASCOT-LLA the diabetes incidence was higher by 15% as compared to the placebo.
There was reduction in incidence of diabetes by about 30% on post hoc analysis of benzafibrate infarction prevention trial (BIP).
Several ongoing studies to determine the efficacy of various pharmacological agents in the primary prevention of diabetes are reported.
This diabetes reduction assessment with ramipril and rosiglitazone medication trial is evaluating whether the combination therapy of ramipril and rosiglitazone in subjects with IGT or IFG could prevent the onset of diabetes. This was a double-blind, randomized clinical trial with a 2-by-2 factorial design, which randomly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose or impaired glucose tolerance to receive ramipril or placebo and rosiglitazone or placebo, with a median follow-up of 3 years. Overall, the DREAM trial showed that rosiglitazone has a substantial benefit on prevention of diabetes and regression to normoglycaemia, and ramipril modestly improves glycemic status in IFG/IGT.
Future ongoing research
The nateglinide and valsartan in impaired glucose tolerance outcome research trial has recruited 7500 subjects with IGT with cardiovascular disease or at least one risk factor for cardiovascular disease. The primary outcomes to be studied in this trial are the incidence of diabetes and cardiovascular events. The design of the trial is a 2 x 2 factorial evaluating nateglinide and / or valsartan versus placebo.
ACT NOW TRIAL 
The ACT NOW Trial is compared the effects of the TZD pioglitazone
There are other ongoing studies like FHS and ORIGIN (the outcome reduction with an initial glargine intervention trial)  that are evaluating the role of gliclazide and glargine in the prevention of diabetes or diabetes and cardiovascular diseases, respectively.
To summarize, the current literature favors the use of lifestyle interventions as a first line modality. The use of drugs remains as a secondary approach largely due to
Lifestyle modification, on the basis of current evidence appears to be more efficacious
All drugs, at least to some extent, do cause adverse side effects
The current evidence has not shown the beneficial effect of drugs (except metformin) on CVD morbidity / mortality (although trails are ongoing), whereas the lifestyle modifications have a proven reduction in CV morbidity.
Prescribing the medication to prevent / delay the onset of disease will in effect increase the duration for drug therapy since the trials so far have not shown a lasting protective effect on discontinuation of the drug. This will have potential cost implications as well.
It probably may not be realistic to suggest that we could totally prevent diabetes but the studies so far suggest that diabetes is preventable to a large extent. Current evidence is in favor of adopting lifestyle interventions especially targeted towards the high risk individuals. This evidence has also illustrated that there are immense cost s and difficulties associated with their implementation. In theory, a change in lifestyle for whole community is the best way to stop this epidemic. However, these strategies are difficult to implement and require massive resources. Drugs may be an attractive option but currently there are no drugs which are as effective as lifestyle changes. Therefore, unit a drug is discovered, we need to practice and preach lifestyle changes.