25 / 30
VOLUME 17 NUMBER 2 • NOVEMBER 2020
61
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Report
agent for glycaemic control at some point on their diabetes journey.
In these cases, rational drug combinations with the least potential
for worsening diabesity and with maximum benefits in preventing
its complications, such as cardiovascular disorders and renal disease,
should be chosen when devising the appropriate management
strategy. In patients without contraindications (advanced liver and
kidney diseases) and drug intolerance, metformin remains the
first-line agent for medical management of diabesity. Add second-
line agents for glycaemic control depending on the degree of
hyperglycaemia, choosing an agent with the least propensity for
weight gain.
15
Summary of interventions
• Addition of insulin to metformin is the best approach for rapid
reversal of severe hyperglycaemia and glucotoxicity. However,
every attempt should be made to switch from insulin to another
antidiabetic agent with weight-loss potential or that is weight
neutral once glycaemic control is achieved.
• Although addition of sulphonylureas to metformin worsens
diabesity because of the weight-gain potential, this combination
is economical and effective in controlling hyperglycaemia and
therefore still preferred by many funders.
• Because of the weight-loss potential and beneficial effects on
an adverse lipid profile, the combination of GLP-1 RAs with
metformin is potentially a very promising regimen for patients
with diabesity.
• Combination therapy with metformin and a SGLT-2 inhibitor
is encouraging for medical management of diabesity, showing
reduction in body weight and improvement of
β
-cell function.
• Because of weight neutrality and different mechanisms of
action, a combination of a DPP-4 inhibitor and metformin is
promising in the early management of diabesity in patients
reluctant to use injections or intolerant of GLP-1 RAs; a fixed
combination should be considered early on.
• Addition of pioglitazone to metformin raises concerns about the
management of diabesity, although it may be an appropriate
choice among patients with NAFLD and PCOS.
Clinical focus with Dr Lombard
And do not forget about other medications
Many medicines tend to increase body weight (Table 3). In general,
net weight gain varies between individuals and from drug to drug.
Take time to distinguish between weight gain related to a specific
treatment and weight gain that is due to other factors, such as a
poor diet or lack of exercise.
1,20
It is important to note significant co-morbid association between
diabesity and neuropsychiatric disease, particularly depression.
Importantly, not only is the prevalence of mood disorders elevated
in patients with T2DM, but depressed patients are also more prone
to develop diabetes. Similarly, there is an association between mood
disorders and obesity. Some antidepressants, antipsychotics and
anti-epileptic medications lead to an increased appetite, whereas
other medicines such as
b
-blockers slowly induce weight gain over
time due to associated fatigue and thus lower patient activity levels.
Importantly, treatment of obesity improves depressive symptoms
in patients with mood disorder; and patients being treated for
depressive symptoms show improved weight loss and weight
management.
20,21
Table 3.
Different drug types and their observed trends in weight gain
1
Drug class
Weight effect
Antidepressant agents
Tricyclic antidepressants
Amitriptyline, nortriptyline
+/–
MAO inhibitors
Phenelzine, tranylcypromine
+++
Moclobemide
0/–
SSRI
Citalopram, fluoxetine, paroxetine, sertraline
+/–
SNRI
Duloxetine, venlafaxine, milnacipran
0/–
Others
Bupropion
0/–
Mirtazapine
++
Lithium
+++
Antipsychotic agents
Clozapine
+++
Olanzapine
+++
Risperidone
++
Quetiapine
++
Aripiprazole
0/+
Ziprasidone
0/+
Haloperidol
+++
Pherphenazine
+/–
Anti-epileptics
Valproic acid
++ to +++
Carbamazepine
+ to ++(+)
Gabapentin
+ to +++
Steroid hormones
Oral corticosteroids (prednisone)
+ to ++(+)
Hormone therapy – contraception (DMPA)
+ to ++
Miscellaneous agents
Beta-adrenergic blockers (propanolol, metoprolol, atenolol)
+ to ++
+++ significant, ++ moderate, + slight weight gain; 0/+ slightly increasing
effect; +/– inconsistent data; 0/– minimal to no weight reduction;
– – moderate; – – – significant weight loss.
From obesity to diabetes
When diet-derived fat intake is increased, fat storage occurs within and
around other tissues and organs including the liver, skeletal muscle and
β
-cells, which under normal conditions do not store lipids. This in turn
results in excessive mitochondrial production of toxic reactive lipid species
that cause organ-specific oxidative damage and cellular dysfunction, leading
progressively to the development of insulin resistance, impaired glucose
metabolism and finally to diabetes. The accumulation of toxic metabolites
within the
β
-cells in particular affects insulin secretion and enhances
β
-cell
apoptosis.
6
Obesity-associated inflammation may be due to increased circulatory
pro-inflammatory cytokines, decreased anti inflammatory cytokines, reactive
oxygen species, increased lipids, free fatty acids, endoplasmic reticulum stress,
mitochondrial dysfunction and activation of diverse signalling cascades. In the
initial stages, inflammatory responses are triggered by a pro-inflammatory
imbalance in the brain and adipose tissue, leading to dysregulated insulin
and leptin sensitivity. Over time, ectopic lipids accumulate in the muscle,
liver and blood vessels, leading to activated tissue leukocytes, organ-specific
diseases and exacerbated systemic insulin resistance. Obesity also induces
inflammation via lipopolysaccharide-related endotoxaemia involving gut
microbiota. Inflammation is characterised by an upsurge of T-lymphocytes
and macrophages secreting pro-inflammatory cytokines that act to
perpetuate systemic inflammation and induce insulin resistance. Increasing
evidence suggests that chronic low-grade inflammation in adipose tissue
affects the pathogenesis of diabetes in obese patients.
6