ISSN: 2249-8648 (Online)
Research & Reviews: A Journal of
Medicine
ISSN: 2348-7917 (Print)
Volume 13, Issue 2, 2023
DOI (Journal): 10.37591/RRJoM
STM JOURNALS
http://medicaljournals.stmjournals.in/index.php/RRJoM/index
Research
RRJoM
Limitations to Therapeutic Approaches to T2DM in Light
of Different HbA1C Values Suggested by Different
Scientific Associations: A Review
Ravishankar Polisetty1, Teja Sree Bitla2,*, Purna Divya Singanamala3, Shaik Aminabee4
Abstract
The present article provided a comprehensive review of international and national guidelines for
managing Type-2 diabetes, with a focus on personalized treatment strategies. It discussed the
recommended glycated haemoglobin targets and the initial treatment approach involving lifestyle
modifications and the use of metformin. The present article underlined the necessity for treatment
intensification due to the progressive nature of type-2 diabetes. It also emphasized the complexity of
selecting additional antidiabetic medications, which considers various patient-specific factors and the
therapeutic characteristics of the drugs. Despite the presence of extensive treatment choices and
established guidelines, it was emphasized that a considerable number of patients were unable to attain
favourable metabolic control. The present article concluded with a discussion on the glucose utilization
of different organs in conscious rat’s post-endotoxin treatment, illustrating the differential responses
of various organs.
Keywords: Diabetic, HbA1C, hyperglycaemia, antidiabetic pharmacotherapy, insulin
INTRODUCTION
Emerging global guidelines on diabetes management, which propose a revised approach to longestablished norms, have sparked a significant dispute among healthcare professionals. The principal
concern of Indian medical practitioners is that these guidelines, which suggest a relaxation of blood
glucose targets, may exacerbate complications in
diabetics and create ambiguity in treatment
*Author for Correspondence
protocols. It is widely suggested that these new
Teja Sree Bitla
E-mail: tejasree.b@sgprs.com
directives be disregarded in favour of existing ones
more suitable to the Indian demographics.
1
CEO, Founder, Department of Metabolic Syndrome, Sai
Ganga Panakeia Private Limited, Hyderabad, Telangana, India
2
Executive Secretary to CEO (Academics and IP), Senior
Clinical and Research Assistant, Department of Metabolic
Syndrome, Sai Ganga Panakeia Private Limited, Hyderabad,
Telangana, India
3
Executive Secretary to CEO (Research), Senior Clinical and
Research Assistant, Department of Metabolic Syndrome, Sai
Ganga Panakeia Private Limited, Hyderabad, Telangana, India
4
Professer, Department of Pharmacology, V. V. Institute of
Pharmaceutical Sciences, Gudlavalleru, Krishna District,
Andhra Pradesh, India
Received Date: August 07, 2023
Accepted Date: August 15, 2023
Published Date: September 06, 2023
Citation: Ravishankar Polisetty, Teja Sree Bitla, Purna Divya
Singanamala, Shaik Aminabee. Limitations to Therapeutic
Approaches to T2DM in Light of Different HbA1C Values
Suggested by Different Scientific Associations: A Review.
Research & Reviews: A Journal of Medicine. 2023; 13(2):
13–26p.
© STM Journals 2023. All Rights Reserved
Brief Overview on HbA1c Values
The epicentre of the controversy is the proposed
relaxation of the long-term blood glucose target,
Haemoglobin A1c (HbA1c) or glycated
haemoglobin. HbA1c, obtained via a blood test,
provides an estimate of a person's average blood
sugar level over the previous months. An HbA1c of
6.5% is traditionally indicative of diabetes. The
American College of Physicians, a body of internal
medicine physicians, recently proposed in the
Annals of Internal Medicine that clinicians aim for
an HbA1c level between 7% and 8% for most
patients with Type 2 diabetes (T2D). The
conventional target range of 6.5% to 7%, which has
been followed for a long time, is contradictory to
this finding.
13
Limitations to Therapeutic Approach to T2DM
Polisetty et al.
Such recommendations have ignited a divide in medical opinions, with some factions expressing
staunch opposition. They argue that diabetes in India manifests more aggressively, leading to complex
complications. These critics believe that the lower blood sugar target should not be obligatory but rather
adapted to individual patient needs. They argue for the continued adherence to the advice of Indian
advisory bodies, which are more attuned to Indian cases [1].
According to Dr Anoop Misra, who serves as the Chairperson at Fortis-C-DOC in Delhi, Indian
medical practitioners frequently follow guidelines that are rooted in the United States. Consequently,
he anticipated that the American College of Physicians' recommendations might significantly impact
diabetes management in India. Relaxing blood sugar control could potentially heighten the already high
burden of diabetic complications in India. Therefore, it is advised to disregard these new
recommendations and adhere to the previous HbA1c control limit of 7%.
The argument for this non-standardized approach to guidelines is reinforced by significant disparities
in lifestyle, physiology, and dietary habits between regions. Emphasis is placed on the fact that Asian
Indians, who frequently experience diabetes, exhibits insulin resistance and distinct phenotypes in
contrast to western populations. Consequently, the North American or European guidance is deemed
not applicable to Asian geographies [2]. It is also noted that Asians consume more carbohydrates,
resulting in a different response to medication and dosages.
Moreover, the Research Society for the Study of Diabetes in India (RSSDI) recommended the use of
pharmacotherapy in conjunction with lifestyle modification therapies to achieve an HbA1c target of
less than 7%. RSSDI, with over 7,000 members, is Asia's largest organization of physicians specializing
in diabetes care. The initial publication of these guidelines was in the year 2015, followed by an update
in January 2018, incorporating evidence specific to India [3].
Findings from the India Diabetes Care Index survey, carried out by the Novo Nordisk Education
Foundation, demonstrated that the average HbA1c levels in Hyderabad saw a rise from 8.30% to 8.49%
during the initial quarter of the year. This aligns with the earlier cautionary statement issued by
diabetologists at the start of the lockdown. The demographic data from this assessment were from
individuals averaging 52 years old, with a nearly even gender distribution (52% male, 48% female) [4].
This collective's typical rising blood sugar measurement was 172 mg/dl and afterwards the glucose level
was 244 mg/dl [5].
Table 1. Comparative analysis of various methods for lowering HbA1c for patients with Type-2
diabetes.
Year
Group
Source
HbA1c %
Caveats/Notes
2005
Clinical
Guidelines
Task Force [6]
IDF Global
> 6.5
If feasible and easily attained; raise if
hypoglycaemia risk
2009
Consensus Group [7]
ADA/EASD
> 7.0
Follows ADA Standards of Care 2008
2012
Clinical
Guidelines
Task Force
IDF Global
> 7.0
Lower if easily achieved; higher if
comorbidities or unfeasible
2013
Consensus Statement
AACE
> 6.5
Unless unsafe or inappropriate
2012/2015
Position Statement [8]
ADA/EASD
> 7.0
More and less stringent individualization
emphasized
2018
Consensus Report
ADA/EASD
>7.0
Personalized on preferences, risk of
adverse events, frailty, comorbidity
AACE, American Association of Clinical Endocrinologists; ACP, American College of Physicians; ADA: American
Diabetes Association; IDF, International Diabetes Federation; A project of WHO Europe & IDF Europe. Published
and revised every year, although this standard remains the same. Revisions made later in cooperation with the
American College of Endocrinologists did not modify the aim.
These findings were substantiated by local experts who reported that patients who had previously
maintained controlled blood sugar levels are now grappling with imbalance (Table 1). Observations
© STM Journals 2023. All Rights Reserved
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Research & Reviews: A Journal of Medicine
Volume 13, Issue 2
ISSN: 2249-8648 (Online), ISSN: 2348-7917 (Print)
indicated that around 60%–65% of patients experienced a rise in their blood sugar levels. The reported
causes for this escalation included reduced physical activity due to lockdown measures, heightened
stress and concerns related to COVID-19, as well as challenges in accessing insulin.
Furthermore, this upward trend in HbA1c levels coincides with medical studies linking higher risk
for severe complications from COVID-19 to uncontrolled diabetes. It is, therefore, imperative to follow
a healthy regime, undertake indoor physical exercises, and adhere to prescribed medications to maintain
blood glucose levels within the desired range.
Additionally, there are concerns that many senior citizens may be incorrectly classified as diabetic or
pre-diabetic based on the elevated levels of blood sugar reflected in the HbA1c test, which is a standard
test for diabetes. Consequently, there have been calls for age-specific cut-offs for the test to minimize
the risks of unnecessary treatment and associated side effects.
A pan-India study published in Acta Dibetologica has shown that HbA1c levels increase with age in
non-diabetic individuals, indicating that a uniform standard may not be suitable for all adults. Hence, it
is advisable for laboratories to provide age-adjusted reference ranges for their laboratory tests. This step
can help prevent unwarranted treatments in older individuals, subsequently reducing the potential for
severe medication-related side effects [9].
Adverse Consequences of Antidiabetic Pharmacotherapy
Biguanides, sulfonylureas, meglitinides, thiazolidinediones (TZDs), dipeptidyl peptidase 4 (DPP-4)
inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and α-glucosidase inhibitors are just a
few of the groups of pharmaceuticals available for dietary hypoglycemic treatments. When the HbA1C
levels escalate to 7.5% under medication or if the initial HbA1C level equals or surpasses 9%,
therapeutic regimens may require modification to encompass dual oral agents or insulin. While these
therapies are generally weight-independent, medications such as liraglutide may showcase amplified
benefits in obese patients relative to lean individuals suffering from diabetes [10, 11].
Biguanides
Tracing back to the medieval period, the first discovery of biguanides for diabetic management was
derived from Galega officinalis, a plant species known to contain guanidine, galegine, and biguanides,
all of which possess glucose-reducing properties. Metformin, a representative biguanide, is recognized
as the primary choice of oral antidiabetic drug for treating T2DM across all demographic groups. This
compound promotes hepatic glucose uptake and impedes gluconeogenesis via intricate effects on
mitochondrial enzymes [11], through the activation of adenosine monophosphate-activated protein
kinase in the liver. Its clinical safety profile is sound, with mild side effects, low hypoglycemic risk,
and minimal weight gain propensity.
Metformin has been validated to slow T2DM progression, decrease complication likelihood, and
reduce patient mortality through diminishing hepatic gluconeogenesis and enhancing insulin sensitivity
in peripheral tissues. Additionally, it regulates lipid plasma levels through a peroxisome proliferatoractivated receptor (PPAR)-α pathway, offering protective effects against cardiovascular diseases. It
might also curtail food intake by inducing glucagon-like peptide-1 (GLP-1) mediated incretin-like
actions, potentially leading to modest weight reduction in individuals at risk of diabetes with excessive
body weight.
After oral administration, metformin undergoes absorption via organic cation transporters and
remains unmetabolized, spreading widely into various tissues such as the intestine, liver, and kidney.
The primary elimination route is renal [12]. Renal insufficiency, especially when the glomerular
filtration rate (GFR) falls below 30 ml/min/1.73 m2, is a contraindication for metformin. In case of
significant GFR reduction, metformin dosage should be adjusted. Patients should be instructed to
© STM Journals 2023. All Rights Reserved
15
Limitations to Therapeutic Approach to T2DM
Polisetty et al.
discontinue the medication, in case of nausea, vomiting, or dehydration from any cause (risk factors for
ketoacidosis). Renal function must be evaluated before initiating this therapy [13].
Despite its excellent safety profile, metformin may instigate gastrointestinal disturbances in
approximately 30% of patients shortly after commencement. Gradual introduction of metformin at
lower doses generally enhances tolerance. Extended-release formulations are known to cause less
gastrointestinal side effects. A rare yet severe adverse event related to metformin use is lactic acidosis,
predominantly in patients with severe renal insufficiency. Another potential concern arises when
diabetes progression leads to a reduction in metformin’s efficacy, which occurs predominantly when
there is sufficient insulin production. However, metformin’s efficacy diminishes in the phase of β-cell
failure resulting in a type 1 phenotype [14].
Deficiencies of Vitamin B12 and folic acid are potential side effects of metformin that necessitate
monitoring, particularly in elderly patients. In situations where patients are intolerant to or have
contraindications for metformin, alternative categories of oral antidiabetic medications could be
contemplated for initial treatment. However, it is important to note that there are limited clinical trials
directly comparing supplementary therapies to the use of metformin alone. A meta-analysis suggested
that the introduction of each new class of non-insulin medications in addition to initial therapy reduces
A1C by around 0.9–1.1%. Ongoing research called the "Glycemia Reduction Approaches in Diabetes:
A Comparative Effectiveness Study" (GRADE) is examining the impact of four primary drug categories
on glycaemic control and other outcomes over a span of four years [15]. Although the introduction of
oral agents to supplement metformin therapy in gestational diabetes is desirable, current US Food &
Drug Administration (FDA) regulations do not permit this.
Incretin Mimetics
The contrast in insulin release between oral glucose consumption and intravenous glucose delivery
is termed as the incretin effect. This effect contributes to 50–70% of the total insulin secretion after
ingesting oral glucose. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP, or incretin)—
two organically produced steroids—are essential for sustaining control of blood sugar. However, their
longevity is brief, as they are rapidly broken down by DPP-4 inhibitors within about 90 sec. In
individuals with T2DM, the incretin effect is often reduced or entirely absent, particularly the insulinstimulating function of GIP. Incretins slow gastric emptying and promote weight loss, rendering them
increasingly suitable for the treatment of "diabesity" (diabetes + obesity) [16].
Sulfonylureas
Sulfonylureas, one of the earliest classes of antidiabetic drugs, function by inducing the secretion of
insulin by pancreatic beta cells. Despite being overtaken by newer therapies, these drugs remain in use
due to their efficacy and cost-effectiveness. Sulfonylureas include glibenclamide, glipizide, and
gliclazide. By binding to the SUR1 receptor, they promote the closure of potassium channels on the
surface of beta cells, leading to cell depolarization, calcium influx, and insulin secretion. It is crucial to
consider that sulfonylureas may contribute to weight gain, and they carry a heightened risk of
hypoglycemia, especially in the elderly and those with impaired renal function.
Thiazolidinediones (TZDs)
TZDs, which include rosiglitazone and pioglitazone, function by activating the peroxisome
proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor that controls the transcription of
various genes involved in glucose and lipid metabolism, adipocyte differentiation, and insulin signaling.
Despite their strong efficacy, the use of TZDs has been limited due to concerns about potential side
effects. These include fluid retention leading to heart failure, bone fractures, and a potential, albeit
debatable, risk of bladder cancer with pioglitazone use.
Meglitinides
Meglitinides, which include repaglinide and nateglinide, are insulin secretagogues like sulfonylureas
but differ in their binding site and pharmacokinetics. They act rapidly and have a short duration of action,
© STM Journals 2023. All Rights Reserved
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Research & Reviews: A Journal of Medicine
Volume 13, Issue 2
ISSN: 2249-8648 (Online), ISSN: 2348-7917 (Print)
making them suitable for controlling postprandial blood glucose levels. Potential side effects include
weight gain and hypoglycaemia, though the risk of hypoglycaemia is less than that of sulfonylureas.
α-Glucosidase Inhibitors
α-Glucosidase inhibitors, such as acarbose, retard the digestion and absorption of carbohydrates in
the small intestine, thereby reducing the postprandial rise in blood glucose. These medications are
generally well tolerated; nevertheless, individuals might experience gastrointestinal adverse effects
such as flatulence, diarrhoea, and abdominal discomfort.
In conclusion, a myriad of antidiabetic drugs is available, each with distinct mechanisms of action
and side-effect profiles. Their judicious use, with attention to patient-specific factors such as age,
comorbidities, and risk of side effects, is essential for optimizing glycemic control and reducing the
burden of diabetes complications. Furthermore, the constant evolution in the understanding of T2DM
pathophysiology is poised to provide new therapeutic targets and drug classes in the future, thereby
refining and individualizing the management of T2DM.
Insulin
In instances where non-insulin monotherapy such as metformin at its highest tolerable dose fails to
achieve or maintain the A1C target for a period of three months, another oral agent, a GLP-1 receptor
agonist, or basal insulin may be added. Insulin therapy, either on its own or in combination with other
treatments, is suggested for patients newly diagnosed with T2DM who exhibit severe symptoms, such
as weight loss, ketosis, or hyperglycaemia symptoms like polyuria/polydipsia, or have notably high
blood glucose levels [≥300–350 mg/dl (16.7–19.4 mmol/L)] or A1C [≥10%–12%]. The progression and
treatment options of T2DM should be regularly and thoroughly explained to patients [17, 18].
Insulin therapy may become necessary for many patients with T2DM throughout the course of their
disease. If glycaemic targets are not being achieved, there should be no delay in initiating insulin
treatment. Healthcare providers should promote the use of insulin as a treatment in a non-judgmental,
empathetic, and non-punitive manner, ensuring adherence to treatment. The practice of self-monitoring
of blood glucose (SMBG) has shown notable enhancements in glycaemic control for individuals with
T2DM who are commencing insulin therapy. A crucial aspect involves closely and consistently
monitoring the patient, which facilitates dosage adjustments for attaining glycaemic targets and
preventing episodes of hypoglycemia [19].
The initial insulin regimen typically involves introducing basal insulin, with a starting dose of 10 U
or 0.1–0.2 U/kg, based on the severity of hyperglycaemia. This dose is commonly increased by 2–3 U
every 4–7 days until the desired glycemic target is achieved. If more than 0.5 U/kg of basal insulin is
necessary, it is advisable to consider an additional agent. Basal insulin is often combined with oral
metformin and potentially another non-insulin medication such as a DPP-4 or SGLT-2 inhibitor. Neutral
Protamine Hagedorn (NPH) insulin is cost-effective and carries a minimal risk of hypoglycemia in
individuals without any significant history. Modern, extended-release basal insulin analogs offer
improved pharmacodynamic profiles, delayed onset, longer duration of action, and reduced
hypoglycemic risk, albeit at a higher cost. U-500 regular and other concentrated initial insulin solutions
have nearly five times the potency of U-100 standard per sugar volume. The compositions of U-300
glargine and U-200 degludec are potent, ultra-long-acting formulations.
When basal insulin effectively manages fasting blood glucose but A1C levels persistently remain
above the desired target. Rapid-acting insulin analogs such as lispro, aspart, or glulisine can be
employed, administered just before meals, and necessitating glucose monitoring prior to meals and after
injections. Alternately, twice-daily prepared (or biphasic) synthetic insulin (such as 70/30 aspart mix,
75/25, or 50/50 lispro mix) might be administered to manage changes in preprandial blood glucose
levels. U-500 regular and other intensified basic insulin solutions have five times the potency of U-100
© STM Journals 2023. All Rights Reserved
17
Limitations to Therapeutic Approach to T2DM
Polisetty et al.
regular per insulin volume. The formulations U-300 glargine and U-200 degludec are powerful and
extremely long-acting. The current total insulin dosage can be calculated, with half of this amount
administered as basal and the remaining half during meals, divided equally across three meals. In
comparison to rapid-acting insulin analogs and premixed insulin analogs, conventional human insulin,
and normal NPH-Regular prepared preparations (70/30) are less expensive solutions. However, their
unpredictable pharmacodynamic profiles can render them inadequate for effectively addressing
postprandial glucose fluctuations [20–23].
On occasions, bolus insulin might be required alongside basal insulin. Rapid-acting analogs are
preferred for bolus administration due to their immediate action onset. Numerous administrations can
be avoided by using a pump for insulin (that is, continuous insulin delivery via subcutaneous infusion).
Often, both patients and healthcare providers are hesitant to escalate treatment due to concerns about
hypoglycaemia, complex treatment schedules, and the rise in daily injections. Therefore, a flexible
alternative for intensification is needed, considering the unique needs of each patient to achieve or
sustain glycemic targets. The optimal insulin regimen should imitate natural insulin release patterns
while ensuring effective glycemic control with minimal risk of hypoglycemia, weight gain, and reduced
daily injections.
Inhaled insulin (Technosphere insulin-inhalation device, Arezzo) is at present available for prandial
handling, although its dose range is constrained. The utilization of inhaled insulin mandates pulmonary
function assessments before and after commencing treatment, and it is not recommended for individuals
with asthma or other respiratory disorders.
Medication such as sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are routinely
stopped while using complex glucagon protocols exceeding baseline insulin. For individuals with
inadequate blood glucose control, particularly those necessitating increasing insulin doses, the addition
of TZDs (typically pioglitazone) or SGLT2 inhibitors might be considered as supplementary treatment
alongside insulin.
Administering insulin through injections can lead to fluctuations in weight, either resulting in gain or
loss. Insulin facilitates the cellular uptake of potassium, which could potentially lead to hypokalaemia.
There's a possibility of allergic reactions due to components in the insulin formulation. Additionally, the
use of insulin injections, coupled with drugs such as TZDs, has the potential to trigger cardiac failure.
Stressful situations including illness, surgery, and trauma can impair blood sugar regulation and
increase the risk of developing diabetic ketoacidosis (DKA) or a non-kenotic hyperosmolar state, all of
which are serious illnesses that need to be treated right away. Deterioration in glycaemic control
mandates heightened blood glucose monitoring frequency within a hospital environment. Individuals
susceptible to ketosis must also undergo urine or blood ketone monitoring. If significant
hyperglycaemia is accompanied by ketosis, vomiting, or changes in mental state, hospitalization
becomes necessary. Patients managed with non-insulin treatments or solely medical nutrition therapy
might also necessitate insulin intervention. Patients must be thoroughly hydrated and infections should
be managed.
Without proper treatment, prolonged hyperglycaemia can lead to glucose toxicity, which can
progressively impair insulin secretion. Starting treatment with insulin is crucial to lessen the negative
effects of elevated blood sugar levels on the organ that produces insulin. Once consistent glycaemic
control is established, a gradual reduction of insulin and its substitution with oral medications can be
considered. In the management of T2DM, there comes a juncture where β-cell reserves deplete, leading
to a transition toward a pathophysiological state resembling type 1 diabetes (T1DM). Careful
monitoring can identify such states, at which point the necessity for continued insulin therapy can be
explained to patients.
© STM Journals 2023. All Rights Reserved
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Research & Reviews: A Journal of Medicine
Volume 13, Issue 2
ISSN: 2249-8648 (Online), ISSN: 2348-7917 (Print)
Weight Gain Can Pose a Barrier to T1DM
With the improvements in the formulations of insulin, there are now more options available for the
management of T1DM. Patients with T1DM have impaired insulin production and thus they need to be
given insulin. Multiple-dose insulin injections along with frequent self-monitoring of blood glucose
levels and carbohydrate counting can help to achieve the glycemic targets. However, it is critical to
offer customized care to the patients of T1DM.
Gestational Diabetes Mellitus (GDM)
Addressing gestational diabetes mellitus (GDM) is crucial to avert unfavourable consequences for
both the mother and the baby. Initial management of GDM primarily involves lifestyle interventions
encompassing modifications in diet, moderate physical activity, and weight management. When
lifestyle interventions do not achieve the desired glycaemic targets, pharmacological treatment is
required. The first-line pharmacological treatment for GDM is insulin. If insulin therapy does not result
in desired glycaemic control, adjunctive therapy with oral antidiabetic agents can be considered.
Type 2 Diabetes Mellitus
The treatment strategy for patients with T2DM should be personalized based on the patient's age,
comorbidities, and personal preferences. At the outset, treatment involves adopting lifestyle changes
including dietary adjustments, heightened physical activity, and weight reduction. If lifestyle
modifications prove insufficient in achieving the targeted glycemic control, it is appropriate to
commence pharmacological interventions. Pharmacological treatment can be initiated with metformin,
followed by the addition of other oral antidiabetic agents or insulin, depending on the patient's
glycaemic control. Insulin therapy can be initiated with basal insulin, followed by the addition of
prandial insulin, if needed.
For individuals diagnosed with T2DM, the primary treatment objective is to attain and sustain
glycemic control. If metformin alone is unable to lower the target A1C level for three months, it is
advised to add an additional oral diabetes medication, a GLP-1 receptor agonist, or basal insulin. In
cases of recently diagnosed T2DM with intense hyperglycaemia or symptomatic hyperglycaemia, the
initiation of insulin therapy is advised. It is important for healthcare providers to discuss the importance
of insulin therapy in the management of T2DM and to encourage adherence to therapy.
Patients with T2DM starting insulin therapy should put self-blood glucose monitoring first. Regular
monitoring is needed to adjust the insulin dose to achieve the target glycemic control and to prevent
hypoglycemia. Basal insulin is usually started at a dose of 10 units or 0.1–0.2 units/kg, depending on
the severity of hyperglycaemia. The dose is then adjusted by 2–3 units every 4–7 days until the target
glycemic control is achieved.
If the basal insulin dose is not enough to achieve the target glycemic control, prandial insulin can be
added. Prandial insulin can be administered using rapid-acting insulin analogs just before meals. Prior
to and following meals, it is advisable to monitor blood glucose levels. Alternatively, twice-daily
premixed insulin can be used.
Patients with T2DM may experience weight gain with insulin therapy. Pairing GLP-1 receptor
agonists with insulin can aid in addressing weight gain. It is important to change the injection site
regularly to prevent lipohypertrophy, which can affect insulin absorption and glycemic control.
It is important to monitor patients with T2DM regularly and adjust the treatment plan as needed to
achieve the desired glycemic control. Patients with T2DM who are not achieving the desired glycemic
control with oral antidiabetic agents may need to switch to insulin therapy. During stressful events such
as illness or surgery, blood glucose levels may increase, and additional insulin may be required. If
prolonged hyperglycaemia is not treated, it can lead to glucose toxicity, which can damage the pancreas
© STM Journals 2023. All Rights Reserved
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Limitations to Therapeutic Approach to T2DM
Polisetty et al.
and impair insulin secretion. Insulin therapy can help to reverse the effects of glucose toxicity and
improve glycemic control. Once the desired glycemic control is achieved, insulin therapy can be
gradually reduced and replaced with oral antidiabetic agents.
Patients with T2DM should be educated about the importance of glycemic control and adherence to
therapy. It is important for healthcare providers to discuss the potential side effects of insulin therapy,
such as hypoglycemia and weight gain, and to provide support to patients to manage these side effects.
Patients with T2DM should be encouraged to monitor their blood glucose levels regularly and to report
any changes to their healthcare provider. With the appropriate treatment and support, patients with
T2DM can achieve and maintain glycemic control and prevent complications.
Inhaled insulin is now available for use before meals. Nevertheless, there are restrictions to the dosing
range, and pulmonary function tests are necessary both before and after initiating the therapy. Individuals
with bronchitis or other respiratory conditions should not use diabetes that is intended to be inhaled.
When switching to more complex insulin regimens, it is normal to stop using additional oral diabetes
drugs such as sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists during the duration of
treatment with insulin. Other oral antidiabetic agents such as TZDs or SGLT2 inhibitors can be added
to insulin therapy, if needed to achieve the desired glycemic control.
Insulin injections can cause weight gain or weight loss, hypokalemia, and allergic reactions.
Subcutaneous injections of insulin can result in cardiac arrest when taken in conjunction with other
medications such as TZDs. Patients with T2DM who are receiving insulin therapy should be monitored
closely to manage these potential side effects and to adjust the insulin dose as needed.
Effective management of T2DM necessitates tailoring the approach to each patient's distinct
requirements and preferences. The treatment plan should be adjusted regularly based on the patient's
glycemic control and response to therapy. With the appropriate treatment and support, patients with
T2DM can achieve and maintain glycemic control and prevent complications or intestinal
disturbances [24–32].
Need For a Personalized Treatment Algorithm for T2DM
In recent times, there has been a concerning rise in the incidence of type 2 diabetes (T2D), primarily
attributed to the increased occurrence of the condition among adults between the ages of 20 and 79. If
prompt measures are not implemented, the International Diabetes Federation projects that the T2D
population could surge to 552 million by the year 2030 (Table 2) [25].
Type 2 diabetes (T2D) is characterized by a gradual advancement and intricate, multifaceted
pathophysiology, demanding a personalized evaluation and intervention for every individual afflicted
by the condition. Rapid attainment of glucose control and management of other risk factors such as
dyslipidemia and hypertension are essential to prevent diabetes-related complications in the long run
and to sustain the advantageous metabolic control effects over time, often referred to as the recognized
and legacy effect. In addition to insulin, nowadays we have a complex armamentarium of both oral and
injectable antidiabetic agents [25].
Each therapeutic drug class addresses different pathogenic mechanisms of T2D. Moreover, each class
encompasses pharmacological compounds with distinct pharmacodynamic and pharmacokinetic
attributes, resulting in specific advantages, disadvantages, constraints, and side effects. Additionally,
new drugs are in various stages of development within the current pharmacological classes for treating
T2D, and novel therapeutic categories are emerging. At the moment, there exist seven distinct categories
of antidiabetic medications, which include metformin within the biguanides class, sulfonylureas and
glinides under insulin secretagogues, α-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase
4 inhibitors and glucagon-like peptide 1 receptor agonists as part of incretin-based therapies, sodiumglucose cotransporter 2 inhibitors, and insulin.
© STM Journals 2023. All Rights Reserved
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Research & Reviews: A Journal of Medicine
Volume 13, Issue 2
ISSN: 2249-8648 (Online), ISSN: 2348-7917 (Print)
Table 2. Treatment approaches of diabetes mellitus.
Class of
Representative Mechanism HbA1C Risk of Effect Metabolic Cardiovas
Other
antidiabetic
agents
of action reduction hypogly on body alterations
cular
adverse
medication (route
(%)
cemia weight
benefit
effects/
of administration)
and risk additional
comments
Biguanide (o)
Metformin
Insulin
1–2
None
Mild
Lactic
Decreased Vitamin
sensitizes;
weight acidosis is the risk of B12
Numerous
loss due an
myocardial deficiency,
effects
on
to
exceptionall infarction which may
inhibition of
anorectic y infrequent by 39% and cause
hepatic
effect
occurrence. coronary anemia and
glucose
It has the fatalities by neuropathy
production
potential to 50%
(risk
in
induce
according elderly)
nausea,
to
the Very safe
vomiting, or UKPDS
drug
but
diarrhea
study.
stop
upon
metformin,
introduction,
if
which could
creatinine
lead to shifts
>1.5 mg/dl
in
in
males
electrolytes
and
or pH levels.
>1.4 mg/dl
in females.
DPP-IV inhibitor Sitagliptin
Inhibition of 0.5–0.8
Low
Long-term Pancreatitis
(o)
degradation
trials
to ,
of GLP
assess CV Upper RTI
Saxagliptin
risk;
decreases
postprandia
l lipemia;
however,
may cause
CHF
by
degradatio
n of BNP
SGLT2 inhibitor Canagliflozin
Glucosuria
Low
Positive
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(o)
due
to
CV effect is (rare)
blocking
due
to Genital
Dapagliflozin
(90%)
of
reduction mycosis
of sodium Bone
Empagliflozin glucose
reabsorption
and
uric fractures
in
renal
acid
PCT;
absorption
insulinand
independent
reduction
mechanism
of
blood
of action
pressure
Insulin (p)
Short-acting
Activation 1–2.5
Promine Weight
HF if used Lipoatroph
of
insulin
nt
gain
in
y
and
receptors
combinatio lipohypertr
and
n with TZD ophy
at
downstream
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of
signaling in
injection
Regular
(R) multiple
Allergy to
(Humulin
R, sensitive
injection
tissues
Novolin R)
component
s
Intermediate
Levemir
Food and
Drug
© STM Journals 2023. All Rights Reserved
21
Limitations to Therapeutic Approach to T2DM
Polisetty et al.
Administra
tion
approved
for
gestational
diabetes
mellitus
GLP-1 agonists (p) Exenatide
Increased
0.5–1.5
No (risk Weight
Reduce CV Nausea,
insulin
if used in loss
risk
vomiting,
secretion,
combina
pancreatitis
decreased
tion with
, C cell
glucagon,
SU)
tumor of
delayed
thyroid
gastric
(contraindi
emptying,
cated
in
increased
MEN type
satiety
2)
SU (o)
Glimepiride
Insulin
1–2
Promine Weight
Increased Use betasecretion
nt
gain
CV disease blockers
(severe
risk,
with
in renal
mainly due caution
failure)
to
hypoglyce
mia
TZD (o)
Rosiglitazone True insulin 0.5–1.4
Weight
Cardiac
Bladder
sensitizer
gain
failure,
cancer;
Pioglitazone
pedal
fractures
edema
DPP-IV Dipeptidyl peptidase 4; GLP glucagon-like peptide; CV cardiovascular; RTI respiratory tract infection; BNP B-type
Natriuretic peptide; CHF congestive heart failure; TZD thiazolidinediones; PCT proximal convoluted tubule; SGLT-2
Sodium-glucose cotransporter; MEN multiple endocrine neoplasia type 2; HF heart failure.
The international and global best practice guidelines for managing T2DM suggest an ideal HbA1c
target, such as less than 7%, as put forward by the 2012 American Diabetes Association and the
European Association for the Study of Diabetes. However, this target should be personalized for each
patient. Lifestyle changes are recommended initially, with metformin added if necessary either at the
outset or when lifestyle changes fail to achieve the target HbA1c.
T2D is a progressive condition, and so it's likely that the metabolic control achieved initially will
worsen over time, necessitating more intensive treatment. If metformin therapy fails, current guidelines
advise the introduction of a second, and then a third drug, chosen from a range of different classes,
considering factors such as their mechanisms of action, efficacy, long-term effects, glycemic impacts,
additional effects beyond controlling blood sugar, safety considerations including not just
hypoglycemia and weight gain, simplicity of use, and cost.
The choice of additional antidiabetic medications can be complex, taking into account various
patient-specific factors such as age, duration of diabetes, presence of diabetes-related microvascular
and macrovascular complications, other illnesses such as heart disease or kidney disease, risk of
hypoglycemia, cognitive and socio-economic status, patient preferences, compliance with treatment,
and life expectancy. The "glycemic pattern" of the patient is also a key factor for achieving set glycemic
targets. Unfortunately, the joint declaration of the American Diabetes Association and the European
Association for the Study of Diabetes in 2012 acknowledges that not all conceivable combinations of
medications possess strong endorsement from randomized controlled trials. This makes treatment
decisions challenging for many healthcare professionals [31].
While diabetologists and endocrinologists are the primary specialists managing T2D, other doctors
and general practitioners also treat these patients. Hence, the guidelines are aimed at this broad
audience. Given the current scenario, it's unsurprising there's a pressing need for the implementation of
© STM Journals 2023. All Rights Reserved
22
Research & Reviews: A Journal of Medicine
Volume 13, Issue 2
ISSN: 2249-8648 (Online), ISSN: 2348-7917 (Print)
clinical practice guidelines as evidence-based algorithms. Yet, it's notable that, despite the availability
of comprehensive treatment options and guidelines for managing T2D, many patients still fail to achieve
good metabolic control.
Existing Guidelines
• List available treatment options for T2D, their mechanisms of action, pros, cons, and possible
combinations, thus presenting multiple options to practitioners.
• Set a general HbA1c target, with some recommending personalized targets.
• Indicate that the HbA1c level at the start of treatment doesn't usually impact treatment choices.
• Propose lifestyle adjustments and metformin as the primary steps in treatment; it's important to
note that not all conceivable combinations of suggested medications have sufficient evidence to
support their effectiveness after metformin proves ineffective.
• Prioritize cost when selecting medication, favouring sulfonylureas as a second-line treatment.
• Recommend starting insulin therapy using basal or premixed insulin, and less frequently with
rapid-acting insulin at meal times.
• Routine self-monitoring of blood glucose is not typically advised for patients with T2D who are
not undergoing insulin treatment.
• Advise evaluating the need for treatment intensification every 3–6 months.
As understanding of T2D treatment has evolved, so have the guidelines, updated in response to new
findings, criticism, and the need for a more practical, personalized approach. Other national guidelines
and algorithms have been developed in response to these needs.
The role of different organs in glucose consumption has been studied extensively. For example, in
vivo studies on conscious rats treated with endotoxin revealed that glucose uptake by various organs
was markedly increased at certain time points post-treatment. Organs like Liver and spleen rich in
mononuclear phagocytes showed a prolonged increase in Glucose uptake. However, the majority of the
increase in the overall body glucose utilization was due to larger tissues like skin, intestine, and muscle,
which exhibited a more moderate and temporary increase in glucose usage.
CONCLUSION
Managing T2DM is a complex endeavour requiring a personalized and multi-faceted approach. While
existing international and national guidelines provide a comprehensive roadmap for treatment, a
significant number of patients still struggle to achieve good metabolic control. This underscores the
need for a more nuanced and patient-specific strategy that considers not just the general medical
guidelines, but also factors in individual variables such as age, duration of diabetes, presence of
complications, other comorbidities, risk of hypoglycaemia, and socioeconomic status among others.
The therapeutic choice is further complicated by the range of options available and the need to balance
efficacy, safety, cost, and patient preference.
Moreover, not all possible drug combinations are supported by evidence from randomized controlled
trials, which further adds to the challenge faced by clinicians. This underlines the critical need for
further research and the development of evidence-based algorithms to aid clinical decision-making.
The present article also highlights the contribution of various organs in glucose consumption, a
subject that opens avenues for further research. Understanding the role of different organs in glucose
metabolism could yield valuable insights into the systemic impact of T2DM and may guide the
development of more targeted treatment strategies.
In conclusion, managing T2DM requires a deep understanding of the disease, careful consideration
of the patient’s individual circumstances, and the ability to navigate the complexities of treatment
options. To improve patient outcomes, there is a pressing need for more research to support evidence© STM Journals 2023. All Rights Reserved
23
Limitations to Therapeutic Approach to T2DM
Polisetty et al.
based decision-making, a greater focus on patient education and engagement, and the development of
more personalized treatment approaches. The exploration of glucose utilization across different organs
also presents exciting opportunities for furthering our understanding of this complex disease and its
systemic effects [32].
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