Effect of Tight Glycemic Control on Microvascular Complications in Type 2 Diabetes Mellitus: A Randomized Controlled Trial in an Egyptian Cohort
Phase: NA
Conditions: Diabetes Mellitus
Sponsor: Ain Shams University

 
 
 
 
 
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PROTOCOL OF A THESIS FOR PARTIAL FULFILMENT OF 
MD DEGREE IN INTERNAL MEDICINE 
 
Title of the Protocol: Effect of Tight Glycemic Control on Microvascular 
Complications in Type 2 Diabetes Mellitus: A Randomized Controlled Trial in an 
Egyptian Cohort   
Date of document: May 1st, 2022 
 
Postgraduate Student: Ola Mohamed Mostafa Shaheen 
Degree: Master of internal medicine- Faculty of Medicine – Ain Shams University  
 
 
DIRECTOR: Dr. Manal Mohamed Abu Shady 
Academic Position: Professor 
Department: Internal Medicine, Endocrinology Department – Ain Shams University 
 
Co-DIRECTOR: Dr. Mona Mohamed Abdelsalam 
Academic Position: Professor 
Department: Internal Medicine, Endocrinology Department – Ain Shams University 
 
Co-DIRECTOR: Dr. Meram Mohamed Bekhet 
Academic Position: Assistant Professor 
Department: Internal Medicine, Endocrinology Department – Ain Shams University 
 
Co-DIRECTOR: Dr. Salah Hussein Elhalawany 
Academic Position: Lecturer 
Department: Internal Medicine, Endocrinology Department – Ain Shams University 
 
Co-DIRECTOR: Dr. Hany Khairy Mansour 
Academic Position: Lecturer 
Department: Internal Medicine, Endocrinology Department – Ain Shams University 
 
Faculty of Medicine 
Ain Shams University  
2021 

 
 
 
 
 
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What is already known on this subject? AND 
What does this study add? 
Near normalization of blood glucose levels has been known to reduce the long-term 
risk of diabetic retinopathy. However, transient worsening of preexisting 
retinopathy has also been demonstrated when glucose control is intensified (Bethel 
A. et al., 2021). 
The pathophysiology of this phenomenon is not well understood. Furthermore, the 
circumstances under which it appears remain to be not fully elucidated. Since its 
discovery, early worsening has been described in patients with type 1 and type 2 
diabetes, including those undergoing various diabetic therapies, those who have 
undergone bariatric surgery, and pregnant women (Feldman‐Billard et al., 2018). 
Hence, this study will assessthe relationship between the glycemic control in 
patients with diabetes mellitus and the contemporary statements on the value of 
tight glycemic control, when compared with less tight control with regard to 
microvascular outcomes including diabetic retinopathy, nephropathy and 
neuropathy. 
 
 
1.INTRODUCTION/ REVIEW 
Diabetes mellitus (DM) is a metabolic disorder characterized by chronic 
hyperglycemia due to either insulin deficiency or resistance or both (Goyal&Jialal 
2021). Hyperglycemia induces tissue damage through mitochondrial superoxide 
production, affecting retina, glomerulus, and neurons. It requires continuing medical 
care and ongoing self-care management to prevent and delay acute and long-term 
micro and macrovascular complications (Fasil A et al., 2019).  
Chronic diabetes complications like retinopathy, nephropathy, neuropathy, 
self-reported chest pain, vision decrement, painful paresthesia, and psychiatric 

 
 
 
 
 
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events result in decrement of health-related quality of life (Jacobson et al., 2013).  
Diabetic retinopathy (DR) is the most common microvascular complication of DM 
and is a leading cause of blindness in the working age population worldwide 
(Leasheret al., 2016). It is a progressive sight-threatening eye disease caused by 
hyperglycemia, which damages the retinal microvasculature leading to vascular 
permeability, retinal ischemia, neovascularization, retinal detachment, and blindness 
(Augustine et al., 2020).  
After the DCCT (Diabetes Control and Complications Trial) found that tight 
glycemic control (a glycohemoglobin A1c (HbA1c) <7% ) could prevent or slow the 
progression of nephropathy, retinopathy, and neuropathy in patients with diabetes 
mellitus, a consensus, extended to patients with type 1 and type 2 diabetes mellitus, 
emerged: normalizing glycemia prevents diabetes mellitus complications (Garber et 
al., 2013). Guidelines, quality improvement interventions, quality-of-care measures 
and patient-directed marketing have since focused on achieving tight glycemic 
control. (Rodriguez &Montori2016). 
Appropriate glycemic control and management is fundamental to prevent and delay 
DM complications. Poor glycemic control is highly correlated with high burden of 
diabetes complications. However, data are scanty regarding factors for poor 
glycemic control and the relationship between glycemic control and DM 
complications (Fasil A et al., 2019). 
 
2.AIM / OBJECTIVES 
This randomized controlled study will examine the relation between tight glycemic 
control and microvascular complications of Diabetes in comparison with patients 
with good (less tight) glycemic control. 
Research question: Does tight glycemic control worsens microvascular 
complications of Diabetes? 
 

 
 
 
 
 
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3.METHODOLOGY: 
Patients and Methods/ Subjects and Methods/ Material and Methods 
• Type of Study: 
Randomized controlled trial.  
• Study Setting: 
      The study will be conducted at Ain Shams University Hospitals “outpatient 
diabetes clinic and inpatient department.” 
• Study duration: 
This study will be conducted during the period from May 2022 to October 2023 
• Labs (see later), thorough clinical examination with special emphasis on 
microvascular complications (neurological and Fundus examination) will 
be done for every patient at time of recruitment and 6 months following 
glycemic control.  
 
 
• Study Population: 
o 80subjects with uncontrolled Diabetes Mellitus with HbA1c 8% or 
above all will receive standard medical care (nutritional therapy and 
pharmacological therapy) and will be divided into two groups: 
(a) Group (A) will undergo tight glycemic control (HbA1c <7%) done 
by nutritional education and medication adjustment. 
(b) Group (B)will undergo conventional glycemic control (HbA1c <7.5 
%). 

 
 
 
 
 
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Subjects will be collected from patients with Diabetes Mellitus referred to Ain 
Shams University Hospitals for evaluation with the following criteria: 
• Inclusion criteria: 
1. Both sexes. 
2. Age 18-60years old. 
3. Patients diagnosed with Diabetes Mellitus (Type 2) according to ADA 
guidelines. 
4. Patients willing to participate after signing a written consent to be enrolled in 
the study after being explained to them in an interview. 
5. Diabetic patients with mild and moderate non proliferative diabetic 
retinopathy  
Exclusion criteria: 
1. Patients with age above 60 or below 18 years old. 
2. Patients with severe non proliferative diabetic retinopathy up to advanced 
proliferative diabetic retinopathy. 
3. Patients diagnosed with type 1 DM. 
4. Patients with malignant tumors. 
5. Patients with end stage renal disease and end stage liver disease. 
6. Patients with history of myocardial infarction. 
7. Patients with recurrent attacks of hypoglycemia and hypoglycemia 
unawareness. 

 
 
 
 
 
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Sampling Method: 
Purposive sampling 
Sample Size: 
The study will be conducted on 80subjects. 
Ethical and Safety Consideration: 
This study will be done after approval of the Ethical Committee of the Department 
of Internal Medicine, Faculty of Medicine, Ain Shams University. Informed 
consent will be taken from all participants before recruitment in the study, and after 
explaining the purpose and procedures of the study. The investigator will retain the 
original signed informed consent form. All data will be collected confidentially. 
The study will be based on the investigator self-funding. 
Study procedures and interventions: 
1. After approval of study protocol, patients will be enrolled into the study 
according to inclusion and exclusion criteria. 
2. All participants will sign written informed consent that is approved by the 
local ethics committee. 
3. All patients will be subjected to: 
➢ Detailed history taking of the patient medical condition. 
➢ Anthropometric and blood pressure measurements: 
✓ Weight and height of all patients will be measured using a calibrated 
scale. Body mass index (BMI) will be calculated by dividing weight in 
kilograms by height in meters squared. 

 
 
 
 
 
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✓ Blood pressure will be measured in both standing and seated position 
after a 5-min rest using an aneroid sphygmomanometer and 
stethoscope. 
✓ Basal heart rate measurement 
➢ Biochemical assays: 
✓ Laboratory measurements will include: 
❖ Fasting, 2 hour post prandial glucose levels and HbA1C. 
❖ Kidney function tests including serum urea and creatinine. 
❖ Albumin/creatinine ratio. 
❖ Estimated GFR calculation using MDRD 4 variable equation. 
❖ Complete blood count. 
 
➢ Fundus examination using Optomed aurora portable fundoscopy. 
➢ Neurological assessment usingDN4 (Douleur Neuropathique 4 
questions). 
 
• Labs, neurological and Fundus examination will be done at time of 
recruitment and 6 months following glycemic control.  
▪ Outcomes: 
Effect of tight glycemic control on microvascular complications of Diabetes. 
 
 
 
▪ Statistical analysis: 

 
 
 
 
 
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      To summarize characteristics of study patients based on TyG quartiles, one-way 
analysis of variance (ANOVA) and chi-square (c2) tests will be used, where 
appropriate. To determine the association of liver fibrosis with TyG, multivariable-
adjusted odds ratios (ORs) will be applied. Two-sided significance at P < 0.05 will 
be significant.  
Statistical Package: 
Data will be analyzed with the use of IBM SPSS Statistics. 
4.REFERENCES: 
 
•  Bain S,Klufas M, Allen H, et al. (2019): Worsening of diabetic retinopathy 
with rapid improvement in systemic glucose control: Diabetes ObesMetab.; 
21(3): 454–466. 
• Bethel A, Diaz R, Lakshmanan M, et al. (2021): HbA1c Change and Diabetic 
Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcome 
Trials: A Meta-analysis and Meta-regression. Diabetes care. ;44(1): 290-296. 
• Fasil A, Biadgo B and Abebe M. (2019): Glycemic control and diabetes 
complications among diabetes mellitus patients attending at University of 
Gondar Hospital, Northwest Ethiopia. Diabetes, Metabolic Syndrome and 
Obesity: Targets and Therapy, Volume 12: pages 75-83. 
• Feldman‐Billard S, Larger É and Massin P. (2018): Early worsening of 
diabetic retinopathy after rapid improvement of blood glucose control in 
patients with diabetes. Diabetes Metab.;44:4‐14.  
• Garber AJ, Abrahamson MJ, Barzilay JI, et al. (2013): comprehensive 
diabetes management algorithm. EndocrPract.; 19:327–336. 
• GoyalR and Jialal I. (2021) Diabetes Mellitus Type 2. Stat pearls. 

 
 
 
 
 
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• Jacobson AM, Braffett BH, Cleary PA, et al. (2013):  DCCT/EDIC Research 
Group. The long-term effects of type 1 diabetes treatment and complications 
on health-related quality of life. Diabetes Care.;36(10):3131–3138. 
• Rodriguez-Gutierrez R and Montori M. (2016): Glycemic Control for 
Patients with Type 2 Diabetes: Our Evolving Faith in the Face of Evidence. 
CircCardiovascQual Outcomes.; 9(5): 504–512. 
• Leasher JL, Bourne RRA, Flaxman SR, et al. ((2016): Global estimates on the 
number of people blind or visually impaired by diabetic retinopathy: A meta-
analysis from 1990 to 2010. Diabetes Care 39:1643–9.  
• Augustine J, Troendle E, Curtis T etal. (2020):  The Role of Lipoxidation in 
the 
Pathogenesis 
of 
Diabetic 
Retinopathy. 
Front 
Endocrinology 
(Lausanne),11:621938.