Present State and Perspectives of Type 2 Diabetes Management

Abstract

Diabetes mellitus is a common metabolic disorder characterised by chronic hyperglycaemia that results from a defect in insulin secretion, action, or both. There are different types of diabetes mellitus, but type 2 diabetes mellitus is the most common type globally. Type 2 diabetes mellitus results from a complex interaction between predisposing genes and unhealthy lifestyle choices. The risk factors for type 2 diabetes include obesity, prediabetes, sedentary lifestyle, unhealthy diets, and hypertension. Poorly controlled diabetes causes microvascular and macrovascular complications. The goals of management are to prevent these complications and optimise quality of life. Fasting plasma glucose, 2-hours post glucose load, random plasma glucose or HbA1c above a certain threshold diagnoses diabetes in the presence or classic symptoms otherwise, the tests are repeated on a second occasion. HbA1c is convenient and reliable but, it is affected by conditions affecting the turnover of red cells. Management of type 2 diabetes is individualised with focus on diabetes education, lifestyle changes, pharmacological therapy, management of co-morbidities, and monitoring of treatment. Various factors determine the drugs used, but metformin remains the cornerstone. Other cardiovascular risk factors must be adequately controlled.

1. Introduction

Diabetes mellitus (DM) is a heterogeneous group of metabolic disorders characterised by chronic hyperglycaemia, which results from insufficient insulin secretion or impaired action of insulin or both [1]. Β-cells depletion as well as insulin resistance are the key mechanisms driving the hyperglycaemia seen in diabetes. Underlying the myriad of complications of diabetes mellitus is chronic hyperglycaemia. Chronic hyperglycaemia is primarily responsible for the microvascular and macrovascular complications of diabetes [2]. DM is closely linked with gradual and sustained damage to different organs, especially the nerves, kidneys, eyes, heart and blood vessels. Diabetes raises the risk of cardiovascular disease by 2 to 4 folds. The aetiopathogenesis of DM depends on the type.

According to the latest World Health Organisation (WHO) classification of diabetes mellitus, there are six basic types, namely, type I DM, type 2 DM, hybrid forms of diabetes, other specific types, hyperglycaemia first detected during pregnancy, and unclassified diabetes [3]. The most common type of DM (90–95%) is T2D (T2D) [4]. In T2D, insulin resistance accompanied by inadequate compensatory insulin secretion from the β-cells is the central theme in its pathogenesis. Insulin resistance is defined as the deficient responsiveness of cells to insulin. Essentially, insulin resistance results from an interplay of genetic predisposition and unhealthy lifestyle choices. Genome wide association studies (GWAS) have isolated some genetic variants implicated in β-cell dysfunction and insulin resistance [5]. Some of the reported genes include PPARG, GCK, TCF7L2, WFS1 and IGF2BP2 [6].

The treatment of a disorder is often dependent on the pathophysiology. The current thinking in the pathophysiology of T2D, which also influences the therapeutic approach, is termed the ominous octet [7]. The ominous octets represent eight fundamental defects in the body homeostasis that contributes to the development of T2D. These defects are β-cells dysfunction, enhanced hepatic glucose production, reduced insulin-mediated uptake of glucose in the muscles, and increased release of free fatty acids from adipose tissue. Others include reduced incretin secretion, hyperglucagonemia, and impaired appetite regulation in the brain. So, there are pharmacological agents which target one or more of these pathways in controlling plasma glucose concentration.

Obesity, especially the central type, has been repeatedly fingered as the central phenomenon in the development of insulin resistance seen in T2D. Basically, insulin resistance is surmounted by enhanced secretion of insulin, but this counterbalancing response attenuates over time and T2D ensues. When insulin fails to exert its expected effects on the cells, the metabolism of carbohydrates, proteins and fats is greatly impaired [8]. The risk factors for T2D include obesity, western diets, sedentary lifestyle, hypertension, dyslipidaemia, gestational diabetes, prediabetes and polycystic ovarian syndrome [9]. In T2D, typically, insulin is not required for survival, although there are rare exceptions, especially in the late stage of the disease.

Β-cell dysfunction, characterised initially by the impaired first phase of insulin secretion and later the second phase, is a crucial factor in the pathogenesis of T2D [10]. The defective first phase of insulin secretion is depicted by crippled intake of glucose into Β-cell. The second phase problem is a result of the paradoxical suppression of insulin secretion by hyperglycaemia, a phenomenon termed glucotoxicity. Β-cell dysfunction, in the presence of insulin resistance, progresses to type 2 diabetes. Insulin resistance could be peripheral or hepatic (in which hepatic glucose production is unchecked). Inappropriate glucagon secretion, enhanced gluconeogenesis and alteration of incretin dynamics have also been implicated in the pathogenesis of T2D.

1.1 The burden of type 2 diabetes

There are ongoing global concerns about the unrelenting burden of T2D. Diabetes is a pandemic. According to the International Diabetes Federation (IDF), 10.5% of the adult population (20–79) years are living with diabetes, of which about 98% is T2D [11]. In terms of absolute numbers, China, India, Pakistan, USA, Indonesia, and Brazil have the highest tally of individuals living with diabetes in the world. This global estimate of diabetes prevalence is projected to increase significantly in the coming years. Interestingly, about 50% of individuals living with type 2 diabetes are undiagnosed [12]. Africa has the largest prevalence of undiagnosed diabetes globally [13]. Diabetes is more common in urban areas when compared with rural areas. Similarly, type 2 diabetes is mainly a disease of middle and old age, but the prevalence among the young is rising significantly. The recent upsurge of T2D among young adults, adolescents and children is principally accounted for by the parallel rise in obesity, sedentary lifestyle and widespread adoption of unhealthy Western diets [14]. It is also slightly more common among males compared with females, partly due to a higher frequency of central obesity among men.

The economic impact of the high prevalence of T2D is further worsened by the fact the majority of the persons affected live in low and middle-income countries where healthcare funding is mainly out-of-pocket and largely suboptimal [15]. Apart from economic distress, there are also undesirable psychological and social consequences of being diagnosed with T2D. It is equally noteworthy that a significant proportion of individuals with type 2 diabetes fail to achieve their treatment goals. Since type 2 diabetes is underdiagnosed and sub-optimally managed, it is imperative to intensify efforts in harnessing resources, empowering the clinicians and educating the population to minimise the immense impact of the disease on the general population. Early diagnosis and prompt treatment have been found to have a noteworthy impact long term. The bulk of the overall cost of care in diabetes is spent on managing the complications.

Over a variable period, poorly controlled diabetes may cause neuropathy, nephropathy or retinopathy. DM is the most common cause of peripheral neuropathy. Among adults (20–74 years), DM is the most prominent aetiological factor leading to blindness [16]. Globally, DM is equally the principal cause of end-stage kidney disease. Foot ulcerations, limb amputation, erectile dysfunction, non-alcoholic steatohepatitis, peripheral arterial disease, stroke and coronary artery disease are other potential complications of DM [17, 18]. Cognitive decline is common in type 2 diabetes when compared with individuals of similar age groups but without diabetes. Atrophy of the hippocampus, limbic system and frontal lobe have been documented in type 2 diabetes, and this could be responsible for the observed cognitive dysfunction [19]. Cardiovascular disease is the principal cause of mortality in individuals living with type 2 diabetes. Moreover, DM is commonly associated with other co-morbidities such as hypertension, dyslipidaemia, hyperuricaemia and hypovitaminosis D.

1.2 Objectives

1. To discuss how type 2 diabetes mellitus is diagnosed

2. To examine the principles of managing type 2 diabetes mellitus

2. Diagnosis

The diagnosis would involve taking a comprehensive history, performing a targeted physical examination, and ordering some specific investigations. T2D remains undiagnosed for a long period because the degree of hyperglycaemia in the early stages is not severe enough to produce the classic symptoms. However, a dynamic test such as the oral glucose tolerance test may be helpful for early detection. So, it is important to emphasise that a significant proportion of individuals with diabetes are diagnosed without having any of the classic symptom. Interestingly, diagnosed or not, the microangiopathy and macroangiopathy associated with T2D tend to start at this stage.

2.1 History taking

The classic symptoms of diabetes are polyuria, polydipsia, weight loss and fatigue. Other symptoms include recurrent infections, especially vaginal candidiasis/balanitis, polyphagia, poorly healing wounds, paraesthesia in the feet or hands, and visual blurriness. Sometimes, the first presentation comes in the form of a hyperglycaemic emergency- hyperglycaemic hyperosmolar state (HHS) or diabetic ketoacidosis (DKA).

Family history of diabetes should be asked. Immunisation history is equally important. Prior diagnoses of hypertension, dyslipidaemia need to be sought. It is important to know if the person smokes and how much of alcohol he/she takes.

2.2 Physical examination

Anthropometric metrics such as the body mass index, waist circumference, and hip-to-waist ratio are determined to assess adiposity. A preliminary fundoscopy is done, while the individual is later sent for a comprehensive eye examination with the ophthalmologist to document the presence and the grade of diabetic retinopathy or any other diabetic eye disease such as cataract or glaucoma. Cardiovascular examination entails checking for evidence of peripheral artery disease, measuring the blood pressure and examining the praecordium. The presence of neuropathy is noted by conducting a full neurological examination, 10-g monofilament test and possibly biothesiometry. The signs of autonomic neuropathy should be carefully looked out for as well. A detailed examination of the feet for dystrophic nails, fissures, ulcers, corns, calluses and small muscle integrity needs to be performed. Biomechanical assessment of the feet should also be done before a person is sent for a specialist podiatry review. A yearly foot examination is of crucial importance in the management of diabetes.

2.3 Screening for type 2 diabetes

The American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) recommend screening for diabetes in individuals who are 45 years and above, irrespective of the presence or absence of the risk factors [20, 21]. The interval between screenings is three years, if the prior result is normal. This is to minimise the chances of false negative results. Screening for T2D should be done earlier if a person is overweight, with an additional risk factor for type 2 diabetes. These risk factors include having a family history of diabetes, a sedentary lifestyle, high-risk ethnic groups like Africans or Asians, prior diagnosis of prediabetes, gestational diabetes, and delivery of macrosomic babies. About one-third of individuals with prediabetes will eventually develop type 2 diabetes. Other relevant risk factors are hypertension, dyslipidaemia, prior diagnosis of polycystic ovarian syndrome, insulin resistance-related conditions such as acanthosis nigricans, and the presence of cardiovascular disease.

2.4 Laboratory parameters for diagnosis

To diagnose diabetes, the parameters of interest include glycated haemoglobin (HbA1c), fasting plasma glucose, random plasma glucose or 2-hour post-glucose load (during an oral glucose tolerance test). In persons with the classic symptoms of diabetes (polyuria, polydipsia, weight loss and fatigue), glycated haemoglobin of ≥48 mmol/mol (6.5%) and/or fasting plasma glucose (FPG) of ≥7.0 mmol/L and/or 2 hours post-glucose load (2HPGL) of ≥11.1 mmol/L and/or random plasma glucose (RPG) ≥ 11.1 mmol/L is sufficient to diagnose diabetes. So, HbA1c can be used to diagnose diabetes or identify individuals who are predisposed to developing diabetes later in life.

However, if a person is asymptomatic, a repeat sample has to be analysed later before establishing the diagnosis of diabetes mellitus. It is imperative to repeat the same test for the sake of consistency and avoidance of ambiguity. There are differences in the pre-analytic and analytic variability of the various diagnostic tests. For example, a repeat 2HPGL is most likely to be discordant, while HbA1c has the least variability. If another test is done and the results are discordant (one is above the diagnostic cut-off while the other is not), the test with the higher value is repeated. If the repeat is still above the diagnostic threshold, the individual has diabetes. If the discrepancy persists, the test may be repeated after 3–6 months.

The threshold values for diagnosis are based on the cut-off point at which individuals begin to develop retinopathy, from the findings of previous studies. The values below the diagnostic cut-off were associated with a low prevalence of retinopathy. At the diagnostic cut-off, there was a sharp linear spike in the occurrence of retinopathy. It must be stated that there are no perfect correlations among glycated haemoglobin, fasting plasma glucose or 2-hour post-glucose load, but all three can be used for the diagnosis of diabetes. HbA1c diagnoses one-half of individuals with FPG ≥ 7.0 mmol/L and one-third of people with 2HPGL ≥ 200 mg/dl [22]. Overall, the decision on which diagnostic test to be used is dependent on the accessibility and feasibility of the respective test.

2.4.1 Glycated haemoglobin (HbA1c)

Glycated haemoglobin represents the average blood glucose concentration in the preceding two to three months. Using the ADA criteria, HbA1c of 39–46 mmol/mol (5.7–6.4%) is used to diagnose prediabetes, while HbA1c of ≥48 mmol/mol (6.5%) is diagnostic of diabetes mellitus [23]. HbA1c is equally useful in monitoring glycaemic patterns and profiles in persons living with type 2 diabetes. It correlates well with diabetic microangiopathy (retinopathy, neuropathy and nephropathy) but less well with macroangiopathy (stroke, myocardial infarction and peripheral arterial disease).

The advantage of HbA1c as a diagnostic test includes the fact that it is not affected by recent meals, making it very convenient. It does not require fasting or ingestion of glucose. Also, the turnaround time is short, and the result is not significantly affected by the presence of an acute illness. However, the universally acceptable assaying method must be compliant with the National Glycohaemoglobin Standardisation Program (NGSP), as used in the Diabetes Control and Complications Trial (DCCT). This vital criterion makes HbA1c less readily available in many centres, especially in developing nations. Historically, it was a lack of standardisation that precluded HbA1c from being used as a diagnostic tool for diabetes. Lack of uniformity made generalisability problematic to attain. However, since 2010, ADA has recommended HbA1c as a diagnostic test for diabetes, as long as the assay is compliant with the NGSP standard. Based on this, point-of-care HbA1c assays (which are non-compliant with the NGSP protocol) are not approved for the diagnosis of diabetes. Also, any condition, physiological or pathological, that significantly affects the haematocrit or red cell turnover (such as haemoglobinopathies, other haemolytic anaemias, iron deficiency anaemia, pregnancy, blood loss, and haemodialysis) can give false readings.

2.4.2 Fasting plasma glucose (FPG)

The person is requested to fast overnight for 8–12 hours, following which plasma glucose concentration is obtained. Using the ADA guidelines, FPG of 5.6–6.9 mmol/L is consistent with prediabetes, while FPG ≥ 7.0 mmol/L diagnoses diabetes mellitus. The advantages of FPG include convenience, consistency, and a tight relationship with diabetic microangiopathy (retinopathy, nephropathy, and neuropathy).

2.4.3 2-hour post-glucose load (2HPGL)

This is obtained as a part of the oral glucose tolerance test (OGTT). Following the ingestion of 75 mg of glucose in 300 ml of water, plasma glucose concentration is obtained after 2 hours. This is called the 2-hour post-glucose load. 2-HPGL of 7.8–11.0 mmol/L suggests prediabetes, whereas a value ≥11.1 mmol/L is consistent with diabetes. It is widely validated, but it is more expensive than the FPG test and requires the presence of the person at the laboratory for at least 2 hours, making it cumbersome and time-consuming. The person needs to be instructed to take meals of adequate carbohydrates (at least 150 g/day) for about five days before administering an OGTT. If the person can safely stop steroids several days prior to the test, it is better discontinued.

2.4.4 Random plasma glucose (RPG)

In a person with the classic symptoms, random plasma glucose ≥11.1 mmol/L is sufficient to diagnose diabetes. Similarly, any person presenting with features of hyperglycaemic emergency (HHS or DKA), an RPG ≥ 11.1 mmo/L diagnoses diabetes.

3. Management of type 2 diabetes mellitus

The goals of the management of type 2 diabetes are to minimise the risk of developing microvascular and macrovascular complications, as well as optimising the metabolic profile of the person. Therefore, the approach must go beyond glucocentricity (focusing on controlling the glucose only) but must involve modifying the cardiovascular risk factors in general. The management of type 2 diabetes must be individualised.

The management approach can be divided into four domains:

• Health education and counselling

• Lifestyle management

• Pharmacotherapy

• Miscellaneous

3.1 Health education and counselling

The person needs to see a specialist diabetes educator. Diabetes education has gone beyond handing people a pamphlet of instructions. Health education is an active process that must be undertaken by physicians, diabetes nurses, dieticians, other healthcare professionals, and specialist diabetes educators. Studies have shown that diabetes education has a significant impact on optimising glycaemic control and the general well-being of the people [24]. Similarly, diabetes education has been closely correlated with the prevention of diabetes complications. Diabetes education is a lifelong exercise and not a set of visits to the health educators. However, at the very least, persons living with diabetes must visit the diabetes educators at diagnosis, when glycaemic targets are not attained, when complications arise and when new changes are made to the management plan.

The ultimate aim of patient education is self-management of diabetes mellitus. Education empowers the people and equips them with problem-solving tactics and the necessary strategies to manage themselves. Diabetes self-management education (DSME) improves adherence to medications, dietary therapy and exercise regime. DSME has also been linked to improved quality of life among individuals living with type 2 diabetes mellitus. Persons living with diabetes need to be empowered to make informed decisions as regards their management. Comprehensive education is given on how to perform and interpret self-monitoring of blood glucose (SMBG). They must be able to act based on these interpretations also. Persons living with diabetes must be counselled to stop smoking.

The symptoms, causes and correction options for hypoglycaemia need to be discussed with the people affected. The various devices used in the management of diabetes, such as glucometers, flash glucose monitors, continuous glucose monitors, pens and insulin pumps, are also taught during education sessions. Persons living with diabetes who have been thoroughly educated are better capacitated to handle acute stress. “Education to protect tomorrow” was the theme of the 2022 World Diabetes Day, and this underlies the critical role education plays in the management of diabetes.

3.2 Lifestyle management

The lifestyle approach is the bedrock of managing type 2 diabetes or any other form of diabetes. Lifestyle therapies can be subdivided into dietary approach and physical activity. A major objective of lifestyle management is weight loss. The pillars of lifestyle management include healthy eating, exercise, smoking cessation, adequate sleep, stress reduction, and moderation of alcohol intake.

3.2.1 Dietary therapy

People living with diabetes are advised to visit a professional dietician to get comprehensive nutritional advice. This has been found to aid healthy food choices, maintain healthy weight, and improve quality of life. Based on the dietary needs of each person, the dietician assists in drawing a dietary plan for the people. The constituents, timing and quantity of the food eaten play a central role in reaching glycaemic targets. There is nothing called “diabetic diets”, and people living with diabetes can eat healthy diets prescribed to other members of the population who have not been diagnosed with DM.

Generally, diets rich in complex carbohydrates, fibres and unsaturated fats are better suited for optimal glycaemic control, while refined sugars and saturated fats are avoided. Complex carbohydrates should constitute about 50–55% of the total caloric intake. The people are advised to select less processed or packaged food and eat small, frequent meals spread throughout the day. Proteins are derived from legumes, lean meat, fish and poultry. Vegetables, fruits and whole grains are highly recommended. Ultimately, dietary therapy, especially in the presence of obesity, is targeted at weight reduction [25].

3.2.2 Physical activity

Increased physical activity must be inculcated as a habit. Exercise reduces insulin resistance through decreased visceral fat mass, enhanced muscular skeleton insulin sensitivity, mopping up of free fatty acids, and augmented blood flow to insulin-sensitive tissues. Exercise helps not only in intensifying glucose disposition but in controlling other cardiovascular risk factors. It lowers blood pressure and plasma triglycerides levels while it raises high-density lipoprotein cholesterol (HDL-C).

WHO recommends at least 150 minutes of moderate-intensity aerobic physical activity per week [26]. The exercise is spread throughout the week. Alternatively, 75–150 minutes of vigorous-intensity physical activity could be adopted if reasonably feasible. The physical activities should be a combination of aerobic and muscle-strengthening activities. Twice-weekly muscle-strengthening physical activities have been found to have an additional advantage over aerobic exercises [27]. Sedentary activities must be minimised, and when possible, replaced with light-intensity physical activities. Habitual physical activities not only help in optimising glycaemic control, but it also helps in enhancing muscular strength (thereby preventing falls) and enhancing cardiorespiratory fitness (which has been associated with prolonged life expectancy). It also helps in promoting weight loss, boosting mental health and minimising the risk of developing a cardiovascular event (acute myocardial infarction and stroke). WHO recommends policies such as walking and cycling in place of motorised transport. Workplaces are also encouraged to provide opportunities that would encourage the physical activities of the personnel.

3.3 Pharmacotherapy

There are various classes of antidiabetic drugs available for individuals with type 2 diabetes [28]. These classes include biguanides (e.g. metformin), sulphonylureas (e.g., glyburide and glipizide), meglitinides (e.g., repaglinide and nateglinide), peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, otherwise known as thiazolidinediones (e.g., pioglitazone), and alpha-glucosidase inhibitors (e.g., acarbose and voglibose) [29]. Other classes comprise dipeptidyl peptidase 4 (DPP-4)- inhibitors (e.g., alogliptin and saxagliptin), glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide and liraglutide), and sodium-glucose co-transporter-2 (SGLT-2) inhibitors (e,g., dapaglifozin and empaglifozin). Amylin analogues (e,g., pramlintide), and insulins (basal, pre-mixed, or basal-bolus) are sometimes used in the management of type 2 diabetes. Recently, dual incretin receptor agonists (e.g., tirzepatide) have been approved for the treatment of type 2 diabetes. A new class of anti-diabetic drugs (triagonists) acting on GLP-1 receptor, GIP receptor and glucagon receptor [30]. Retatrutide is an example of this class of drugs [31]. Since the treatment of type 2 diabetes mellitus is individualised, several factors are considered before choosing specific medications for the persons. These factors include efficacy, co-morbidities, risk of hypoglycaemia, cardiovascular safety, weight gain, potential side effects, and cost [28]. The patient’s desires, values and aspirations must also be taken into account.

In most clinical practice guidelines, such as ADA and AACE, metformin remains the drug of choice for the management of type 2 diabetes, except contraindications are precluding its usage [32]. However, recent paradigm shift entails primary assessment of the cardiovascular risk of the person living with diabetes, and if high, the drugs that have been proven in clinical trials to be cardiovascular-friendly, such as SGLT-2 inhibitors and GLP-1 agonists, may be considered first.

3.3.1 Biguanides

Metformin is widely available and highly efficacious. Phenformin, a first-generation biguanide, has been withdrawn from the market on account of severe toxicity. Metformin’s mechanism of action is to decrease hepatic insulin resistance and to a lower extent, the peripheral insulin resistance. Biguanides do not augment insulin release and their chances of hypoglycaemia, independently, are much lower. Metformin is currently the only approved and commercially available member of the class. Metformin does not bring about weight gain, and it mildly lowers total cholesterol as well as triglycerides. In fact, it causes minimal weight loss in about 30% of the people using it. Metformin causes lactic acidosis. Individuals with renal failure, liver failure, or heart failure are more likely to have lactic acidosis. So, it is avoided (or used with extreme caution) in individuals with these organ failures.

3.3.2 Sulphonylureas

Sulphonylureas are insulin secretagogues which means that these drugs act by increasing insulin secretion from Β-cells. They bind to specific receptors on the Β-cell, which closes potassium ATP channels, ultimately leading to the opening of calcium channels and influx of calcium into the cells. The raised concentration of calcium in the cells is responsible for insulin secretion. This implies that a residual Β-cell mass is required for the efficacy of sulphonylureas. Prominent side effects include hypoglycaemia and weight gain. There are inconsistent data on the deleterious cardiovascular effect of sulphonylureas.

3.3.3 Meglitinides

These are also insulin secretagogues. Though dissimilar to sulphonylureas molecularly, they bind to sulphonylureas receptors and elicit a similar effect of augmented insulin secretion. Compared with sulphonylureas, the onset of action of meglitinides is more rapid, and the duration of action is shorter. This implies a lower propensity to hypoglycaemia and weight gain. Additionally, the efficacy of meglitinides is proportionate to that of sulphonylureas.

3.3.4 Thiazolidinediones

Thiazolidinediones are insulin sensitizers, which means that they can lower insulin resistance. They can do this by binding agonistically with peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor for nuclear hormone receptors. Unlike metformin, thiazolidinediones decrease peripheral insulin resistance and to a lower extent hepatic insulin resistance. Thiazolidinediones facilitate free fatty acid uptake by adipose tissue, thereby mobilising excess fat from the liver and the muscle, which makes them useful for individuals with steatotic liver disease. They promote water retention and weight gain and are better avoided in heart failure, renal failure and liver failure. They have a lower risk of hypoglycaemia and predispose to osteoporosis. There are published data linking rosiglitazone with bladder cancer.

3.3.5 α-glucosidase inhibitors

This class of drugs prevents postprandial hyperglycaemia by binding to an enzyme called α-glucosidase on the brush border of small intestines, thereby inhibiting the absorption of complex polysaccharides. Their side effects include flatulence, diarrhoea, and abdominal pain. These side effects often make them less desirable and promote non-adherence. They are to be avoided in individuals with certain gastrointestinal disorders such as inflammatory bowel disease, gastroparesis and intestinal obstruction.

3.3.6 DPP-4 inhibitors

DPP-4 inhibitors are a class of drugs that block an enzyme called dipeptidyl peptidase-4. The enzyme is responsible for the clearance of endogenous incretins, namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins augment insulin secretion in a glucose-dependent fashion, but their half-lives are very short, as they are rapidly cleared by DPP-4. So, DPP-4 inhibitors indirectly assist in raising insulin secretion in a glucose-dependent manner. The drugs do not cause weight gain and have a lower risk of hypoglycaemia. Linagliptin, a member of the class, does not need dose adjustment when there is renal failure, but the others do. There are reports that DPP-4 inhibitors can rarely cause pancreatitis. Other documented side effects include upper respiratory tract infection and headache.

3.3.7 GLP-1 receptor agonists

Glucagon-like peptide 1 (GLP-1) is an incretin produced in the L-cells of the small intestine. It amplifies insulin secretion from β-cells in the presence of glucose. Furthermore, incretins suppress appetite, gastric emptying and glucagon secretion. Endogenous incretins are rapidly degraded by DPP-4, but GLP-1 receptor agonists are not metabolised by DPP-4, yet they do elicit the same effect as the endogenous incretins. While most of the GLP-1 agonists are injectables, there is a formulation of semaglutide (Rybelsus) that is given orally. The GLP-1 receptor agonists have gastrointestinal side effects, such as nausea, diarrhoea and vomiting. They promote weight loss and prevent cardiovascular disease, as found in various cardiovascular outcome trials. (CVOT).

3.3.8 SGLT-2 inhibitors

Sodium-glucose cotransporter-2 (SGLT-2) is a membrane-bound transporter protein which reabsorbs glucose in the proximal convoluted tubules of nephrons. About 97% of filtered glucose is reabsorbed by SGLT-2. The reabsorption is in conjunction with sodium reabsorption at the proximal convoluted tubules. In T2D, SGLT-2 is abnormally upregulated, thereby intensifying glucose reabsorption in the kidneys. SGLT-2 inhibitors prevent glucose reabsorption, consequently causing glucosuria, natriuresis and moderate diuresis. SGLT-2 inhibitors have also been approved for the treatment of heart failure and renal failure. The drugs promote weight loss and prevent cardiovascular disease. Their side effects include genitourinary infection and increased propensity to euglycaemic diabetic ketoacidosis.

3.3.9 Insulins

Improvement in medical technology has seen the evolution of injectable insulin from animal insulin to human insulins (produced from recombinant DNA technology), and now, we have insulin analogues (produced from genetic modifications of human insulins). Inhaled insulins are available, although rarely used, and oral insulin is still being developed experimentally. Insulins, just like endogenous insulins, act by stimulating cellular glucose uptake and inhibiting proteolysis, lipolysis and gluconeogenesis. Various insulins used in clinical practice have different pharmacokinetics. Typically, people requiring insulin are started on basal insulins like neutral protamine Hagedorn (NPH) insulin, glargine, detemir or degludec. If basal insulins are not sufficient, prandial insulins (such as soluble insulin, insulin aspart, insulin lispro, and insulin glulisine) may be added. There are also human and analogue pre-mixed insulins. The side effects of insulin are hypoglycaemia, weight gain and local skin reactions.

3.3.10 Amylin analogues

Β-cells co-secrete amylin and insulin. Amylin prevents postprandial excursion of blood glucose. Just as it is applicable to insulin, in type 2 diabetes, there may be eventual β-cell failure with resultant insulinopenia and amylinopenia. In terms of mechanisms of action, amylin analogues reduce appetite, suppress gastric emptying, inhibit glucagon secretion and reduce hepatic glucose production. Pramlintide is an amylin mimetic that can be used as an adjunct in the management of type 2 diabetes mellitus. Pramlintide causes weight loss. The reported side effects are gastrointestinal, such as nausea and vomiting.

3.4 Treatment of co-morbidities

Other co-morbidities such as hypertension, obesity and dyslipidaemia must be treated to targets. Cardiovascular disease tends to kill people with diabetes; therefore, it is not enough to control the glucose but to treat all the cardiovascular risk factors holistically. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) are preferred in managing hypertension in individuals living with type 2 diabetes. In managing dyslipidaemia, statins (e.g., atorvastatin, rosuvastatin) remain the drugs of choice. However, in individuals who cannot tolerate statins or who are not achieving their targets despite the maximum tolerable doses of statins, ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can be used.

3.5 Miscellaneous

The management of type 2 diabetes requires a multidisciplinary approach. A person with type 2 diabetes may be referred to a podiatrist, cardiologist, nephrologist, ophthalmologist or vascular surgeon. A yearly fundal examination is recommended for individuals with type 2 diabetes, starting from the time of diagnosis. Urinary albumin: creatinine ratio should be monitored yearly or twice yearly. Foot examinations must be done at each clinic visit, and a yearly schedule with the podiatrist for a comprehensive foot examination is equally essential.

3.6 Targets of treatment

Targets of treatments are individualised. Glycated haemoglobin (HbA1c) is a validated test for monitoring people with T2D undergoing treatment. The target HbA1c is <7.0% (and sometimes <6.5%, provided that safety and affordability have been carefully considered). HbA1c target is <8% in those with low life expectancy or established cardiovascular disease. The target blood pressure, according to the ADA guidelines, is <140/90 mmHg [33]. In people with established atherosclerotic cardiovascular disease, the low-density lipoprotein cholesterol (LDL-C) target is <70 mg/dl. In others who do not have atherosclerotic cardiovascular disease, the LDL-C target is <100 mg/dl. About 60% of persons with type 2 diabetes do not meet their glycaemic, blood pressure and lipid targets [34, 35]. This emphasises that physicians and other health professionals must intensify their efforts in treating the individuals to target. The target for weight loss is 5–7%, and this has been found to contribute immensely to cardiovascular risk control.

3.7 Monitoring of treatment

Monitoring of treatment is individualised. HbA1c is done every three months. In persons with stable and optimal glycaemic profiles, HbA1c interval can be extended to six months. People on intensive insulin therapy need to monitor the fasting, preprandial, occasional postprandial and bedtime glucose values. Glucose checks are encouraged anytime the patient feels unwell. Glucose checks are also vital before (and after) exercise, driving and operations of machines. Suspicion of hypoglycaemia warrants immediate blood glucose check. Using ADA guidelines, the target FPG is 4.4–7.2 mmol/L and 2-hour postprandial value of <1o mmol/L [21]. Glucose checks can be done with glucometers, flash glucose monitors and continuous glucose monitors. Blood pressure is checked at every hospital visit. Fasting lipid profile is checked at least annually.

List of abbreviations

2HPGL	2 hours post-glucose load
AACE	American Association of Clinical Endocrinologists
ACE	Angiotensin-converting enzyme
ADA	American Diabetes Association
ARB	Angiotensin receptor blockers
ATP	Adenosine triphosphate
CVOT	Cardiovascular outcome trials
DCCT	Diabetes Control and Complications Trial
DKA	Diabetic ketoacidosis
DM	diabetes mellitus
DPP-4	Dipeptidyl peptidase 4
DSME	Diabetes self-management education
FPG	Fasting plasma glucose
GIP	Glucose-dependent insulinotropic polypeptide
GLP-1	Glucagon-like peptide-1
GWAS	Genome-wide association studies
HbA1c	Glycated haemoglobin
HDL-C	High-density lipoprotein cholesterol
HHS	Hyperglycaemic hyperosmolar state
IDF	International Diabetes Federation
LDL-C	Low-density lipoprotein cholesterol
NGSP	National Glycohaemoglobin Standardisation Program
NPH	Neutral Protamine Hagedorn
OGTT	Oral glucose tolerance test
PCSK9	Proprotein convertase subtilidin/kexin type 9
PPAR-γ	Peroxisome proliferator-activated receptor-gamma
RPG	Random plasma glucose
SGLT-2	Sodium-glucose co-transporter-2
SMBG	Self-monitoring of blood glucose
T2D	Type 2 diabetes mellitus
WHO	World Health Organisation