Clinical Review of Antidiabetic Drugs: implications for Type 2 Diabetes Mellitus Management

Sahil Nivangune, Shradha Singhi  , Shravani Kulkarni, Abhijeet Satpute , Vedanti Walzade , Prathmesh Kadam ,

doi:10.5281/zenodo.14993126

Review Paper | Open Access
Volume 03 | Issue 03 | Article Id IJPS/250302265

Clinical Review of Antidiabetic Drugs: implications for Type 2 Diabetes Mellitus Management
Sahil Nivangune* Shradha Singhi Shravani Kulkarni Abhijeet Satpute Vedanti Walzade Prathmesh Kadam
^1,2,4,5,6Bharati Vidyapeeth (Deemed to be University) Poona College of Pharmacy, Erandwane, Pune, Maharashtra
³Vishwakarma University, University in Pune, Maharashtra

Abstract

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance, impaired insulin secretion, and elevated blood glucose levels. Effective management of T2DM is critical to reducing its associated complications, including cardiovascular disease, nephropathy, neuropathy, and retinopathy. This review examines the pharmacological agents currently available for T2DM management, including their mechanisms of action, efficacy, safety profiles, and potential implications for clinical practice. Classes of antidiabetic drugs discussed include insulin, sulfonylureas, meglitinides, biguanides (e.g., metformin), thiazolidinediones, alpha-glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Emerging therapies and combination regimens are also highlighted, with a focus on personalized treatment strategies that consider patient-specific factors such as age, comorbidities, and risk of adverse effects. By providing an updated understanding of antidiabetic agents, this review aims to guide healthcare professionals in optimizing T2DM management and improving patient outcomes.

Keywords

diabetes, clinical management, chronic, insulin, primary care, Type 2 Diabetes Mellitus, Antidiabetic drugs

Introduction

Diabetes mellitus (DM) is a complex chronic illness associated with a state of high blood glucose level, or hyperglycemia, occurring from deficiencies in insulin secretion, action, or both. The chronic metabolic imbalance associated with this disease puts patients at high risk for long-term macro- and microvascular complications, which if not provided with high quality care, lead to frequent hospitalization and complications, including elevated risk for cardiovascular diseases (CVDs). The clinical diagnosis of diabetes is reliant on either one of the four plasma glucose (PG) criteria: elevated (i) fasting plasma glucose (FPG) (>126 mg/dL), (ii) 2 h PG during a 75-g oral glucose tolerance test (OGTT) (>200 mg/dL), (iii) random PG (>200 mg/dL) with classic signs and symptoms of hyperglycemia, or (iv) hemoglobin A1C level >6.5%. Recent American Diabetes Association (ADA) guidelines have advocated that no one test may be preferred over another for diagnosis. The recommendation is to test all adults beginning at age 45 years, regardless of body weight, and to test asymptomatic adults of any age who are overweight or obese, present with a diagnostic symptom, and have at least an additional risk factor for development of diabetes. Furthermore, a condition called prediabetes or impaired fasting glucose (IFG), in which the fasting blood glucose is raised more than normal but does not reach the threshold to be considered diabetes (110–126 mg/dL), predisposes patients to diabetes, insulin resistance, and higher risk of cardiovascular (CV) and neurological pathologies . Type 2 diabetes mellitus (T2DM) can co-occur with other medical conditions, such as gestational diabetes occurring during the second or third trimester of pregnancy or pancreatic disease associated with cystic fibrosis. T2DM may also be iatrogenically induced, e.g., by use of glucocorticoids in the inpatient setting or use of highly active antiretroviral agents like protease inhibitors and nucleoside reverse transcription inhibitors in HIV-positive individuals. Chemical diabetes or impaired glucose tolerance (IGT) may also develop with the use of thiazide diuretics, atypical antipsychotic agents, and statins. Type 2 diabetes mellitus is a common and increasingly prevalent disease and is thus a major public health concern worldwide. The International Diabetes Federation estimates that there are approximately 387 million people diagnosed with diabetes across the globe. According to Centers for Disease Control and Prevention, in 2012, 29.1 million adults, or 9.3% of the population, were identified with diabetes in the United States (US). Also in the same year, 86 million people had prediabetes condition and 15–30% of them developed into full-blown diabetes . In general, 1.4 million newly diagnosed cases in the US are being reported every year. If this trend continues, it is projected that in 2050 one in three Americans will have diabetes. Patients with diabetes have increased risk of serious health complications including myocardial infarction, stroke, kidney failure, vision loss, and premature death. Diabetes, with its associated side effects, remains the seventh leading cause of mortality in the US. The World Health Organization estimates that by 2030, mortality related to diabetes will double in number if not given deliberate attention. In addition, epidemiological studies report that diabetes causes more deaths in Americans every year compared to breast cancer and acquired immunodeficiency syndrome (AIDS) combined . The increasing trend in the incidence and prevalence of diabetes is worrisome and poses a great burden on medical costs and in our current healthcare system. The ADA has released a range of recommendations called Standards of Medical Care in Diabetes to improve diabetes out comes. The recommendations include cost-effective screening, diagnostic and therapeutic strategies to prevent, delay, or effectively manage T2DM and its life-threatening complications . Per recommendations of ADA and other organizations, modern approaches to diabetes care should involve a multidisciplinary team of health professionals working in tandem with the patient and the family. The primary aim of these approaches is to obtain optimal glycemic control through dietary and lifestyle modifications and appropriate medications along with regular blood glucose level monitoring. The burden of diabetes can be potentially reduced if the standard of care is implemented as well as patients’ compliance and participation is clinically implemented. The traditional presentations of T2DM occurring only in adults and type 1 diabetes mellitus (T1DM) only in children are not entirely correctly representative, as both diseases occur in both age groups. Occasionally, patients with T2DM may develop the morbid complication of diabetic ketoacidosis (DKA) . Children with T1DM typically present with polyuria and polydipsia and approximately one-third of them present with DKA, which may also be the first presenting feature . The onset of T1DM may be variable in adults, and they may not present with the classic symptoms that are seen in children. The true diagnosis may become apparent with disease progression. The heterogeneity of the presentations should be kept in mind while caring for the patient with T2DM. The scope of this review encompasses current clinical guide lines on the pharmacological management of T2DM.

Clinical diagnosis of type 2 diabetes

The clinical diagnosis of Type 2 Diabetes Mellitus (T2DM) is based on specific criteria established by organizations like the American Diabetes Association (ADA) and the World Health Organization (WHO). Diagnostic tests include the following, with specific cut-off values:

1. Fasting Plasma Glucose (FPG) Test

Diagnostic threshold: ≥126 mg/dL (7.0 mmol/L) after an overnight fast (no caloric intake for at least 8 hours).

2. Oral Glucose Tolerance Test (OGTT)

Diagnostic threshold: ≥200 mg/dL (11.1 mmol/L) 2 hours after a 75g glucose load.

3. Hemoglobin A1c (HbA1c)

Diagnostic threshold: ≥6.5%.
Reflects average blood glucose levels over the past 2–3 months.

4. Random Plasma Glucose (RPG) Test

Diagnostic threshold: ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia (e.g., polyuria, polydipsia, unexplained weight loss) or a hyperglycemic crisis.

Clinical management of Type 2 Diabetes

Comprehensive care for a patient with diabetes requires an initial evaluation of the patient’s risk factors, the presence or absence of diabetes complications, and initial review of previous treatments . This will enable the healthcare providers to optimally manage patients with either prediabetes or diabetes. The cornerstones of diabetes management include lifestyle intervention along with pharmacological therapy and routine blood glucose monitoring.

Lifestyle Measures

Clinical trials have shown that lifestyle modifications are cost effective in preventing or delaying the onset of diabetes, with approximately 58% reduction in risk in 3 years . It is highly recommended by the ADA that patients with IGT, IFG or HbA1C level of 5.7–6.4% be counseled on lifestyle changes such as diet and exercise. On the other hand, for patients who are already diagnosed with diabetes, nutrition advice provided by a registered dietitian is recommended. A goal of moderate weight loss (≈7% of body weight) is an important component in the prevention and treatment of diabetes, as it can improve blood glucose levels, and can also positively impact blood pressure and cholesterol levels. Weight loss can be achieved through a healthy balanced diet, with control of total calories and free carbohydrates. However, for patients with diabetes adhering to a low carbohydrate diet, they should be informed on possible side effects such as hypo glycemia, headache and constipation . Other studies have suggested consumption of complex dietary fiber and whole grains to improve glycemic control . Studies show that exercise can improve glycemic control (lower HbA1C level by 0.66%), with or without significant decrease in body weight, and improve the total well-being of patients. It is considered an integral part in the prevention and management of both prediabetes and diabetes. According to the U.S. Department of Health and Human Services, adults ≥18 years of age should do a minimum of 150 min/week of moderate intensity exercise (e.g., walking at a 15- to 20-min mile pace) or 75 min/week of vigorous physical activity (e.g., running, aerobics) spread over at least 3 days/week with no more than two consecutive days without exercise to achieve maximum benefits . For patients ≤18 years old, 60 min of physical activity every day is adequate. Other lifestyle measures that need to be considered in the treatment plan for patients with diabetes are moderate alcohol consumption (≤1 drink for women, ≤2 drinks/men) and reduction in sodium intake especially in patients with comorbidities such as hypertension, habitual tobacco use, and lacking immunizations (influenza, diphtheria, pertussis, tetanus, pneumococcal, and hepatitis B). Consumption of alcohol, especially in a fasted state, can precipitate life-threatening hypoglycemia and coma and should be explicitly counseled to patients during their visits . Moreover, patient education, counseling, and psychosocial support are very important to successfully combat the deleterious effects of diabetes.

Pharmacological Management

An “ominous octet” that leads to hyperglycemia, which occur in isolation or in combination, has been proposed for eight pathophysiological mechanisms underlying T2DM . These include (i) reduced insulin secretion from pancreatic β-cells, (ii) elevated glucagon secretion from pancreatic α cells, (iii) increased production of glucose in liver, (iv) neurotransmitter dysfunction and insulin resistance in the brain, (v) enhanced lipolysis, (vi) increased renal glucose reabsorption, (vii) reduced incretin effect in the small intestine, and (viii) impaired or diminished glucose uptake in peripheral tissues such as skeletal muscle, liver, and adipose tissue. Currently available glucose-lowering therapies target one or more of these key pathways. Good glycemic control remains the main foundation of managing T2DM. Such approaches play a vital role in preventing or delaying the onset and progression of diabetic complications. It is important that a patient-centered approach should be used to guide the choice of pharmacological agents. The factors to be considered include efficacy, cost, potential side effects, weight gain, comorbidities, hypoglycemia risk, and patient preferences. Pharmacological treatment of T2DM should be initiated when glycemic control is not achieved or if HbA1C rises to 6.5% after 2–3 months of lifestyle intervention. Not delaying treatment and motivating patients to initiate pharmacotherapy can considerably prevent the risk of the irreversible microvascular complications such as retinopathy and glomerular damage . Monotherapy with an oral medication should be started concomitantly with intensive lifestyle management. The major classes of oral antidiabetic medications include biguanides, sulfonylureas, meglitinide, thiazolidinedione (TZD), dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter (SGLT2) inhibitors, and α-glucosidase inhibitors. If the HbA1C level rises to 7.5% while on medication or if the initial HbA1C is ≥9%, combination therapy with two oral agents, or with insulin, may be considered .Though these medications may be used in all patients irrespective of their body weight, some medications like liraglutide may have distinct advantages in obese patients in comparison to lean diabetics . A schematic of currently approved medications for T2DM is summarized in Table 1

Biguanide

The discovery of biguanide and its derivatives for the management of diabetes started in the middle ages. Galega officinalis, a herbaceous plant, was found to contain guanidine, galegine, and biguanide, which decreased blood glucose levels. Metformin is a biguanide that is the main first-line oral drug of choice in the management of T2DM across all age groups. Metformin activates adenosine monophosphate-activated protein kinase in the liver, causing hepatic uptake of glucose and inhibiting gluconeogenesis through complex effects on the mitochondrial enzymes. Metformin is highly tolerated and has only mild side effects, low risk of hypoglycemia and low chances of weight gain. Metformin is shown to delay the progression of T2DM, reduce the risk of complications, and reduce mortality rates in patients by decreasing hepatic glucose synthesis (gluconeogenesis) and sensitizing peripheral tissues to insulin. Furthermore, it improves insulin sensitivity by activating insulin receptor expression and enhancing tyrosine kinase activity. Recent evidence also suggest that metformin lowers plasma lipid levels through a peroxisome proliferator-activated receptor (PPAR)-α pathway, which pre vents CVDs . Reduction of food intake possibly occurs by glucagon-like peptide-1 (GLP-1)-mediated incretin-like actions. Metformin may thus induce modest weight loss in overweight and obese individuals at risk for diabetes. Once ingested, metformin (with a half-life of approximately 5 h) is absorbed by organic cation transporters and remains unmetabolized in the body and is widely distributed into different tissues such as intestine, liver, and kidney. The primary route of elimination is via kidney. Metformin is contraindicated in patients with advanced stages of renal insufficiency, indicated by a glomerular filtration rate (GFR) <30 mL/min/1.73 m² . If metformin is used when GFR is significantly diminished, the dose should be reduced and patients should be advised to discontinue the medication if nausea, vomiting, and dehydration arises from any other cause (to prevent ketoacidosis). It is important to assess renal function prior to starting this medication. Metformin has an excellent safety profile, though may cause gastrointestinal disturbances including diarrhea, nausea, and dyspepsia in almost 30% of subjects after initiation. Introduction of metformin at low doses often improve tolerance. Extended release preparations seldom cause any gastrointestinal issues. Very rarely, metformin may cause lactic acidosis, mainly in subjects with severe renal insufficiency. Another potential problem arising from the use of metformin is the reduction in the drug's efficiency as diabetes progresses. Metformin is highly efficient when there is enough insulin production; however, when diabetes reaches the state of failure of ?-cells and resulting in a type 1 phenotype, metformin loses its efficacy. Metformin can cause vitamin B12 and folic acid deficiency .This needs to be monitored, especially in elderly patients. Though very rare, in patients with metformin intolerance or contraindications, an initial drug from other oral classes may be used. Although trials have compared dual therapy with metformin alone, few directly compare drugs as add-on therapy. A comparative effectiveness meta-analysis suggests that overall each new class of non-insulin medications introduced in addition to the initial therapy lowers AIC around 0.9-1.1%. An ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) has compared the effect of four major drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 analog, and basal insulin) over 4 years on glycemic control and other psychosocial, medical, and health economic outcomes . Though it will be a welcome development for introduction of oral agents for metformin for gestational diabetes, current FDA regulations do not support it.

Incretin Mimetics

Incretin effect is the difference in insulin secretory response from an oral glucose load in comparison to glucose administered intravenously. The incretin effect is responsible for 50–70% of total insulin secretion after oral glucose intake. The two naturally occurring incretin hormones that play important roles in the maintenance of glycemic control: glucose-dependent insulinotropic polypeptide (GIP, or incretin) and glucagon-like peptide (GLP-1); these peptides have a short half-life, as these are rapidly hydrolyzed by DPP-4 inhibitors within 1½ min. In patients with T2DM, the incretin effect is reduced or absent. In particular, the insulinotropic action of GIP is lost in patients with T2DM. Incretins decrease gastric emptying and causes weight loss. Because of impact on weight loss, these medications may find increasing use in diabesity. Targeting the incretin system has become an important therapeutic approach for treating T2DM. These two drug classes Incretin effect is the difference in insulin secretory response from an oral glucose load in comparison to glucose administered intravenously. The incretin effect is responsible for 50–70% of total insulin secretion after oral glucose intake.The two naturally occurring incretin hormones that play important roles in the maintenance of glycemic control: glucose-dependent insulinotropic polypeptide (GIP, or incretin) and glucagon-like peptide (GLP-1); these peptides have a short half-life, as these are rapidly hydrolyzed by DPP-4 inhibitors within 1½ min. In patients with T2DM, the incretin effect is reduced or absent. In particular, the insulinotropic action of GIP is lost in patients with T2DM. Incretins decrease gastric emptying and causes weight loss. Because of impact on weight loss, these medications may find increasing use in diabesity. Targeting the incretin system has become an important therapeutic approach for treating T2DM. These two drug classes include GLP-1 receptor agonists and DPP-4 inhibitors. Clinical data have revealed that these therapies improve glycemic control while reducing body weight (specifically, GLP-1 receptor ago nists) and systolic blood pressure in patients with T2DM .Furthermore, hypoglycemia is low (except when used in combi nation with a sulfonylurea) because of their glucose-dependent mechanism of action

Table no 1 Pharmacological agents for glycemic control.

Class of antidiabetic medication (route of administration)	Representative agents	Mechanism of action	T1/2 and metabolism	HbA1C reduction (%)	Risk of hypoglycemia	effect on body weight	Metabolic alterations	Cardiovascular (Cv) benefit and risk	Other adverse effects/ additional comments
Biguanide (o)	Metformin	Insulin sensitizer Numerous effects on inhibition of hepatic glucose production	5 h; unmetabolized, renal excretion	1–2	None	Mild weight loss due to anorectic effect	Lactic acidosis (very rare) May cause nausea/vomiting or diarrhea after introduction, which may result in electrolyte or pH alterations	Reduce MI by 39% and coronary deaths by 50% (UKPDS)	Vitamin B12 deficiency, which may cause anemia and neuropathy (risk in elderly) Very safe drug, but stop metformin if creatinine >1.5 mg/dL in males and >1.4 mg/dL in females
Dipeptidyl peptidase 4 (DPP-IV) inhibitor (o)	Sitagliptin Saxagliptin Upper RTI infection Vidagliptin Linagliptin Alogliptin	Inhibition of degradation of GLP	Excreted by kidneys (except linagliptin) (needs dose reduction in renal failure)	0.5–0.8	Low			Long-term trials to assess CV risk; decreases postprandial lipemia, however, may cause CHF by degradation of BNP	Pancreatitis Saxagliptin Upper RTI infection
Sodium-glucose cotransporter (SGLT2) inhibitor (o)	Canagliflozin Dapagliflozin Empagliflozin	Glucosuria due to blocking (90%) of glucose reabsorption in renal PCT; insulin independent mechanism of action			Low			Positive CV effect due to reduction of sodium and uric acid absorption and reduction of BP	Ketoacidosis (rare) Genital mycosis May increase LDLc Bone fractures
Insulin (p)	Short-acting Regular (R) (Humulin R, Novolin R) Intermediate NPH (N) Long-acting Insulin glargine (Lantus) Insulin detemir (Levemir) Insulin degludec (Tresiba) Rapid-acting Humalog (Lispro)	Activation of insulin receptors and downstream signaling in multiple sensitive tissues	30 min-1 r (onset of action) Peak 2–5 h Duration of action 8 h 1.5–4 h (onset of action) Peak 4–12 h Duration of action 24 h 0.8–4 h (onset of action) Peak minimal Duration of action 24 h 10–30 min (onset of action)	1–2.5	Prominent	Weight gain		HF if used in combination with thiazolidinediones (TZD)	Lipoatrophy and lipohypertrophy at sites of injection Allergy to injection components Levemir Food and Drug Administration -approved for gestational diabetes mellitus
	Novolog (Aspart) Glulisine (Apidra) Pre-mixed 75% insulin lispro protamine/25% insulin lispro (Humalog Mix 75/25) 50% insulin lispro protamine/50% insulin lispro (Humalog Mix 50/50) 70% insulin lispro protamine/30% insulin aspart (Novolog 70/30) 70% NPH insulin/30% regular		Peak 30 min–3 h Duration of action 3–5 h 5–15 min (onset of action) Peak dual Duration of action 10–16 h 30–60 min (onset of action) Peak dual Duration of action 10–16 h
GLP-1 agonists (p)	Liraglutide Exenatide Dulaglutide	Activate GLP1 receptor Increased insulin secretion, decreased glucagon, delayed gastric emptying, increased satiety	24 h 4–6 h (short acting) 7 days (long acting, extended release) 7 days	0.5–1.5	No [risk if used in combination with sulfonylureas (SU)]	Weight loss		Reduce CV risk	Nausea, vomiting, pancreatitis, C cell tumor of thyroid (contraindicated in MEN type 2)
SU (o)	Glimepiride Glipizide Glyburide	Insulin secretion		1–2	Prominent (severe in renal failure)	Weight gain		Increased cardiovascular disease risk, mainly due to hypoglycemia	Use beta-blockers with caution
TZD (o)	Rosiglitazone Pioglitazone	True insulin sensitizer		0.5–1.4		Weight gain		Cardiac failure, pedal edema	Bladder cancer; fractures

GLP-1 Receptor Agonists

The currently GLP-1 receptor agonists available are exenatide and liraglutide. These drugs exhibit increased resistance to enzymatic degradation by DPP4. In young patients with recent diagnosis of T2DM, central obesity, and abnormal metabolic profile, one should consider treatment with GLP-1 analogs that would have a beneficial effect on weight loss and improve the metabolic dysfunction. GLP-1 analogs are contraindicated in renal failure.

Exenatide. Exenatide, an exendin-4 mimetic with 53% sequence homology to native GLP-1, is currently approved for T2DM treatment as a single drug in the US and in combination with met formin ± sulfonylurea. Because of its half-life of 2.4 h, exenatide is advised for twice-daily dosing. Treatment with 10 µg exenatide, as an add-on to metformin, resulted in significant weight loss (−2.8 kg) in comparison to patients previously treated with met formin alone. Exenatide is generally well tolerated, with mild-to moderate gastrointestinal effects being the most common adverse effect. Liraglutide. Liraglutide is a GLP-1 analog that shares 97% sequence identity to native GLP-1. Liraglutide has a long duration of action (24 h). Liraglutide causes 1.5% decrease in A1C in individuals with type 2 diabetes, when used as monotherapy or in combination with one or more selected oral antidiabetic drugs. Liraglutide decreases body weight; the greatest weight

Liraglutide. Liraglutide is a GLP-1 analog that shares 97% sequence identity to native GLP-1. Liraglutide has a long duration of action (24 h). Liraglutide causes 1.5% decrease in A1C in individuals with type 2 diabetes, when used as monotherapy or in combination with one or more selected oral antidiabetic drugs. Liraglutide decreases body weight; the greatest weight

loss resulted from treatment with liraglutide in combination with combined metformin/sulfonylurea (−3.24 kg with 1.8 mg liraglutide). Liraglutide also diminishes systolic pressure (mean decrease −2.1 to −6.7 mmHg) (37). Liraglutide is well tolerated, with only nausea and minor hypoglycemia (risk increased with use of sulfonylureas). Serum antibody formation was very low in patients treated with once-weekly GLP-1 receptor agonists. The formation of these antibodies did not decrease efficacy of their actions on blood glucose lowering.

DPP-4 Inhibitors

Dipeptidyl peptidase 4 inhibitors include sitagliptin, saxagliptin, vidagliptin, linagliptin, and alogliptin. These medications may be used as single therapy, or in addition with metformin, sulfonylurea, or TZD. This treatment is similar to the other oral antidiabetic drugs. The gliptins have not been reported to cause higher incidence of hypoglycemic events compared with controls. Dipeptidyl peptidase 4 inhibitors impact postprandial lipid levels. Treatment with vidagliptin for 4 weeks decreases post prandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal in T2DM patients who have previously not been exposed to these medications. In diabetic patients with coronary heart disease, it was demonstrated that treatment with sitagliptin improved cardiac function and coronary artery perfusion. T he three most commonly reported adverse reactions in clinical trials with gliptins were nasopharyngitis, upper respiratory tract infection, and headache. Acute pancreatitis was reported in a fraction of subjects taking sitagliptin or metformin and sitagliptin. An increased incidence of hypoglycemia was observed in the sulfonylurea treatment group. In the elderly, DPP-4 inhibitors lower blood glucose but have minimal effect on caloric intake and therefore less catabolic effect on muscle and total body protein mass. In decreased doses, DPP-4 inhibitors are considered safe in patients with moderate to severe renal failure.

SGLT2 Inhibitors

Sodium-glucose cotransporter inhibitors are new classes of glucosuric agents: canagliflozin, dapagliflozin, and empagliflozin. SGLT2 inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2. Because of glucose-independent mechanism of action, these drugs may be effective in advanced stages of T2DM when pan creatic β-cell reserves are permanently lost. These drugs provide modest weight loss and blood pressure reduction. Urinary tract infections leading to urosepsis and pyelonephritis, as well as genital mycosis, may occur with SGLT2 inhibitors. SGLT2 inhibitors may rarely cause ketoacidosis. Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have symptoms of ketoacidosis (frank nausea or vomiting, or even non-specific features like tiredness or abdominal discomfort).

Insulin

Insulin is a peptide hormone produced by the beta cells of the pancreas. It plays a crucial role in regulating blood glucose levels by facilitating glucose uptake into cells, particularly in muscle, liver, and adipose tissues. Insulin also promotes anabolic processes like glycogenesis and lipogenesis while inhibiting catabolic processes such as glycogenolysis and gluconeogenesis.

Mechanism of Action

Insulin binds to insulin receptors on cell surfaces, activating the tyrosine kinase pathway.
This activation triggers intracellular signaling cascades, including the phosphorylation of insulin receptor substrates (IRS).
These cascades promote the translocation of glucose transporter proteins (e.g., GLUT4) to the cell membrane, enabling glucose uptake.

Types of Insulin

Insulin formulations are categorized based on onset, peak, and duration of action:

Rapid-Acting (e.g., Insulin lispro, aspart): Onset in 5–20 minutes; lasts 3–5 hours. Used before meals.
Short-Acting (e.g., Regular insulin): Onset in 30–45 minutes; lasts 5–8 hours.
Intermediate-Acting (e.g., NPH insulin): Onset in 2 hours; peaks at 4–12 hours, lasting up to 24 hours.
Long-Acting (e.g., Insulin glargine): Onset in 1 hour; lasts up to 24 hours without a significant peak.
Ultra Long-Acting (e.g., Insulin degludec): Onset in 6 hours; lasts over 42 hours.

Clinical Uses

Type 1 Diabetes Mellitus: Insulin replacement is essential due to autoimmune destruction of beta cells.
Type 2 Diabetes Mellitus: Used when oral hypoglycemics and lifestyle modifications are insufficient.
Gestational Diabetes: Preferred for managing high blood glucose during pregnancy.
Other uses include managing diabetic ketoacidosis and hyperosmolar hyperglycemic states.

Adverse Effects

Hypoglycemia: The most common side effect, often caused by an imbalance between insulin dose and dietary intake.
Injection-Site Reactions: Including lipodystrophy, which can alter absorption.
Allergic Reactions: Rare, may occur due to additives in insulin preparations.
Weight Gain: A common effect due to the anabolic nature of insulin.

Sulfonylureas

Sulfonylureas lower blood glucose level by increasing insulin secretion in the pancreas by blocking the KATP channels. They also limit gluconeogenesis in the liver. Sulfonylureas decrease breakdown of lipids to fatty acids and reduce clearance of insulin in the liver

Mechanism of Action:

Sulfonylureas are oral hypoglycemic agents that stimulate insulin secretion from pancreatic beta cells. They act by binding to the sulfonylurea receptor (SUR1) on ATP-sensitive potassium channels in beta-cell membranes. This binding leads to closure of these channels, depolarization of the cell membrane, and subsequent opening of voltage-dependent calcium channels. The influx of calcium triggers the release of insulin.

Clinical Uses:

Type 2 Diabetes Mellitus (T2DM): Sulfonylureas are used primarily in patients with residual beta-cell function. They can be prescribed as monotherapy or combined with other antidiabetic drugs like metformin, DPP-4 inhibitors, or thiazolidinediones.
Specific Situations: They are sometimes used for managing steroid-induced hyperglycemia and in elderly patients with long-standing diabetes who have retained some beta-cell function.

Common Sulfonylureas:

First-generation: Tolbutamide, Chlorpropamide (rarely used now).
Second-generation: Glipizide, Glyburide (Glibenclamide), Gliclazide, Glimepiride (preferred for lower risk of prolonged hypoglycemia).

Advantages:

Effective in reducing blood glucose.
Relatively low cost.

Limitations and Adverse Effects:

Hypoglycemia: The most common side effect, especially with longer-acting agents or in older adults with impaired renal function.
Weight Gain: Due to increased insulin levels promoting fat storage.
Gastrointestinal Issues: Nausea, vomiting, or diarrhea may occur in some patients.
Cardiovascular Risks: Although debated, some sulfonylureas may influence cardiac ATP-sensitive potassium channels, raising concerns about potential adverse effects on the heart.
Other Risks: Rare allergic reactions or hemolytic anemia in individuals with G6PD deficiency.

Prescribing Considerations:

Start at low doses and titrate based on blood glucose monitoring.
Avoid use in patients with severe renal or hepatic impairment.
Prefer shorter-acting agents like gliclazide to minimize hypoglycemia risk in fasting states or with comorbid conditions.

Meglitinide

Meglitinides (repaglinide and nateglinide) are non-sulfonylurea secretagogues, which was approved as treatment for T2DM in 1997.

Meglitinides are a class of oral antidiabetic medications used in the management of Type 2 Diabetes Mellitus (T2DM). They act by stimulating insulin secretion from the pancreatic beta cells, specifically targeting the early phase of insulin release. Their effects are glucose-dependent, meaning they primarily act when blood glucose levels are elevated, which helps reduce the risk of severe hypoglycemia compared to some other agents.

Mechanism of Action

Meglitinides bind to a specific site on the ATP-sensitive potassium channels in pancreatic beta cells, causing depolarization. This triggers calcium influx and stimulates insulin secretion.
The two commonly used meglitinides are repaglinide and nateglinide.

Clinical Uses

Postprandial Glucose Control: These drugs are particularly effective at controlling blood sugar spikes after meals.
Adjunctive Therapy: Meglitinides are often used in patients for whom metformin is not suitable or as an add-on to other antidiabetic agents.

Administration

Taken orally before meals (typically 30 minutes prior) to coincide with glucose absorption from food.

Benefits

Rapid onset and short duration of action, allowing for flexible meal timing.
Lower risk of prolonged hypoglycemia compared to sulfonylureas.

Adverse Effects

Hypoglycemia: Mild and less frequent compared to sulfonylureas.
Weight Gain: A common concern in most studies.
Other Side Effects: Include headaches, gastrointestinal symptoms (nausea, diarrhea), and upper respiratory tract infections.

Limitations and Considerations

They are less commonly used than metformin or sulfonylureas due to their cost and requirement for multiple daily dosing.
Not suitable for patients with severe hepatic impairment due to their metabolism in the liver.

Efficacy

Repaglinide has shown a more substantial reduction in HbA1c (0.1% to 2.1%) compared to nateglinide (0.2% to 0.6%) in trials, with both drugs being comparable to metformin in glucose-lowering effects

Thiazolidinedione

Mechanism of Action:

Thiazolidinediones, also known as "glitazones," are oral antidiabetic agents that enhance insulin sensitivity. They primarily act as agonists of the peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor involved in regulating gene expression related to glucose and lipid metabolism. This activation improves insulin sensitivity in adipose tissue, skeletal muscle, and the liver, reducing insulin resistance a core abnormality in Type 2 Diabetes Mellitus (T2DM). TZDs also promote the differentiation of smaller, more insulin-sensitive adipocytes, decrease free fatty acid levels, and reduce inflammation linked to insulin resistance.

Examples of TZDs:

Pioglitazone
Rosiglitazone
(Note: Troglitazone was withdrawn due to hepatotoxicity.)

Clinical Uses:

Type 2 Diabetes Mellitus: TZDs are used to manage hyperglycemia in T2DM, especially in patients with significant insulin resistance.
Potential Pleiotropic Effects: Emerging evidence suggests benefits in improving lipid profiles, reducing inflammation, and possibly offering cardiovascular and neuroprotective effects.

Advantages:

Durable glycemic control, with reductions in HbA1c by 0.5%–1.5%.
Improvement in lipid profiles, particularly with pioglitazone, which raises HDL-C and reduces triglycerides.
Potential cardiovascular and anti-inflammatory benefits under investigation.

Limitations and Side Effects:

Weight Gain: Primarily due to fluid retention and fat redistribution.
Edema: Increased risk, especially when combined with insulin.
Heart Failure Risk: Use is contraindicated in patients with moderate-to-severe heart failure due to fluid retention risks.
Bone Fractures: Higher incidence, particularly in postmenopausal women.
Bladder Cancer: Long-term pioglitazone use has been associated with a small but notable increased risk of bladder cancer.
Liver Dysfunction: Though rare, liver enzymes should be monitored periodically during treatment.

Current Role in Therapy: While TZDs are not first-line treatments due to safety concerns, pioglitazone remains a viable option for patients with significant insulin resistance, especially those who might benefit from its cardiovascular or lipid-modulating effects. Their use is often considered in combination with metformin or other antidiabetic agents.

Other Glucose-Lowering Pharmacologic Agents

Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is a Food and Drug Administration (FDA)-approved therapy for use in adults with T1DM. Pramlintide induces weight loss and lowers insulin dose. Concurrent reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycemia. Other medications that may lower blood sugar include bromocriptine, alpha-glucosidase inhibitors like voglibose and acarbose, and bile acid sequestrants like colesevelam. It may be noted that metformin sequesters bile acids in intestinal lumen and thus has a lipid-lowering effect, also the same mechanism may contribute to gas production and gastrointestinal disturbances.

Pharmacologic Management of Diabetes Complications

Important components of the Standards of Medical Care in Diabetes involves taking care of complications of diabetes and comorbidities including hypertension, atherosclerotic cardio vascular disease (ASCVD), dyslipidemia, hypercoagulopathy, endothelial cell dysfunction, nephropathy, and retinopathy. CVD is the most important cause of morbidity and mortality in patients with diabetes. The currently recommended goal blood pressure is ≤140/80 for patients with diabetes and hypertension. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the preferred antihypertensive medication . Optimal blood pressure and blood glucose control can effectively delay the progression of nephropathy and retin opathy in these patients. Patients with existing CVD should be continuously managed with aspirin, including providing primary prevention in subjects less than 50 years old. Patients with diabetes are also recommended to undergo annual lipid profile measurement, and those diagnosed with hyperlipidemia should be treated with statins with a low-density lipoprotein goal of <70 mg/dL. Moreover, it should be noted that an important aspect in the success of pharmacotherapy is patient's adherence and compliance to medications; therefore, close and regular patient follow-up, monitoring, and education are necessary.

Glucose Monitoring

Glucose monitoring is a crucial part of diabetes management, offering real-time insights into how glucose levels fluctuate. Traditionally, this has been done through fingerstick testing using blood glucose meters. However, more advanced methods, such as Continuous Glucose Monitoring (CGM), are becoming increasingly popular due to their ability to track glucose levels continuously, providing more detailed data.

Continuous Glucose Monitoring (CGM):

CGM devices use a small sensor inserted under the skin to measure glucose in the interstitial fluid. These systems transmit data to a receiver, smartphone, or insulin pump, offering real-time glucose readings every few minutes. CGMs help detect fluctuations in glucose levels that might not be captured by intermittent fingerstick testing. This technology can significantly improve diabetes management by allowing users to make timely adjustments to their treatment plan, potentially reducing both hyperglycemia and hypoglycemia.

CGMs offer several benefits:

More comprehensive data: They track glucose trends throughout the day, allowing for better understanding of how diet, exercise, and insulin affect glucose levels.
Alerts: Most CGMs have alarms that notify users when glucose levels go too high or low, helping to prevent dangerous situations.
Reduced fingersticks: While some calibration may still be needed, the frequency of fingerstick checks decreases significantly

SUMMARY /CONCLUSION

The article "Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management" outlines current pharmacological strategies for managing type 2 diabetes mellitus (T2DM), emphasizing the chronic nature of the condition. T2DM is marked by insulin resistance and eventual beta-cell dysfunction, leading to progressive hyperglycemia. The review covers the various classes of drugs used to manage elevated blood glucose levels in T2DM, focusing on their mechanisms, benefits, and limitations.

The management approach incorporates lifestyle modifications such as dietary changes and physical activity, which significantly reduce the risk of developing T2DM in high-risk individuals. Pharmacological treatment includes drugs like metformin, sulfonylureas, SGLT2 inhibitors, GLP-1 receptor agonists, and others, each targeting different aspects of the disease's pathophysiology. The review emphasizes the need for individualized treatment based on patient-specific factors such as comorbid conditions and the risk of complications.

Moreover, the paper stresses the importance of early diagnosis and continuous monitoring to optimize long-term outcomes. Regular blood glucose monitoring and HbA1c testing remain key tools in assessing treatment efficacy and preventing complications.

REFERENCES

1. 1. 1. American Diabetes Association (ADA). Standards of Medical Care in Diabetes—2023. Diabetes Care, 46(Supplement 1): S1–S260.
    2. World Health Organization. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia. 2006.
    3. Cochrane Database of Systematic Reviews: Overview of meglitinides in T2DM treatment.
    4. Wikipedia: Details on pharmacology and clinical application of meglitinides.
    5. Type2Diabetes.com: Insights on effectiveness, side effects, and patient considerations.
    6. Standards of medical care in diabetes-2016: summary of revisions. Diabetes Care (2016) 39(Suppl 1):S4–5. doi:10.2337/dc16-S003
    7. Internal Clinical Guidelines Team. Type 2 Diabetes in Adults: Management. London: National Institute for Health and Care Excellence (2015). 28 p.
    8. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care (2014) 37(1):514–80. doi:10.2337/dc14-S014
    9. Sukhija R, Prayaga S, Marashdeh M, Bursac Z, Kakar P, Bansal D, et al. Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients. J Investig Med (2009) 57(3):495–9. doi:10.2310/JIM.0b013e318197ec8b
    10. Kalra S, Agrawal N. Diabetes and HIV: current understanding and future per spectives. Curr Diab Rep (2013) 13(3):419–27. doi:10.1007/s11892-013-0369-9
    11. Sukhija R, Prayaga S, Marashdeh M, Bursac Z, Kakar P, Bansal D, et al. Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients. J Investig Med (2009) 57(3):495–9. doi:10.2310/JIM.0b013e318197ec8b
    12. Mancia G. Preventing new-onset diabetes in thiazide-treated patients. Lancet Diabetes Endocrinol (2016) 4(2):90–2. doi:10.1016/S2213-8587(15)00391-5
    13. Centers for Disease Control and Prevention. Diabetes Latest. (2014). Available from: www.cdc.gov/features/diabetesfactsheet
    14. Santos-Longhurst A, Krucik G. Type 2 Diabetes Statistics and Facts. Healthline (2014). Available from: www.healthline.com/health/type-2-diabetes/statistics
    15. American Diabetes Association. National Diabetes Statistics Report: Statistics about Diabetes. (2014). Available from: www.diabetes.org/diabetes-basics/ statistics/
    16. Centers for Disease Control and Prevention. Diabetes Latest. (2014). Available from: www.cdc.gov/features/diabetesfactsheet.
    17. (2016). Available from: http://care.diabetesjournals.org/content/39/ Supplement_1
    18. Nyenwe EA, Kitabchi AE. The evolution of diabetic ketoacidosis: an update of its etiology, pathogenesis and management. Metabolism (2016) 65(4):507–21. doi:10.1016/j.metabol.2015.12.007
    19. Stoppler M, Shiel W. Hemoglobin A1C Test. EMedicine health. (2016). Available from: http://www.emedicinehealth.com/hemoglobin_a1c_hba1c/ article_em.htm
    20. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ (2000) 321:405–12. doi:10.1136/bmj.321.7258.405
    21. For People of African, Mediterranean, or Southeast Asian Heritage: Important Information about Diabetes Blood Tests. National Institute of Diabetes and Digestive and Kidney Diseases (2011). Available from: http://www.niddk. nih.gov/health-information/health-topics/diagnostic-tests/people-afri can-mediterranean-southeast-asian-heritage-important-information-diabe tes-blood-tests/Pages/index.aspx
    22. Dansinger M. The Hemoglobin A1C Test for Diabetes. WebMD (2015). Available from: http://www.webmd.com/diabetes/guide/glycated-hemoglobin-test- hba1c
    23. Tabak A, Herder C, Rathmann W, Brunner E, Kivimaki M. Prediabetes: a high risk state for developing diabetes. Lancet (2012) 379(9833):2279–90. doi:10.1016/S0140-6736(12)60283-9.
    24. American Diabetes Association. Screening for Type 2 Diabetes. (Vol. 18). Clinical Diabetes (2000). Available from: http://journal.diabetes.org/clinical diabetes/v18n22000/pg69.htm
    25. Tabak A, Herder C, Rathmann W, Brunner E, Kivimaki M. Prediabetes: a high risk state for developing diabetes. Lancet (2012) 379(9833):2279–90. doi:10.1016/S0140-6736(12)60283-9
    26. Tuso P. Prediabetes and lifestyle modification: time to prevent a preventable disease. Perm J (2014) 18(3):88–93. doi:10.7812/TPP/14-002
    27. Riccardi G, Rivellese A. Effects of dietary fiber and carbohydrate on glucose and lipoprotein metabolism in diabetic patients. Diabetes Care (1991) 14(12):1115–25. doi:10.2337/diacare.14.12.1115
    28. Consumption of Carbohydrate in People with Diabetes. Diabetes UK. (2011). Available from: https://www.diabetes.org.uk/Professionals/Position-stateme nts-reports/Food-nutrition-lifestyle/Consumption-of-carbohydrate- in-people-with-diabetes/
    29. Umpierre D, Ribeiro PA, Kramer CK, Leitão CB, Zucatti AT, Azevedo MJ, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA (2011) 305(17):1790–9.
    30. Pietraszek A, Gregersen S, Hermansen K. Alcohol and type 2 diabetes. A review. Nutr Metab Cardiovasc Dis (2010) 20(5):366–75. doi:10.1016/j. numecd.2010.05.001
    31. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes (2009) 58(4):773–95. doi:10.2337/db09-9028
    32. Bailey CJ. The current drug treatment landscape for diabetes and perspectives for the future. Clin Pharmacol Ther (2015) 98(2):170–84. doi:10.1002/ cpt.144
    33. James JC, Andrew SR, Charles FS Jr, Annie N. PA-C diagnosis and management of diabetes: synopsis of the 2016; American Diabetes Association standards of medical care in diabetes. Ann Intern Med (2016) 164:542–52. doi:10.7326/M15-3016
    34. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient- centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care (2015) 38(1):140–9. doi:10.2337/dc14-2441
    35. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care (2009) 32(1):193. doi:10.2337/dc08-9025
    36. Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, et al. Comparison of clinical outcomes and adverse events associated with glu cose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA (2016) 316(3):313–24. doi:10.1001/jama.2016.9400
    37. (2016). Available from: http://www.clevelandclinicmeded.com/medicalpubs/ diseasemanagement/endocrinology/diabetes-mellitus-treatment/
    38. Viollet B, Guigas B, Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metfromin: an overview. Clin Sci (Lond) (2012) 122(6):253–70. doi:10.1042/CS20110386
    39. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA (2014) 312(24):2668–75. doi:10.1001/jama.2014.15298
    40. Fogelman Y, Kitai E, Blumberg G, Golan-Cohen A, Rapoport M, Carmeli E. Vitamin B12 screening in metformin-treated diabetics in primary care: were elderly patients less likely to be tested? Aging Clin Exp Res (2016). doi:10.1007/ s40520-016-0546-1
    41. Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol (2016) 4(6):525–36. doi:10.1016/ S2213-8587(15)00482-9
    42. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med (2016) 164(11):740–51. doi:10.7326/M15-2650
    43. Harris KB, McCarty DJ. Efficacy and tolerability of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab (2015) 6(1):3–18. doi:10.1177/2042018814558242
    44. Riser Taylor S, Harris KB. The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2diabetes mellitus. Pharmacotherapy (2013) 33(9):984–99. doi:10.1002/phar.1303
    45. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glu cose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet (1998) 352(9131):854–65; Erratum in: Lancet (1998) 352(9139):1558. doi:10.1016/S0140-6736(98)07037-8
    46. Ismail-Beigi F. Pathogenesis and glycemic management of type 2 diabetes mellitus: a physiological approach. Arch Iran Med (2012) 15(4):239–46.
    47. Siraj ES, Rubin DJ, Riddle MC, Miller ME, Hsu FC, Ismail-Beigi F, et al. Insulin dose and cardiovascular mortality in the ACCORD trial. Diabetes Care (2015) 38(11):2000–8. doi:10.2337/dc15-0598
    48. Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes (2002) 51(3):5368–76. doi:10.2337/diabe tes.51.2007.S368
    49. Al-Arouj M, Bouguerra R, Buse J, Hafez S, Hassanein M, Ibrahim-Asharaf M, et al. Recommendations for management of diabetes during Ramadan. Diabetes Care (2005) 28:2305–11. doi:10.2337/diacare.28.9.2305
    50. Echouffo-Tcheugui JB, Dagogo-Jack S. Preventing diabetes mellitus in devel oping countries. Nat Rev Endocrinol (2012) 8(9):557–62; Erratum in: Nat Rev Endocrinol (2012) 8(11):692. doi:10.1038/nrendo.2012.46
    51. 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) 104:787–94. doi:10.1172/JCI7231
    52. Ronacher K, Joosten SA, van Crevel R, Dockrell HM, Walzl G, Ottenhoff TH. Acquired immunodeficiencies and tuberculosis: focus on HIV/AIDS and diabetes mellitus. Immunol Rev (2015) 264(1):121–37. doi:10.1111/imr.12257
    53. Insulin mechanism of action, types, uses, adverse effects 2024 by bring.com
    54. DrugBank-Insulin human: Uses, Interactions, Mechanism of Action | DrugBank Online
    55. Cleveland Clinic - Insulin: What It Is, What It Does, How To Take It & Side Effects
    56. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm-2016 executive summary. Endocr Pract (2016) 22(1):84–113. doi:10.4158/EP151126.CS
    57. Evers SS, Sandoval DA, Seeley RJ. The physiology and molecular underpin nings of the effects of bariatric surgery on obesity and diabetes. Annu Rev Physiol (2016).
    58. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on car diovascular disease in type 2 diabetes. Eur Heart J (2015) 36(34):2288–96. doi:10.1093/eurheartj/ehv239
    59. Koch L. Obesity: teaching an old drug new tricks – amlexanox targets inflammation to improve metabolic dysfunction. Nat Rev Endocrinol (2013) 9(4):185. doi:10.1038/nrendo.2013.42
    60. Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, et al. An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice. Nat Med (2013) 19(3):313–21. doi:10.1038/ nm.3082.