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Type 2 diabetes mellitus is a complex metabolic disease with complex derangements of metabolic pathways that are involved in the glucose metabolism in different organs: the liver, muscles, pancreas, the gut, kidneys, fat cells and the brain. The objectives of the treatment of Type 2 diabetes mellitus are to reverse the underlying eight pathophysiologies called the ‘ominous octet’, achieve glycaemic control, control comorbidities and prevent or reduce the chronic complications. Lifestyle management and pharmacotherapy remain the mainstay of treatment of Type 2 diabetes mellitus. The development of the newer oral hypoglycaemic agents such as the sodium-glucose transporters 2 receptor inhibitors, the dipeptidyl peptidase 4 inhibitors and the injectables such as the glucagon-like peptide 1 receptor agonists and the analogue insulin in the last decades has provided broad and extended treatment options to achieve the treatment objectives. The recent announcement of the novel combinational peptides, Tirzapatide and Rezatrutide, promises a new era of pharmacotherapy for T2DM.
Internal Medicine Division, Port Moresby General Hospital, Papua New Guinea
*Address all correspondence to: lesliebahnkawa740@gmail.com
1. Introduction
Diabetes is a metabolic condition associated with elevated blood sugar levels because of either a relative or an absolute insulin deficiency [1]. Type 2 diabetes mellitus (T2DM) is now known to develop from disturbances in the glucose metabolic pathways in the muscles, liver, pancreas, gut, fat cells, kidneys and brain. These core pathophysiological pathways are called the ‘ominous octet’; insulin resistance in the muscles and liver, ßeta cell failure, α-cell hyperplasia with glucagonoma, gastrointestinal incretin resistance/failure, accelerated lipolysis in fat cells, increased uptake of glucose via SGLT2 receptors in the kidneys and insulin resistance in the brain [2, 3, 4]. Additionally, cardiovascular risk factors such as smoking, high blood pressure, and depression are also known to be associated with the increased risks in the development of T2DM [5].
Treatment of T2DM essentially aims to address the environmental risk factors with lifestyle modifications (LSM). Primary and secondary preventative approaches with dietary, exercise and combined interventions have been shown to reduce T2DM among those at high risk and even remit T2DM in those with overt diabetes [6, 7, 8, 9]. Pharmacological treatment of T2DM, on the other hand, aims at reversing the core pathological mechanisms through a multidrug therapeutic approach [2] recommended by the current international diabetes guidelines on pharmacotherapy of T2DM.
The development of newer oral hypoglycaemics, the sodium-glucose transporters 2 receptor inhibitors (SGLT2R-i), oral glucagon-like peptide 1 receptor agonists (GLP1-RA), the injectables, the dipeptidyl peptidase-4 inhibitors (DPP4-i) and the analogue insulins have expanded the pharmacological armamentarium of the treatment of T2DM. In addition to their targeted actions on the core pathophysiology of T2DM, the SGLT2R-i, GLP1-RA and DPP4-i classes of drugs provide pleiotropic benefits in reducing the comorbidities associated with T2DM, such as obesity, hypertension and dyslipidaemia [10, 11, 12, 13]. Moreover, studies have also shown that these drugs, especially the SGLT2R-i and the GLP1-RA protect and improve renal and cardiac functions [14, 15, 16, 17].
The insulin analogues also have better efficacies and safety and offer patients greater flexibility in the management of diabetes [18, 19, 20]. Additionally, the improvement in the different insulin delivery systems has made insulin easy for patients to use to achieve optimal glycaemic control in both types of diabetes [21, 22, 23].
This chapter reviews the treatment modalities of T2DM (LSM + pharmacotherapy) with specific emphasis on pharmacotherapy (oral, injectables and insulin) and their roles and hierarchy in the contemporary pharmacological management of T2DM and their modes of delivery to reverse the pathophysiological mechanisms, achieve effective glycaemic control and reduce complications and comorbidities.
The great diabetologist of the century, Elliot Joslin said “The three pillars of T2DM are Dieting, Exercise and Pharmacotherapy.” Dieting and exercise prescriptions are collectively called ‘lifestyle modifications’ (LSM) and are fundamental to the management of T2DM. Recent preventative trials among the prediabetic populations have shown that glycaemic control is achievable with LSM [6, 7, 8, 9] and improves glycaemic control among overt T2DM patients [24, 25, 26]. Combined exercise and dieting have more pronounced effects on the glycaemic control, comorbidities and patient’s quality of life (QoL) than individually. The effects are more prominent with supervised exercise than with the unsupervised exercise regimen [27, 28, 29].
2.1 Dietary prescription
Dietary prescription is an integral part of the LSM strategy for all T2DM patients; however, there is no standardised dietary regimen. Therefore, dietary prescription is personalised according to the local availability with the caveat of eating healthy (more vegetables, less carbohydrates and alcohol). The Mediterranean diet is a dietary practise prevalent among the countries bordering the Mediterranean Sea. Whilst it has no specific definition, it is rich in vegetables, fruits, nuts, whole grains and olive oil. This diet has been extensively studied, and a meta-analysis of these studies shows that it is associated with reduced blood pressure, cholesterol and heart attacks [30]. Another meta-analysis shows that it significantly prevents diabetes among those at high risk of developing T2DM and confers optimal control of those with established T2DM [31]. Diet alone, however, has minimal effect [6] but dietary prescription with exercise does have a greater impact on the glycaemic control, improvement of other comorbidities and the quality of life (QoL) of patients [7]. The Mediterranean diet, therefore, provides a great dietary option for people with diabetes (Figure 1).
Figure 1.
Mediterranean diet pyramid. Image adapted from Oldways.
2.2 Exercise prescription
Although supervised and unsupervised exercise regimens have been shown to reduce T2DM among those with impaired fasting glucose (IFG), the Italian Diabetes Exercise Study (IDES) showed that the supervised group had significant improvement in blood sugar, blood pressure, cholesterol control, weight reduction and improved physical fitness [27]. These are further supported by a meta-analysis showing that supervised aerobic or resistance exercises improve glycaemic control in T2DM regardless of dietary prescription [28]. Supervised exercise, therefore, leads to better outcomes, lending the term ‘exercise prescription’ for the management of T2DM.
2.3 Pharmacotherapy
Studies have shown that optimal pharmacological management of T2DM based on the HBA1c leads to the reduction in chronic complications [32, 33, 34]. Treatment guidelines recommend that management of T2DM also consider the management of cardiovascular risk factors and other comorbidities [35, 36, 37] as shown in Figure 2. However, the guidelines do not provide specific recommendations on the selection and titration of the pharmacological therapeutics [35, 36] but rather a multifactorial management approach and thereby provide a hierarchy of pharmacological escalation [37, 38] as shown in Figure 3, with the choice of diabetic drug selection and titration dependent on the patient’s clinical profile, preferences, comorbidities and the likelihood of its long-term benefits [37].
Figure 2.
Pharmacological management of T2DM according to patient profile.
Figure 3.
Hierarchical of treatment escalation. Adapted from Inzucchi et al. [39].
The drugs in this section are reviewed as traditional or new hypoglycemic agents in order of their guideline hierarchy (Table 1).
The hypoglycaemic agents have been the mainstay of the pharmacological management of the T2DM for over half a century and remain relevant today. In fact, they are either first and or second-line treatments according to current treatment guidelines.
2.3.1.1 Traditional oral hypoglycaemic agents (OHGA)
The traditional classes of OHGA have been in use since the 1960s for their glycaemic control. In 1998, the United Kingdom Prospective Diabetes Study (UKPDS) showed that sulfonylurea, metformin, and human insulin could reduce the chronic complications of T2DM [32] and demonstrated long-term metabolic benefits of metformin. Studies of the thiazolidinediones class of drugs have also shown significant glycaemic control and conferred other benefits, including the reduction of cardiovascular events [40, 41, 42]. The current traditional classes of the OHGA in practice are, in their order of hierarchy on the guidelines, biguanide, sulfonylureas and thiazolidinediones.
2.3.1.1.1 Metformin
Metformin is a traditional oral hypoglycaemic agent and the only biguanide currently in use in the management of T2DM. It is the first drug recommended by all guidelines for the treatment of T2DM and the prevention of overt diabetes among the high-risk prediabetes population [49]. It is cheap and readily available in all healthcare systems.
It inhibits hepatic gluconeogenesis, increases insulin sensitivity, decreases glycogenolysis, reduces fatty acid oxidation, facilitates glucose disposal, and protects the cardiovascular system from effects of hyperglycaemia [50, 51, 52]. Metformin in the intensive arm with sulphonylureas/insulin vs. standard arm in the UKPDS showed a significant reduction in the microvascular complication (retinopathy, nephropathy, and neuropathy) by 25% with a median HBA1c of 7% compared with the conventional therapy with a median HBA1c of 7.9% [32]. The 10-year follow-up epidemiological analysis of the patient’s taken metformin showed persistent correlation between glycaemic control and their clinical outcomes [39]. For every percentage decrease in HBA1c, there was a 25% reduction in diabetes-related deaths and 7% reduction in both fatal and non-fatal myocardial infarction and an 18% reduction in all-cause lending the term ‘metformin’s metabolic memory’ [39]. Additionally, metformin shows pleiotropic effects in the improvement of endothelial function, redistribution in lipid and fat metabolisms, stress oxidation and homeostasis [53].
The common side effect of metformin relates to gastric distress (nausea and vomiting). This can be overcome by slow titration of the doses over weeks or by using the slow-release form called glucophage. Metformin can be used in patients with an eGFR of <60mls/min/1.73m² but it is advised that benefits versus risks must be weighted in those with eGFR of 30 – 45mls/min/1.73m² [54].
2.3.1.1.2 Sulphonylurea
Sulphonylurea is a class of traditional oral hypoglycaemic drugs used in the treatment of T2DM since the 1960s. It binds on the K+ channel of the pancreatic beta-cell and prevents K+ exit. This depolarises the cell, causing an influx of Ca2+, which causes the fusion of insulin granules with the cell membrane, leading to the exudation of insulin into the blood [55]. The sulphonylureas, unlike many other oral Type 2 Diabetes hypoglycaemic agents, are ‘glucose independent’ meaning they can cause hypoglycaemia even in the stage of low plasma glucose.
They are categorised into two generational classes based on their efficacies, hypoglycaemic and cardiovascular effects [56]. The first generation is no longer in use because of increased adverse effects.
First generation
Chlorpropamide
Tolbutamide
Second generation
Glibenclamide
Glipizide
Gliclazide
Glimepiride
The sulphonylureas only work in patients who have preserved ßeta cell function, but they do not have any effects on those with declining and or absent functions. They are recommended as a second-class oral hypoglycaemic agent on the ADA/ EASD guideline to be used either as an alternative to metformin if contraindicated as monotherapy or either as dual or triple therapy [11, 36, 38].
Their use with metformin and insulin in the UKPDS shows significant reduction of microvascular complications, underscoring the importance of early intensive management [32]. However, whether the effect is specific of sulfonylurea is not known. Their effects wane over 6 months of continuous treatment and return if restarted after a pause. Furthermore, there were some cardiovascular concerns about their effects of negating the protective effects of preconditioning [57, 58, 59, 60, 61]. However, systematic reviews do not show any such effects [62]. Their other adverse effects include a modest weight gain [62]. They are, however, cheap, accessible, and readily available in many under resourced healthcare systems and remain fundamental in the management of T2DM.
2.3.1.1.3 Thiazolidinediones (glitazones)
The glitazones are insulin sensitisers and have a high glucose efficacy [63] with an internuclear mechanism of action. They bind on peroxisome proliferator-activated receptors (PPARɣ) in the nucleus, leading to the translation of increased GLUT-4 receptors on adipocytes, liver and muscle cells, which increases the glucose uptake [64]. The PRoActive study suggested that pioglitazone reduces cardiovascular diseases [40] and stroke [41, 42] and has a beneficial effect on non-alcoholic fatty liver disease. The risks and benefits must be weighed out before initiation. The risks include weight gain, bone fracture, fluid retention and heart failure.
Rosiglitazone was shown to precipitate an increased incidence of heart failure [65]. This led to the withdrawal of rosiglitazone from the market in 2008. Consequentially, the FDA released new criteria to all pharmaceutical companies to ensure all diabetic drugs are tested for cardiovascular safety as an integral safety assurance for meeting the FDA criteria. The data from the study by Nissen et al. was later reviewed, and restriction has now been relaxed [66] with an FDA recommendation for the use of rosiglitazone together with lifestyle modification in the management of T2DM.
The glitazones are second and or third line of drugs on the treatment guidelines recommendations. However, pioglitazone and rosiglitazone can still be used as a monotherapy if metformin is contraindicated or not tolerated as the first option. The decision must be balanced between glycaemic efficacy and its side effect profile.
2.3.1.2 New Hypoglycaemic agents
The incretin mimetics, SGLT2R-i, biagonist tirzapatide and the investigational triagonist rezatrutide are four new classes of diabetic drugs that possess pleiotropic effects in addition to their hypoglycaemic effects.
The incretin mimetics includes the GLP1-RA and the DPP4-i. The incretin mimetics specifically the GLP1-RA negate some of the pathophysiological processes of T2DM at the gut, pancreas and at the brain levels. They have better glycaemic efficacies and are safe. Additionally, they have cardiorenal protective effects and reduce obesity, hypertension and dyslipidaemia associated with T2DM.
The SGLT2R-i is a glucosuric class with extended pleiotropic effects. It reduces cardiovascular risk factors, heart failure hospitalisation in both the diabetic and the non-diabetic patients. Additionally, it reduces the progression of renal failure in chronic renal failure patients, though with an initial ‘permissive hypercreatinemia’. This class, however, has not been studied in patients with eGFR ≤20mls/min/1.73m².
The groundbreaking combined drugs (Tirzepatitde and investigational Rezatrutide) offer optimism of a new era in the pharmacological treatment of T2DM with extended-spectrum over and above the incretin mimetics.
These new classes of hypoglycaemic agents in their order of hierarchy are GLP1-RA, SGLT2R-i, DPP4-i, Bi-agonist—Tirzepatitide and Triagonist—Rezatrutide.
GLP1 is an incretin peptide secreted from the L-cells of the distal ileum and colon in response to glucose in the stomach. It has pleiotropic effects on many organs including stimulation of pancreatic insulin release, reduction in glucagon, delays gastric emptying, causes early satiety through its effect on the satiety centre in the hypothalamus and reduces liver glycogenolysis [67]. Its effects are terminated by the dipeptidyl peptidase 4 enzyme (DPP4) within 2 minutes of secretion.
The GLP1-RA are synthetic analogues of the native GLP1 that are stable and have improved biological and pharmacokinetic effects [68]. They are mostly injectables with one oral preparation (semaglutide), and they have a glucose-dependent action, which reduces the risks of hypoglycaemia unless used concomitantly with sulphonylureas or insulin. They are two classes of GLP1-RA based on their duration of actions:
Short acting GLP1-RA (half-life 2–5 h)
• Lixisenatide
• Exenatide
• Dulaglutide
Long acting GLP1-RA (half-life >12 h)
• Albiglutide
• Liraglutide
• Exenatide extended release
• Semaglutide
• Dulaglutide
The long-acting GLP1-RA have a predominant effect on the fasting plasma glucose (FPG) whilst the short-acting acts predominantly on the postprandial glucose excursion [68].
The head-to-head trials of the short- and long-acting GLP1-RA show that the long-acting class achieves better glycaemic control and cardiovascular risk factor reduction in addition to reducing the major adverse cardiovascular events (MACE) compared with the shorter class [10, 11]. A meta-analysis of all studies further suggests that the long-acting GLP1-RA has effective HBA1c reduction, with more patients achieving their HBA1c targets, increased weight loss, and fewer hypoglycaemic episodes compared with the short-acting GLP1-RA [69].
The commonest side effect of the GLP1-RA is gastric distress (nausea, vomiting and diarrhoea), which tends to diminish as treatment progresses into the second week [70]. Education on mindful eating (eating small at a time, only when hungry and stopping when full) and gradual titration of drug dosages help overcome these effects. Preclinical studies have suggested increased thyroid malignancies [71, 72, 73], but no human trials have demonstrated any trends. Post-marketing pancreatitis has also been reported as a complication, but no causal relationship has been established [70]. However, it is prudent not to prescribe in those with a history of pancreatitis or acute pancreatitis. Caution should be exercised in prescribing GLP1-RA for those with moderate renal failure. It is not recommended for those with end-stage renal failure [74, 75].
2.3.1.2.1.1 Personalised management of T2DM using GLP1-RA
The GLP1-RA is now used in combination therapy with other treatments for both glycaemic control and management of other comorbidities. For example, liraglutide 3 mg once weekly and semaglutide 2.4 mg once weekly are currently recommended for chronic weight management [12, 13]. Liraglutide and semaglutide can be used to reduce major adverse cardiovascular events (MACE) as shown in the LEADER and SUSTAIN-6 studies respectively [10, 11]. The PIONEER study, however, showed that oral semaglutide was non-inferior to injectable liraglutide in glycaemic control but was superior in reducing weight [76]. This finding shows that oral semaglutide can be used earlier in T2DM to provide comparative glycaemic control, used as a weight reducing drug among those with T2DM with obesity and reduce patient’s needle phobia to overcome patient’s clinical inertia. The initial dose of semaglutide is 3 mg oral daily for 30 days. If more glycaemic control is required, then the dose is escalated to 7 mg daily for another 30 days. Further escalation to 14 mg once daily if more glycaemic and weight control is required [77]. The initiation dose is 3 mg and maintenance doses are 7 and 14 mg oral once daily.
The use of GLP1-RA with insulin as a fixed-dose combination is a novel strategy that offers several potential benefits for patients with T2DM whereby weight gain and hypoglycaemic effects of insulin are negated and insulin doses are often reduced. In November 2016, the US Food and Drug Authority (FDA) approved two fixed-dose combinations of insulin and GLP1-i for this purpose.
The SGLT2R-i is a new class of oral hypoglycaemia drug approved for use in patients with T2DM as dual and or triple therapy. Canagliflozin was the first in the class to be approved in 2013 [78, 79] followed by others. The SGLT2R-i drugs currently on the market are:
Dapagliflozin
Empagliflozin
Canagliflozin
Ertugliflozin
Sotagliflozin
The sodium glucose transporters 2 receptors (SGLT2R) in the kidneys reabsorbed all filtered glucose. 90% of the receptors are in the proximal convoluted tubules and 10% in the distal convoluted tubules. Evidence suggests that they are increased in patients with T2DM, which leads to increased plasma glucose reabsorption [79]. The SGLT2R-i binds to these SGLT2R in the proximal convoluted renal tubules and prevents the reabsorption of 90% of the filtered glucose from the blood. They have a high glycaemic efficacy in non-renal failure patients.
They gained prominence when the EMPA-Reg trial in 2015, using empagliflozin with standard care in patients with T2DM at high risk of cardiovascular events, showed a relative risk reduction (RRR) of 38% in cardiovascular mortality, 35% RRR in heart failure hospitalisation (HFH) and 32% RRR in all-cause mortality [14]. This was supported by the DECALRE-TIMI 58 trial, which showed that dapagliflozin although not inferior to placebo in the reduction of the MACE, did reduce cardiovascular death by 4.9%, HFH by 5.8% and improved cardiovascular risk factors among the T2DM with high risk of cardiovascular events [15]. Further, the use of this class in heart failure has shown that even those T2DM patients with heart failure derive significant clinical benefits compared with standard care. The DAPA-HF trial among T2DM patients with chronic heart failure with reduced ejection fraction (HFrEF) showed a 16% RRR in heart failure mortality and HFH by 3.7% [16]. Similar findings were noted among those without diabetes. Additionally, the EMPEROR Reduced trial attested to the findings of the DAPA-HF trial with additional findings of reduction in the deterioration of renal function [17]. These studies, therefore, demonstrate that the SGLT2R-i offers high-risk T2DM patients with or without heart failure, significant benefit of reduction of HFH and mortality with additional renoprotective effect in those with chronic renal failure. Patients with eGFR ≤20 ml/min/1.73 m2 however, were not included in these trials.
The common side effects of the SGLT2R-i are uncomplicated urethral mycotic infection. Education with basic advice to patients before initiation such as the slogan “wee, wash and dry” will help reduce the risk. Another notable side effect is euglycemic ketoacidosis, noted as a class effect. The incidence is very low [80] and the CV outcome trials report DKA rates between 0.1% and 0.6% compared with < 0.1-0.3% among the placebo [79, 80, 81, 82, 83]. Although the FDA has raised concerns about foot amputation and reduced mineral bone density with canagliflozin, these have not been demonstrated in the heart failure trials.
The DPP4-i is a new class of drug used in T2DM. They are available as single drugs and or fixed-dose combinations to be used as monotherapy or combination therapy. The following are currently on the market:
Vildagliptin
Alogliptin
Linagliptin
Sitagliptin
Saxagliptin Fixed-dose combinations are:
Kazano = alogliptin/metformin (12.5 mg/50 or 1000 mg) bd daily.
Janumet = sitagliptin/metformin has various strengths (50 mg/500 mg, 50 mg/1000 mg, 100 mg/1000 mg) bd daily.
Galvus Met = vildagliptin/metformin (50 mg/500 mg or 50 mg/1000 mg).
Their mechanism of action is based on the reduction of the DPP4 enzymatic degradation of the GLP1 and GIP [84], which thereby prolongs the duration of actions of these incretins. Although they have effects on both the fasting plasma glucose (FPG) and the postprandial glucose (PPG), their effect on the PPG is prominent. They are glucose-dependent and therefore do not cause hypoglycaemia unless combined with other hypoglycaemic agents. They reduce blood pressure by a mean of 2.5 mmHg and have modest effect on the HBA1c reduction by 0.5–1% [85]. A meta-analysis of 80 trials has shown a mean change of HBA1c from −0.6% to −1.1% [12]. They are weight neutral [86] but reduce albuminuria progression with linagliptin [87]. Whilst generally tolerated, saxagliptin has been shown to increase HFH [88] and thus has precautionary warning. Arthralgia and hypersensitivity reactions are rare and are reported as class effect [89].
2.3.1.2.4 Biagonist—Tirzepatide
Tirzepatide is a novel bi-agonist composed of GLP1-RA and glucagon-dependent insulinotropic peptide (GIP) engineered from the native GIP. It has effects on both the GLP1R and glucagon-dependent insulinotropic receptor (GIPPR). It was approved by the Food Drug Administration (FDA) for T2DM in March 2022 [90] and the European Medicine Agency in September 2022 [91]. A phase III randomised controlled trial comparing Tirzepatide doses of 5 mg, 10 mg and 15 mg weekly injection with semaglutide 1 mg once weekly injection showed that Tirzepatide at all doses was superior in glycaemic control and weight reduction compared with semaglutide [92]. Another phase III randomised controlled trial among the non-diabetic obese patients with body mass index (BMI) of ≥30 or ≥ 27 + one obesity complication showed that all doses of Tirzepatide (5 mg, 10 mg, 10 mg) once weekly injection showed a significant and sustained reduction in body weight of 33.9% compared with placebo in the intention to treat analysis [43]. As suggested by Chavda et al., Tirzepatide could set the stage for a new era of dual-targeted therapy for diabetes and obesity [44].
2.3.1.2.5 Trigonist—Retatrutide
Retatrutide is another novel investigational therapy recently presented in the 83rd American Diabetes Association Scientific Session in San Diego on the 26th of June 2023. It is a triple therapy that is composed of a GLP1-RA, GIPR agonist and a glucagon agonist. It is one of the game-breaking agents in clinical trials for the treatment of T2DM with obesity [45, 46, 47]. It has also been shown to improve fat oxidation, mitochondrial function and reduces fibrosis in those with non-alcoholic steatohepatitis (NASH), a condition common among 5–7% of patients with T2DM. Nine out of ten patients with diabetes with concomitant NASH had normalised liver fats on MRI after 48 weeks of high doses of retatrutide [48]. This suggests that retatrutide has the potential to treat T2DM with obesity and NASH [93, 94].
Insulin is secreted in a bimodal fashion by the pancreatic beta cells to control the basal and the postprandial glucose excursion. Exogenous insulin is administered in different regimens such as the basal bolus and the basal plus regimens to simulate the physiological secretion.
Therapy for T2DM patients is indicated for those whose glycaemic control is poor despite being on other treatments. Other criteria include clinical symptoms and signs of glucotoxicities (polyuria, polydipsia, polyphagia and weight loss), HBA1c ≥9%, RBSL 16 mmol/L, uncontrolled glycemia despite optimal glycaemic therapy and acute myocardial infarction [95].
Insulin therapy in T2DM has traditionally been thought of as the last-line therapy. In fact, the current treatment guidelines categorise insulin therapy for T2DM as either second or third-line therapy [96, 97]. Recent studies have however shown that early insulinisation of T2DM patients results in beta cell preservation and clinical remission [32, 96, 98]. Therefore, insulin therapy can be initiated early in T2DM. There are, however, no specific recommendations for the initiation, titration and maintenance of insulin therapy in those with T2DM.
3.1 Insulin types, dosages and regimens
Insulins are categorised according to their duration of action (Table 2).
Administered twice daily with food as basal insulin plus regimen
Humalog mix
25 (Lispro + Protamine)
Humalog Mix 50 (Lispro + Protamine)
30–60 min
(Lispro +Protamine)
10–16 h
Novamix (Aspart + Protamine)
Novamix 30
Novamix 50
5–15 min
Dual (Protamine + Aspart)
10–16 min
NPH (Isophane + Regular insulin)
70/30
50/50
30–60 min
Dual (NPH/Regular)
10–16 h
Mixtard (soluble insulin + Isophane)
30/70
40/60
50/50
30 min
Dual (soluble insulin + isophane)
10–16 h
Degludec/Aspart (70/30)
15 min
Dual (Degludec + Aspart)
>40 h
Table 2.
Pharmacokinetics of different classes of insulins and time to use.
Times are approximate and assume subcutaneous. The effects can vary depending on several factors such as injection technique and factors affecting absorption.
Lispro and aspart are also available in premixed forms with intermediate-acting insulins.
Human insulins have generally been shown to improve glycaemic control in diabetes [32, 33, 34]. The new analogue insulin, however, has better safety and efficacy compared with human insulins. Chlup et al. have shown that short-acting analogue insulin aspart was efficacious with better patient’s acceptance than regular human insulin [18]. Further, studies show that a basal plus insulin regimen with aspart insulin was better [19] and more effective [20] in glycaemic control compared with basal insulin.
Intensive insulin treatment of T2DM has significantly reduced chronic complications [33, 34]. The Diabetes Control and Complication Trial (DCCT) among the T1Dm patient showed that patients with multiple drug injections (MDI) although had greater glycaemic control with a significant reduction of the rates of chronic complications, the episodes of severe hypoglycaemia were significant [97]. Many patients with MDI continue to have erratic fluctuations of plasma glucose. The OpT2Mis study suggested that continuous insulin infusion via insulin pump for patients with erratic blood sugar fluctuations was safe, effective [21], and a durable system of insulin delivery for patients with T2DM [22]. A meta-analysis demonstrated the superior glycaemic control and a 26% insulin reduction by continuous insulin infusion compared with MDI [23]. In the United Kingdom, the continuous insulin infusion pump costs between £2000 and £3000 depending on the supplier.
Simultaneous delivery of multiple insulins is another method of improving insulin delivery and reducing MDI. Studies suggest that improvement of the delivery systems of multiple insulins simultaneously could potentially improve patient insulin inertia, needle phobia and improve compliance. An intensive insulin regimen with a simple manual-operated injector pen for MDI was found to be less painful and very convenient for patients with T2DM [23]. Further, a small Danish study also showed that multiple insulin injection regimens using a self-contained injection device Novopen showed good glycaemic control and patient satisfaction. Out of ten patients who completed the study, eight expressed satisfaction with continuing to use the self-injection device [99].
3.1.1 Insulin initiation
Insulin initiation is based on the clinical profiles of the patients and their preferences. Overcoming patient’s barriers to insulin is important in the process of insulinisation. Pre-insulin education is important in overcoming patients’ insulin inertia [100]. Improvements in insulin delivery systems have also made a significant impact on the management of diabetes [23, 99, 100, 101, 102].
Insulin is initiated in T2DM patients for the purpose of augmentation or replacement for those who meet the criteria. Augmentation dose at 0.3–0.5 units/kg to support those patients with some degree of endogenous insulin secretion. Basal long-acting insulin used in augmentation resulted in better glycaemic control with minimal weight gain and fewer hypoglycaemic episodes compared with the pre-mix and bolus insulins [34]. Replacement insulin is initiated at the dose of 0.1–0.6 units/kg for those who have reached the burnt-out stage. Insulin dose calculation is shown in Table 3.
Criteria
Definition
Dosage
Argumentation
Argumentation of relative insulin deficiency with basal or bolus insulin
0.1–0.5 units/kg
Replacement
Replacement of absolute insulin deficiency with either in T1DM or T2DM with, basal, premix or bolus insulin
0.6–1 units/kg
Carbohydrate Count
Amount of insulin units estimated to cover ingested carbohydrate
500 g of carbohydrate divided by total daily insulin requirement
Insulin sensitivity/correction factor
1 unit of insulin estimated to normalise glucose to defined level
100 divided by total daily insulin dose
Table 3.
Insulin dose calculation.
3.1.2 Insulin titration and maintenance
Titration of insulin is critical to achieve glycaemic target and to reach a maintenance dose which is important to reduce the chronic complications. Education of the patient’s and their careers to escalate and deescalate insulin dosages according to prevailing glucose levels are important to archive glycaemic control and in addition, give patients confidence in their own management.
Pharmacotherapy is an integral part of the management of T2DM since the 1960s. Recent developments of many new drugs have increased the pharmacological armamentarium in addressing the ominous octet. These drugs have variable mechanisms of action, better efficacies and safety profiles. They have pleiotropic effects which have translated into better glycaemic control with the reduction of the chronic complications of T2DM. Additionally, they reduce other cardiovascular risk factors such as obesity, hypertension and dyslipidaemia and have protective cardiorenal effects.
Insulin therapy for T2DM is initiated in those meeting the criteria using an augmentation and replacement principle. The new analogue insulins provide effective glycaemic control compared with the human insulin. They have less weight gain and hypoglycaemic effects than the human insulins. Improvement in their delivery systems improves patient compliance and outcomes.
Two new investigational drugs are on the origin: Tirzepatitide, a biagonist and Rezatrutide, a triagonist. Both are impressive, with similar effects of the GLP1RA and GIP effects but a once-weekly dose. They could provide a new era for pharmacotherapy of T2DM.
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Written By
Leslie Bahn Kawa
Submitted: 11 July 2023Reviewed: 19 July 2023Published: 27 September 2023
Open access peer-reviewed chapter
