Pharmacotherapy and weight management: efficacy and clinical effectiveness in patients with obesity and type 2 diabetes

Aldekhail, Nasser Mohammed N. (2018) Pharmacotherapy and weight management: efficacy and clinical effectiveness in patients with obesity and type 2 diabetes. PhD thesis, University of Glasgow.

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The prevalence of obesity worldwide has more than doubled since 1980. The World Health Organisation (WHO) estimates that more than one in ten adults in the global population is obese. Cardiovascular and metabolic health can be improved with moderate weight loss; losses of 5%–10% have been found to improve conditions such as diabetes, hypertension and cholesterol and low-density lipoprotein (LDL) levels. Within the UK, a number of weight management programmes that depend on lifestyle intervention (tier 2) and others that supplement this with drug therapy (tier 3) and surgery (tier 4) are available.

The guidelines produced by the Scottish Intercollegiate Guideline Network (SIGN) advocate that weight management programmes address changes to diet, physical activity and behaviour. For patients with a body mass index (BMI) ≥30 kg/m2 or ≥28 kg/m2 in patients with comorbidities, orlistat can be considered as a drug intervention on a case-by-case basis following a full risk and benefit assessment. The objective of the Glasgow and Clyde Weight Management Service (GCWMS), a specialist weight-loss programme, is for patients to lose at least 5 kg.

There are a number of metabolic disorders that are associated with obesity. One such disorder is type 2 diabetes mellitus, where weight loss is a standard recommendation to improve blood glucose control. Randomised controlled trials (RCTs) of orlistat indicate that the drug is effective in promoting weight loss and improving metabolic control for those patients with the comorbidity of type 2 diabetes and obesity. There are several different groups of anti-diabetic drugs that can be used to manage diabetes. The effects of the different medications on body weight are considerable. Some, such as biguanides (metformin), dipeptidyl peptidase-4 inhibitors (DPP-IV), Glucagon-like peptide-1 agonist (GLP-1) and sodium-glucose co-transporter-2 inhibitors (SGLT2), either have no effect on weight or can cause weight loss. Others, such as sulfonylureas (SUs) and thiazolidinediones (TZDs) can lead to weight gain.

This thesis explores the impact of lifestyle interventions in weight management services, and the impact of drug interventions, on weight loss and glycaemic control. It is supported by the results of five complementary studies that reviewed the effect of orlistat on type 2 diabetes and assessed the impact of the prescription patterns of anti-diabetic drugs in addition to the effects of these pharmacological interventions on weight change in comorbid patients.
The first aim of this thesis is to review the evidence of the effects of orlistat on diabetic outcomes. The second aim is to evaluate the lifestyle interventions, and phase 2 of the GCWMS. Finally, the third aim is to determine the prescribing patterns of anti-diabetic drugs, and to observe the association between anti-diabetic medications and weight change. This thesis addresses the following objectives:

1. To undertake a systematic review and meta-analysis of published studies in order to review the evidence of the effects of orlistat on weight loss, specifically concerning glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG), using the Cochrane review methodology;
2. To investigate the proportion of patients losing 5 kg of weight, commencing from their entry into the GCWMS programme, until the end of the lifestyle phase of treatment, for individuals of different ages, genders, and socioeconomic groups;
3. To study the proportion of patients losing 5 kg of weight, commencing from their entry into the GCWMS programme, until the end of phase 2, with the three different interventions of orlistat, low-calorie diet (LDL), and further weight loss (FWL);
4. To investigate the proportion of patients referred to the GCWMS on weight-neutral, mixed, and weight-gaining anti-diabetic medications;
5. To investigate the effect of baseline anti-diabetic medications on weight change for patients within a weight management programme.

Chapter 2 presents the first study, which was a systemic review that considered the evidence collected in RCTs on the efficacy of orlistat for type 2 diabetes and weight loss. The effects were considered at the biochemical level and included the levels of glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) in people with overweight and obesity. The results, collected from 2,802 participants in 12 trials, were combined into a meta-analysis. The overall finding was that a combination of orlistat and lifestyle intervention yielded superior results. When the results were compared, it was evident that patients who are overweight or obese who were subjected to combined lifestyle and drug intervention lost more weight and had better glycaemic control than patients who were subjected to lifestyle interventions only.

Chapter 3 presents the second study which appraised the effectiveness of a real-life NHS lifestyle weight management intervention in reducing body weight by ≥5 kg. The study followed 23,650 patients referred to the GCWMS, of whom 7,329 attended at least two lifestyle intervention sessions. Those individuals had either a BMI of ≥30 kg/m2, with obesity-related comorbidities, or a BMI of ≥35 kg/m2 and were aged ≥18 years. The lifestyle interventions included a combination of a 600 kcal deficit diet, exercise, and behavioural changes. 30% of the overall group succeeded in losing ≥5 kg. Out of those who completed the programme, however, a considerably higher number (46%) lost ≥5 kg. The greatest losers were men, those aged ≥40 years, those with a BMI ≥50 kg/m2, and those from areas that are more affluent.

Chapter 4 presents the third study which focused on patients who lost ≥5 kg in phase 2 of the treatment provided by GCWMS which comprised a low-calorie diet (LCD), orlistat 120 mg, three times a day, or further weight loss (FWL). Participants on LCD were prescribed a 1,200 or 1,500 calorie plan; however, those on FWL repeated the lifestyle phase. There were 3,262 participants who attended at least two sessions in phase 2; these were divided into three categories: 536 who took orlistat, 1,043 who followed a LCD and 1,683 who were selected FWL. By the end of phase 2, the levels of success in terms of weight loss across the groups varied from 31% of participants in the orlistat group to 22% of participants in the LCD group and 83% of participants in the FWL group who lost ≥5 kg.

Chapter 5 presents the fourth study, which evaluated the pattern of anti-diabetic drug prescriptions for comorbid patients referred to the GCWMS. The study also looked at the proportion of patients who were referred prior to and after the publication of updated SIGN guidelines for the prescription of anti-diabetic medication. In total, the study enrolled 3,063 participants who received anti-diabetic medications, of whom 47.8% received weight-neutral medications, 39.4% had mixed-effect medications and 12.7% took weight-gaining drugs. Prior to the publication of the SIGN guidelines, 11.6% of participants were on weight-gaining drugs, a proportion that did not change significantly one year after the release of the guidelines. Weight-neutral drugs were more commonly prescribed to women, those with a higher BMI and young people. No relationship was observed between the Scottish Index of Multiple Deprivation (SIMD) and anti-diabetic drug prescriptions. Weight-gaining drugs such as SUs and TZDs were more commonly prescribed to older patients and those with lower BMIs.

Chapter 6 presents the fifth and final study, which investigated the effect on body weight of anti-diabetic medications in 998 participants following the lifestyle phase of the GCWMS. By the end of the programme, patients who were on weight-neutral anti-diabetic drugs achieved a mean weight change of -3.3 kg (95% confidence interval [CI]: -3.8 to -2.9 kg) and those on weight-gaining drugs achieved a mean weight change of -2.5 kg (95% CI: -3.2 to -1.8 kg), p =0.05. Among those who completed the programme, the difference was statistically significant (p =0.005). The association between weight change and anti-diabetic drug type was not explained by differences in sex, initial BMI or age.

To conclude, there was a clinically and statistically significant change in weight, HbA1c and FPG in patients with obesity and type 2 diabetes who used orlistat. Of the patients following the GCWMS lifestyle phase, less than 50% succeeded in losing at least 5 kg, with patients who completed the programme being more successful. Participants who lost weight in the lifestyle phase were selected for FWL and experienced the greatest weight loss by the end of phase 2. Those who were unsuccessful in losing 5 kg through the lifestyle programme, were offered orlistat and LCD. The large sample size increased the precision of the results, while the stratification for potential confounding factors increased the study’s validity. A higher proportion of patients were prescribed weight-neutral medications, compared with mixed and weight-gaining anti-diabetic medications. The proportion of patients on weight-gaining diabetes drugs referred to the GCWMS did not alter appreciably following the release of the SIGN guidelines. By the end of the lifestyle treatment phase, patients receiving weight-neutral drugs (metformin, DPP-IV, GLP-1, and SGLT2) were more successful in losing weight than those receiving weight-gaining drugs (SUs, TZDs, and any combination including insulin). The main recommendation from this research are, that further studies are carried out to better establish the best timing of use of orlistat within a weight management programme, that the intensity of phase 2 of the GCWMS is increased, and that prescribers take account of a patient’s current BMI prior when prescribing anti-diabetic medication, especially when recommending weight loss and referring to a weight management programme.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Type 2 diabetes, obesity, diabetes medications, orlistat, weight loss.
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Supervisor's Name: Logue, Dr. Jennifer and Morrison, Dr. David
Date of Award: 2018
Depositing User: Dr Nasser Aldekhail
Unique ID: glathesis:2018-8659
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 29 Jan 2018 14:07
Last Modified: 23 Mar 2023 10:30
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