Introduction

Diabetes mellitus (DM) is a metabolic disorder characterised by resistance to insulin, insufficient

insulin secretion or both1. Hyperglycemia manifest as a result of these disorders. Type 2 DM (T2DM)
has a strong genetic predisposition and is a category of DM characterised by both insulin resistance
and relative lack of insulin secretion to regulate glucose levels and it reduces over time 2. Patients
with T2DM often exhibit abdominal obesity which also causes insulin resistance, along with
hypertension, dyslipidemia and increased plasminogen activator inhibitor-1 (PAI-1) levels causing
patients to be hypercoagulable 3. As such, patients with T2DM are at increased risk of developing
micro and macrovascular complications. They often present without symptoms though
complications imply that they have been hyperglycemic for years 4. Lethargy, polyuria, polydipsia and
nocturia are often seen at diagnosis of T2DM.

Natural History (Refer to Figure 1)

Impaired glucose tolerance (IGT) or prediabetes precedes T2DM where glucose levels are higher
than normal but not in the diabetic range 5. As the disease progresses, persistent hyperglycemia over
time leads to the complications. This natural history reflects underlying loss of beta-cell function
caused by high glucose and lipids, oxidative stress, amyloid deposits and inflammation 6,7. The first
metabolic defect of insulin resistance reduces the uptake of glucose by skeletal muscle and fat cells.
Initially, the beta cells increase insulin levels to compensate, thus keeping glucose levels normalised
but IGT develops with mild hyperglycemia post meals over time. Consequently, beta cells fail and
insulin secretion falls resulting in hyperglycemia and this mark the progression from IGT to early
T2DM. Also, insulin resistance becomes more prominent due to genetic defects and modifiable
factors such as aging, obesity and reduced physical activity.

Diagnosis and management

The diagnosis of T2DM requires glycemic cut point that differentiates normal from diabetic patients.
The clinical practice guidelines for diagnosis of T2DM in Singapore differs slightly from American
Diabetes Association (ADA) in that HbA1c is not recommended as a screening and diagnostic tool for
T2DM as its performance has not been evaluated in the multi-ethnic population. A person with
fasting glucose of ≥ 7.0mmol/L with typical symptoms is diagnosed as having DM. An oral glucose
tolerance test can also be performed in people with suspected DM but normal fasting glucose and a
confirmatory diagnosis is given if the 2-hour post challenge glucose is ≥ 11.1mmol/L.

In Singapore, the Agency for Care Effectiveness (ACE) published an Appropriate Care Guide (ACG) for
the management of T2DM with the focus on maintaining glycemic control while reducing the risk of
hypoglycemia and other adverse events. It spells out the need to control hypertension and lipid,
smoking prevention or cessation, weight management and healthy lifestyle adoption as glycemic
1
https://tinyurl.com/2uvr38rb
2
Janka, H. U., & Michaelis, D. (2002). Epidemiologie des Diabetes mellitus: Häufigkeit, Pathogenese,
Prognose [Epidemiology of diabetes mellitus: prevalence, incidence, pathogenesis, and
prognosis]. Zeitschrift fur arztliche Fortbildung und Qualitatssicherung, 96(3), 159–165.
3
https://tinyurl.com/3pfx28r4
4
https://tinyurl.com/2p99vh3e
5
Centers for Disease Control and Prevention 2011 National Diabetes Fact Sheet [article online], 2011. Available
from http://www.cdc.gov/diabetes/pubs/factsheet11.htm
6
Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin
resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999;104:787–794
7
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell
apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110
control alone may not improve cardiovascular outcomes in patients with long-standing diabetes.
Glycemic targets is similar to recommendations from ADA2021. In people with lower risk of
hypoglycemia, shorter disease duration, longer life expectancy and yet to develop complications and
comorbidities, a stricter HbA1c is pursued.

Treatment is highly individualised according to the efficacy of the therapy, side effect profiles and
tolerability of the drugs, cost and cost effectiveness of the drug and patient characteristics like body
weight and preferences for oral or injectable like insulins. Common oral therapies used in Singapore
can be found in Table 1. Suggested glucose lowering algorithm can be found on the ACG 8 and ADA’s
guideline9.

8
oral-glucose-lowering-agents-in-t2dm-(updated-on-3-august-2017).pdf (ace-hta.gov.sg)
9
American Diabetes Association; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of
Medical Care in Diabetes—2021. Diabetes Care 1 January 2021; 44 (Supplement_1): S111–
S124. https://doi.org/10.2337/dc21-S009
A)

Figure 1: Natural history of T2DM

B) Table of common oral anti-glycemic agent used in Singapore

Drug class Drug

Biguanides Metformin
Sulfonylureas Glipizide, Gliclazide
SGLT-2 inhibitors Dapagliflozin, Empagliflozin
DPP-4 inhibitors Linagliptin, Sitagliptin
Thiazolidinediones Pioglitazone
Alpha-glucosidase inhibitors Acarbose