Effect of Anti-obesity (orlistat) on Type 2 diabetes Mellitus remission in patients in Saudi Arabia.

Introduction:

Diabetes mellitus could be a chronic illness caused by inheritable and/or nonheritable deficiency in production of hypoglycaemic substance by the duct gland, or by the ineffectuality of the hypoglycaemic agent made. Such a deficiency ends up in enlarged concentrations of glucose within the blood, that results in  injury to several of the body’s systems, particularly the blood vessels and nerves. The figure of individuals with diabetes has nearly quadrupled since 1980. Prevalence is increasing worldwide, significantly in low- and middle-income countries. The causes are complicated, however the increase is due partially to the increase of individuals who are overweight, as well as a rise in obesity,

and during a widespread lack of physical activity. Diabetes will result in complications in several components of the body and increase the chance of premature death. In 2012 Diabetes was the direct reason for 1.5 million deaths globally[5]. A considerable proportion of Diabetes mellitus and its complications are often prevented by a healthy diet, regular physical activity, maintaining a traditional weight and avoiding tobacco use .

There are two types of Diabetes:

Type 1

Diabetes (formerly called insulin-dependent) that during the  pancreas fails to supply the insulin which is crucial for survival. this type develops most often in youngsters and adolescents, however is being more and more noted later in life.

Type 2

Diabetes (formerly known as non-insulin-dependent) which ends up from the body’s inability to retort properly to the action of insulin created by the duct gland. kind two diabetes has high prevalence, it is estimated that type 2 represents 90% of diabetes cases worldwide[6]. It happens most often in adults, however it is being noted  more and more in adolescents.

Type 2 and obesity

It has been demonstrated that T2DM is closely related to obesity, and is the main factor to rising healthcare costs of obesity. Whilst it rarely develops with BMI <21 kg/m2, majority of people with T2DM have a BMI >25 kg/m2 and nearly 50 % have a BMI >30 kg/m. Overweight and obesity are known by an excess accumulation of adipose tissues. Both obisity and T2DM are linked with insulin resistance. Adipose tissue influences metabolism by producing glycerol, hoemones and other substances including leptin, cytokines, adiponectin, and proinflammatory substances, and by releasing NEFAs. These secretions are increased remarkably in individual obese. The main factor results in insulin insensitivity is the NEFAs production. High leveles of NEFAs is observed in type 2 diabetes and in obesity, and it is linked with insulin resistance in both conditions. After an acute increase of NEFA levels in humans, insulin resistance begins to develop. In cntrast, when the level of plasma NEFA decreases, as in the case with antilipolytic treatment, insulin uptake and glucose control will be improved. Moreover, increasing plasma NEFA levels accelrate loss of function of β-cells. Regardless the fact that NEFAs is an important factor in insulin release, the constant exposure to NEFAs can lead to significant insulin secretion failure and destruction of insulin biosynthesis. In addition, the occurrence of insulin resistance in vivo and a failure of the compensatory mechanism of β-cells in humans contributes to increase amounts of NEFA levels produced by lipids.

In coculosion NEFA is a main cause in the development of  insulin resistance and in the impairment of β-cell function.

Body mass index (kg/m2)

Normal weight                           18.5 – 24.9

Overwieght grade 1                  25    – 29.9

Overwieght grade 2                  27    –  29.9

Obesity grade 1                          30 – 34.9

Obesity grade 2                          35 – 39.9

Obesity grade 3 (morbid)        40 – 49.9

Obesity grade 4 (extreme)       >= 50

Adapted from World Health Organization (WHO) 1995, WHO 2000 and WHO 2004.

T2DM diagnosis

In 2011 WHO approved HbA1c as a diagnostic assay for diabetes and a ssome international guiding principles have updated to reflect this [o][p].  To diagnose polygenic disease. For diagnosis of Type 2 diabetes probably the best combination of specificity and sensitivity is afforded by the first test being fasting blood glucose. If this is often higher than 5.6mmol/L, the second check ought to be HbA1c or 75g OGTT. this can provide identification of impaired fasting glucose, impaired glucose tolerance, and T2DM.

Diabetes diagnosis can be conducted by using one of the following:

–

Common Symptoms of diabetes and random plasma glucose concentration > 11.1 mmol/L. (Random is outlined as any time of day without consideration for last meal time. The classic symptoms of diabetes involve polyurea, polydipsia, and unexpected weight loss. )

or

–

Fasting plasma glucose ≥ 7.0 mmol/L. (Fasting is explained  as no caloric intake for a minimum of eight hours7).

or

–

2-hr plasma glucose > 11.1 mmol/L throughout a 75g Oral glucose Tolerance check. The check ought to be performed as represented by W.H.O, employing a glucose load containing the equivalent of 75g anhydrous glucose dissolved in water.

or

–

A HbA1c ≥ 48mmol/mol (≥ 6.5%) The check ought to be performed employing a standardised assay. [=]

HBA1c	mmol/mol	%
Normal	Below 42 mmol/mol	Below 6.0%
Prediabetes	42 to 47 mmol/mol	6.0% to 6.4%
Diabetes	48 mmol/mol or over	6.5% or over

Treatment

Patients with type 2 diabetes are less likely to be dispensing insulin. Instead patients use medication in combination with diet and exercise to encourage or increase the body’s own insulin production. One of the most prevalent medications prescribed upon a diagnosis of type 2 diabetes is Metformin Hydrochloride. Many organisations advice that the patient is initiated on a single oral agent. The ADA, IDF and NICE recommend metformin as an option for first-line or combination therapy. In addition NICE also recommends metformin for those who are overweight (BMI >25.0kg/m2 ) as the first-line glucose-lowering therapy where blood glucose is ineffectively managed using lifestyle interventions alone[?]. The drug reduces glucose production by the liver and rises the insulin sensitivity of body tissues[ ], reducing the rate of complications caused by diabetes. DPP4(Dipeptidylpeptidase-4) inhibitors, also known as Gliptins, prevent the manufacture of the enzyme Dipeptidyl peptidase-4, which breaks the hormone incretin.  Incretin controls insulin production in response to meals; if it is existing then more insulin will be formed. Drugs have now been formulated that act in a similar way to incretin hormones. GLP-1(Glucagon-like-Peptide-1) agonists, mimic the mechanism of action of the most abundant incretin hormones. Other options includes Sulphonylurea e.g (Glipizide), SGLT2 e.g (Dapagliflozin) and insulin.

Diabetes and obesity in Saudi Arabia

The highest occurrence of diabetes global is estimated to occur in the Middle East and North Africa attributable to rapid economic development, urbanisation and deviations in lifestyle patterns in the region[a]. The Kingdom of Saudi Arabia (KSA) is not omitted from this global epidemic and diabetes is the most challenging health problem facing the country[s]. As stated by a report by the Saudi Arabian Ministry of Health, about 0.9 million people were diagnosed with diabetes in 1992, however this number increased to 2.5 million people in 2010, indicating a 2.7 times escalation in the incidence rates in less than two decades[d]. Recent data from the Saudi Health Interview Survey SHIS show high rates of diabetes in the kingdome. This large household survey revealed that the total prevalence of diabetes was 14.8% for males and 11.7% for females in 2013. The incidence of diabetes increased with age and varied from 4.7% among those aged 15-24 years to 50.4% among those aged 65 years and older. The incidence of diabetes varied by region, with the peak prevalence occuring in Ha’il and the lowest prevalence occuring in Jazan. The prevalence of pre-diabetics was very high in Saudi. Borderline diabetes was present in 17% of male and 15.5% oof female. In addition, 40.2% of men and 48.4% of women had diabetes and were not aware of it. The outcomes from the SHIS show that diabetes is associated with obesty and hypertension. Diabetes prevalence was 19.9% among those who were obese compared to 10.7% among those who were not obese.Diabetes prevalence was 33.4% among those who were hypotensive compared to to 9.6% among those who were not hypotensive[f]

The saudi Burden of disease 2010 study showed that elevated body mass index (BMI) was the single leading risk factor for disability-adjusted life years (DALYs) in kingdom of Saudi Arabia. Obesity accounted for 11.8% and 11.1 % of males and females respectively. Recent data from the Saudi Health Interview Survey (SHIS) 2013 show high rates of obesity in the Kingdom. This large household survey displayed that the prevalence of obesity defined as a BMI of 30 kg/m2 or greater was 28.7%.  The prevalence was higher among females than males, 33.5 and 24.1% respectively. The prevalence increased by age was highest among those aged 55 to 64 years with levels of 48.0%. Morbid obesity defined as a BMI greater than 40 kg/m2 was 2.5 % in men and 4.7% in women. The prevalence of obesity varied by region with the highest prevalence in Ha’il while the lowest in Jazan. The results from the SHIS indicate that obesity is associated with diabetes. Obesity prevalence was 44.2% among those who have diabetes compared to 27.8% among those who do not[g].

Prevalence of obesity in Saudi Arabia cholesterol

Benefits of weight loss:

There is a reliable evidence that moderate sustained weight loss, using a variety of diet and lifestyle attitudes to achieve 5–10 % weight loss, will prevent the onset of most new cases of T2DM in those with pre-diabetes[h][j] and that it improves all sides of diabetes control (glycaemia, blood pressure, lipids and micro-vascular damage[k]) with drops in drug doses[l][m]. Recommendation to lose and maintain 5–10 % weight loss, by diet and exercise is involved in most clinical strategies [n][b]. However, most T2DM patients in the UK are now treated in primary care, many do not obtain the required specialist lifestyle guidance and support, from qualified staff, to attain 5 % weight loss. Financial encouragements are dispensed only for diagnosis and for prescribing anti-diabetic drugs [v].

Recent proof for the advantages of more aggressive interventions involving surgery, the 2010 SIGN Obesity guideline established a new weight loss/ maintenance goal of >15–20 % for those with BMI >35 kg/m, or >30 kg/m2 with serious medical problems such as T2DM[c]. This amount of weight loss most consistently led to diabetes remission in a randomized trial of bariatric surgery [x] and several reports have suggested that similar weight loss is crucial to stabilize blood glucose and insulin[z][`]. There is also secondary evidence that such weight loss might normalize life expectancy in those with T2DM[q]. However, routine NHS diabetes care rarely targets for weight loss of >15 kg (generally equal on average to >15 %: most studies have average weight close to 100 kg in obese individuals with T2DM) and vanishingly few obese people with T2DM achieve this goal.

Anti-obesity (Orlistat):

Treatment of overweight and obese diabetic patients is clinically challenging, as the natural course of pharmacologic therapies for type 2 diabetes often involves progressive weight gain which results in further worsening of glycaemic control. Diabetic patients have been shown to have greater difficulty in losing and maintaining weight loss than overweight, non‐diabetic patients. Orlistat 120 mg is a non‐systemically acting lipase inhibitor, which attenuates the rate of triglyceride hydrolysis and thereby leads to a partial reduction of the absorption of dietary fat. In a series of 6‐ and 12‐month randomized, placebo‐controlled studies of overweight or obese subjects with type 2 diabetes, treatment with orlistat 120 mg in combination with a mildly calorie‐restricted diet consistently produced significantly greater mean weight loss than diet alone, with significant improvements in haemoglobin A

_1c

(HbA

_1c

), fasting and postprandial glucose levels, and several cardiovascular risk factors also being observed.

Study objectives:

– To determine whether an addition of anti-obesity treatment to achieve remission of T2DM to normal glucose tolerance by substantial weight loss can be effectively delivered, within the Primary health centers in Saudi Arabia where T2DM is normally managed.

– To evaluate the barriers to successful weight loss and T2DM remission.

Targeted outcomes:

• 10-15 % Reduction in weight or more at one year.
• Remission of diabetes (HbA1c <48 mmol/mol) at 1year.
• Reduction in diabetic medications.
• Quality of life.
• Physical Activity.
• Serum Lipids.
• Plasma glucose.
• Orlistat acceptability.

Study design and participants

A prospective, multicenter, observational cohort study targets patients with type 2 diabetes mellitus who are obese/overweight (BMI of 28–43 kg/m

²

) and are taking anti-obisity treatment (Orlistat). The study compares between data outcomes of T2DM patients who take Orlistat with data outcomes of those who take oral hypoglycemic agents only. Patients on insulin, pregnant women, presence of systemic diseases or organ failure and use of drugs, especially steroids, were excluded. This  study will be conducted at  5 primary health centers in Taif city in Saudi Arabia. Patients should have medical records in the center. The proposed date to establish the study is in Jan 2019 . The study will consist of a 2-week screening phase followed by a 52-week follow-up phase. After screening, All Patients  will be received dietary counseling at baseline and at regular intervals throughout the study and are encouraged to increase their level of physical activity. Patients on orlistat will be recommended to take multivtamin supplement daily at least 2 h before or after the evening dose of study medication. Written informed consent will be obtained from all patients.

Measurements:

The primary screening visit involves  a medical history, physical examination, laboratory assessments, vital signs, and status of body weight, HbA

_1c

, and serum lipids. Body weight, blood pressure, and fasting serum glucose are taken at every clinic visit (weeks 0, 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 52). HbA

_1c

will be measured at weeks 0, 12, 24, 36, and 52. Serum lipids (total, LDL, and HDL cholesterol, LDL/HDL ratio, and triglycerides) will be  requested at weeks 0, 24, and 52. waist circumference (measured midway between the lateral lower rib margin and the iliac crest) at weeks 0, 24, and 52.

Diabetes medications are modified when hypoglycemia occurred or when deterioration in glycemic control is remarkable. The dosage changes will be conducted acording to  National Institute for Health and care Exellence( NICE) guidelines.

All adverse events will be recorded to ensure recognising of gastrointestinal events related to orlistat treatment.

Quality of life will be measured according to AQoL using a Multi Attribute Utility Instrument.

Blood sample collection procedures will be applied. Blood is taken from all the participants. Then samples are  immediately separated and the plasma samples are analyzed for glucose, total cholesterol (TC), low density cholesterol (LDL), high density cholesterol (HDL),triglyceride (TG), HbAIc.

Statistical analyses

The two main efficacy variables are body weight and HbA1c. Changes in fasting serum glucose, diabetes medication, serum lipids and blood pressure are also used to assess efficacy. The null hypothesis is that the expected mean changes in efficacy variables in patients take orlistat are not different from those who use oral hypoglycemic agents only after 1 year of treatment.

Clinical characteristics of T2DM patients on orlistat.

Variables Mean (SD) / (%)

N

Male %

Female %

Age years

ADD years

DOD years

BMI Kg/m2

WC (cm)

DBP MmHg

SBP MmHg

HBA1c (%)

TC mmol/L

LDL mmol/L

HDL mmol/L

TG mmol/L

Baseline

After 52 Week

M = Male, F = Female, SD= Standard deviation, DOD = Duration of diabetes,AAD= Age at diagnosis, BMI = Body mass/index (kg/m2), WC = Waist Circumference (cm), WHR = Waist-hip-ratio, DBP = Diastolic blood pressure, SBP= Systolic blood pressure, TC = Total Cholesterol, LDL = Low density

Clinical characteristics of T2DM patients on oral hypoglycemic only

Variables Mean (SD) / (%)

N

Male %

Female %

Age years

ADD years

DOD years

BMI Kg/m2

WC (cm)

DBP MmHg

SBP MmHg

HBA1c (%)

TC mmol/L

LDL mmol/L

HDL mmol/L

TG mmol/L

Baseline

After 52 Week

M = Male, F = Female, SD= Standard deviation, DOD = Duration of diabetes,AAD= Age at diagnosis, BMI = Body mass/index (kg/m2), WC = Waist Circumference (cm), WHR = Waist-hip-ratio, DBP = Diastolic blood pressure, SBP= Systolic blood pressure, TC = Total Cholesterol, LDL = Low density

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