Diabetes: total risk - benefit of SGLT2 inhibitors and GLP1 agonists

Take-home messages

1. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists should be included in the treatment of patients with diabetes mellitus (DM) and underlying comorbidities such as cardiovascular pathology and cardiovascular risk.
2. SGLT2 inhibitors are used in the treatment of type 2 DM patients with heart failure (HF), either with reduced or preserved ejection fraction of the left ventricle, and they are indicated in the HF treatment regardless of the presence of DM.
3. GLP-1 agonists are indicated in the primary and secondary prevention of cardiovascular incident in patients with DM, and early treatment initiation should be imperative.

Introduction

Diabetes mellitus (DM) is defined as a group of metabolic diseases that are characterised by a tendency for chronic hyperglycaemia [1]. DM develops due to either a lack of insulin production (type 1 DM), as a result of destroyed beta cells of pancreas due to an autoimmune reaction, or resistance to insulin (type 2 DM), where insulin is being produced at least in the early stages of disease because beta cells are still present, but tissues do not respond to insulin [1].

Other types of DM are a) gestational diabetes as, during pregnancy, there is tendency towards hyperglycaemia, characterised by a reduced production of insulin, as well as peripheral resistance of tissues to it; b) latent autoimmune diabetes of adults (LADA), usually occurring in men over 40 years of age, in whom a progressive autoimmune process destroys the beta cells of pancreas, which is similar to type 1 DM. Another type of diabetes that is similar to type 2 DM, but developing at a younger age, is called maturity onset DM (MODY) [1]. Drug-induced diabetes may occur due to different drugs being taken longer term and contributing to the development of chronic hyperglycaemia [1,2].

Myocardial infarction, end-stage renal disease and stroke may be induced due to complications of DM [1]. Diabetic patients are at an increased risk of cardiovascular events and cardiovascular mortality. Moreover, DM is considered a risk factor for the development of heart failure (HF) and the progression of kidney disease. In recent years, studies have suggested that antidiabetic medications may grant renoprotection through a mechanism other than affecting glucose homeostasis [1,2].

Prevalence

In 2021, the global prevalence of DM in people from 20 to 79 years of age was estimated to be 10.5% (536.6 million), and in 2045, it is expected to rise to 12.2% (783.2 million). Diabetes is equally prevalent in both men and women, with those aged from 75 to 79 years of age having the highest rates of the disease [3]. The prevalence was reported to be higher in urban (12.1%) than rural (8.3%) areas, as well as in high-income (11.1%) than low-income (5.5%) countries [3]. Between 2021 and 2045, middle-income countries are expected to have the highest relative increase in DM prevalence (21.1%), followed by high-income (12.2%) and low-income (11.9%) countries [3].

Complications of diabetes mellitus

Complications of DM seen through the prism of coronary artery disease (CAD) involve vascular problems (macro- or microvascular complications), impaired cerebrovascular circulation that develops into ischaemic or haemorrhagic stroke, peripheral arterial disease, and nephropathy (although most kidney disease in diabetic patients is microangiopathic, major vessels that supply the kidney can also develop atheroma, known as diabetic renovascular disease). In youth-onset type 2 DM, complications appear early and develop rapidly [1,2]. Despite the young age of these patients, serious cardiovascular events do occur. Overall, patients with DM have a poorer long-term prognosis after a previous heart attack, including an increased rate of reinfarction, HF and death [1,2,4].

Clinical outcomes of sodium-glucose co-transporter 2 (SGLT2) inhibitors in cardiovascular treatment

Despite the prevalence of type 2 DM, there are few effective long-term treatments for the patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are agents that reduce the level of blood glucose in these patients. In the clinical trials conducted thus far, the use of SGLT2 inhibitors was shown to improve the quality of life of patients with type 2 DM, have benefit in treatment of HF, either with reduced or preserved ejection fraction of the left ventricle. They reduce rate of hospitalisations for acute HF and slowing the progression of chronic kidney disease and they are indicated in the HF treatment regardless of the presence of DM. (Table 1).

Table 1. Sodium-glucose co-transporter 2 (SGLT2) inhibitors in clinical trials.

CV: cardiovascular; DM: diabetes mellitus; HF: heart failure; MACE: major adverse cardiac events

The cardiovascular safety of these drugs has been studied extensively. The new class of SGLT2 inhibitors, namely dapagliflozin, canagliflozin, and empagliflozin were designed to reduce glomerular hyperfiltration and inhibiting proximal tubular hyperreabsorption, excreting glucose from the body, thereby, the blockade of the SGLT2 transporter appears to provide a nephroprotective effect. This effect lowers blood glucose levels without affecting insulin sensitivity, hence with a lower risk of hypoglycaemia. The increase in glycosuria and diuresis produced by these agents leads to a reduction in weight and blood pressure - the weight loss is predominantly due to a loss of fat mass rather than volume depletion. Potential safety concerns include the risks of hypotension and the precipitation of kidney failure among patients with fluctuating volume status and renal function who are receiving treatment with other drugs that might also affect the glomerular filtration rate (GFR). An increased incidence of genitourinary infections, a decrease in bone formation, as well as euglycemic ketoacidosis are known side effects of SGLT2 inhibitors.

Canagliflozin was the first SGLT2 inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Two trials (CANVAS, The Canagliflozin Cardiovascular Assessment Study, and CANVAS-Renal) investigated the use of canagliflozin among patients with type 2 DM and a high risk of cardiovascular disease and deduced that canagliflozin reduces the risk of renal failure and cardiovascular events in diabetic patients with kidney disease, and that this medication was associated with a higher risk of leg and foot amputations [5,6].

Empagliflozin was studied in several multinational clinical trials, and it is an effective long-term treatment of type 2 DM. In patients with type 2 DM and HF with a reduced ejection fraction, empagliflozin mitigates the development and progression of HF [7,8]. Also, in patients with HF and a preserved ejection fraction, empagliflozin demonstrated a 21% lower relative risk of cardiovascular death or hospitalisation for HF, including patients with DM type 2 [9]. The use of empagliflozin was also associated with a reduction in the overall number of hospitalisations for worsening HF. Hence, Zinman et al studied the role of empagliflozin in patients with type 2 DM and high cardiovascular risk and found that the use of empagliflozin was not associated with a reduced risk of cerebrovascular events [7].

Dapagliflozin was shown to improve the glycaemic control in diabetic patients. A study by Heerspink et al study demonstrated that, independently of the presence or absence of type 2 DM, dapagliflozin's use in chronic kidney disease patients significantly lowered the risk of a sustained decline in the estimated GFR by approximately 50% for end-stage kidney disease or death from renal or cardiovascular causes. In addition, dapagliflozin use lowered the risk of hospitalisation for HF and offered longer survival [10]. Dapagliflozin was non-inferior to placebos in the DECLARE-TIMI 58 (The Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) trial in terms of the primary safety outcome of major adverse cardiovascular events (MACE). However, it did result in a significantly lower rate of cardiovascular death or hospitalisation for HF than placebos in a large population of type 2 DM patients [11]. Furthermore, dapagliflozin treatment was linked to significant improvements in HbA1c and reductions in body weight, body mass index (BMI) and systolic blood pressure (SBP). The beneficial effects of dapagliflozin persisted over time, indicating that the drug not only improves HbA1c and SBP, but also prevented them from worsening [12].

Ertugliflozin has been studied for its long-term effects on the kidney and heart of patients with type 2 DM [13]. The VERTIS CV trial revealed that the efficacy of ertugliflozin in patients with type 2 DM and atherosclerotic cardiovascular disease is non-inferior to placebo in terms of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke [13]. Moreover, ertugliflozin lacked significant benefit for the renal composite outcome, as opposed to previous trials of other SGLT2 inhibitors.

Clinical outcomes of glucagon-like peptide 1 agonists in cardiovascular treatment

Glucagon-like peptide-1 (GLP-1) agonists represent a therapeutic modality of type 2 DM in adults, their use is potentiated in patients with cardiovascular pathology or in patients at risk of a cardiovascular incident and they have benefit in primary and secondary prevention of cardiovascular incident in patients with DM [2]. Early treatment initiation should be imperative based on aforementioned characteristics. The effect is based on the effect of delayed gastric emptying and inhibiting the production of glucagon from pancreatic alpha cells (if blood sugar levels are high), in stimulating insulin secretion after an oral glucose load, via the incretin effect, and on decreasing pancreatic beta-cell apoptosis while promoting their proliferation [2].

GLP-1 agonists have an effect on weight loss, the reduction of systolic and diastolic blood pressure, the reduction of cholesterol levels, improve the ejection fraction of the left ventricle, increase myocardial contractility, coronary blood flow, cardiac output and endothelial function, while reducing infarction size and overall risks of an acute cardiovascular event, as well as the risk of mortality in patients with cardiovascular risk. They show an effect on increased glucose uptake in the muscles, decreased glucose production in the liver, neuroprotection, and increased satiety by direct actions on the hypothalamus.

Contraindications include hypersensitivity, pregnancy, presence of gastroparesis and inflammatory bowel disease with severe renal dysfunction, multiple endocrine neoplasia 2A, multiple endocrine neoplasia 2B, or medullary thyroid cancer, history of a pancreatitis and they should be discontinued in patients who develop pancreatitis.

It should be emphasised that the use of GLP-1 agonists achieves a wide range of benefits, but they are primarily intended for patients with type 2 DM, with indications extending primarily to the cardiovascular system. Almost all organ systems have GLP-1 receptors, therefore, it can be assumed that GLP-1 agonists act on all organs. However, due to insufficient research at the molecular level, for a more complete understanding of the mechanism of their action, more studies will have to be done [14,15,16].

The characteristics of the initial studies that established the use of GLP-1 agonists are shown in Table 2. Understanding a clinical trials' results is crucial to the future use of these agents (for instance, albiglutide was withdrawn from the market in 2017).

It should be emphasised that in the REWIND trial, the primary aim was to achieve superiority over other studies that are non-inferiority studies. The REWIND (Dulaglutide and cardiovascular outcomes in type 2 diabetes: a double-blind, randomised placebo-controlled trial) was also the study with the highest number of participants and the highest percentage of women, 46.3% [14]. In this trial, the baseline HbA1C was 7.3%, while it was 8.7% in the LEADER (The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial) and SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) trials [15,16].

The HbA1C value of 7.3% represents relatively well-regulated patients, as opposed to the HbA1C value of 8.7%, which represents unregulated diabetic patients. In the REWIND trial, the HbA1C wanted to set aside and examine the effect of dulaglutide on the cardiovascular segment through MACE-3 events, which was proven by reducing the risk in the terms of primary and secondary prevention by 12%. In the LEADER and SUSTAIN-6 trials, only the secondary prevention was achieved, with a reduction of 13% in the LEADER and 26% in the SUSTAIN-6 trial for MACE-3 [16].

Table 2. Cardiovascular outcome trials which supported the use of GLP-1 agonists.

CI: confidence interval; GLP-1: glucagon-like peptide-1; HR: hazard ratio; MACE: major adverse cardiac events

In the REWIND trial, HbA1C was reduced by 0.6%, resulting in HbA1c below 7% for the trial duration during a 5.4-year period, which is the longest duration of a trial compared to other studies. In the SUSTAIN-6 study, HbA1C was reduced by 1.4%. The LEADER trial lasted 3.8 years, while SUSTAIN-6 lasted even shorter. The SUSTAIN-6 trial was set up as a safety trial, while the LEADER and REWIND trials, aimed to verify 1,200 MACE-3 events when the studies were completed [14,15,16]. For that reason, LEADER and REWIND lasted much longer.

The next parameter that is of interest was the percentage of patients who had cardiovascular (CV) disease. In the LEADER and SUSTAIN-6 trials, this percentage was higher than 80%, while in the REWIND trial, it was 31%. Therefore, REWIND represents evidence of dulaglutide indication in primary prevention, while the LEADER and SUSTAIN-6 trials were oriented towards secondary prevention. Obesity treatment was a secondary effect of these drugs. Semaglutide 2.4 mg subcutaneously received this indication [17].

Increasing the dulaglutide dose from 1.5 mg to 3.0 mg or 4.5 mg in the AWARD-11 (Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomised Controlled Trial) provided clinically relevant reductions in both the HbA1c level and body weight with a similar safety profile [18].

It should be noted that oral semaglutide was also tested for efficacy and safety in the PIONEER 9 trial (dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes: a 52-week, phase 2/3a, randomised, controlled trial) [19].

The main aim of GLP-1 agonists is to regulate glycemia, while weight reduction is a secondary benefit in diabetic patients. From a post hoc analysis of REWIND, the HbA1C reduction was only associated with the cardiovascular benefits of the trial, while weight loss and blood pressure changes did not affect the benefit terms of cardiovascular segment.

In clinical practice, good results are achieved with lower doses of the drug semaglutide 0.5 mg or liraglutide 1.2 mg, in the regulation of glycemia, while trial results are linked to higher doses, especially in the prism of cardiovascular segment.

As with other pharmacological treatments, adherence to the weekly regimen is indispensable. Poor adherence to the treatment is an important barrier to achieving optimal treatment goals and is associated with poorer outcomes.

Future directions

Simultaneous inhibition of SGLT2 and SGLT1 plays a role in the unique safety and efficacy of this class of drugs by inhibiting both intestinal and renal glucose absorption and increasing GLP-1 release, as well as protecting cardiac tissue by lowering glycogen accumulation.

Sotagliflozin represents a dual (SGLT2 and SGLT1) inhibitor, and the mechanism of this drug is related to various physiological effects. Some of these include weight loss, improved oxygen supply, blood pressure reduction, renal and systemic natriuretic effects. It can also slow down the absorption of glucose in the intestine and reduce postprandial glycemia. Side effects that occur with sotagliflozin treatment include diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis.

Inhibition of SGLT1 may be linked to a lower risk of cardiovascular events as well. According to one study, sotagliflozin reduced the risk of cardiovascular events by 45% and all-cause mortality by 49%. Also, its efficacy in patients with chronic kidney disease was improved by the dual inhibition of SGLT1 and SGLT2 [20].

The SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial revealed that dual SGLT inhibition with sotagliflozin reduces total number of deaths from cardiovascular causes, hospitalisations, and urgent visits for HF in patients with diabetes and worsening HF with either reduced or preserved ejection fraction [20].

Treatment with SGLT2 inhibitors should be individualised based on patient characteristics as well as drug properties. The SGLT2 inhibitors' potentially serious side effects, such as genital mycotic infections, bone fractures, and ketoacidosis, should not overshadow their overall benefit on the cardiovascular and renal system, especially in patients with type 2 DM who are at high cardiovascular risk. However, despite the generally favourable safety profile of these drugs, it is still unclear if their benefits are drug-specific, and the existence of a class effect is still a point of contention. Because of the limited understanding of the risk-benefit profile of SGLT2 inhibitors, it is possible that these drugs will be used inefficiently. Therefore, more research is required to investigate these agents.

A conclusion that early treatment initiation greatly enhances the chances of positive outcomes, reflects the novel insights on the clinical utility of dual SGLT inhibition.

Tirzepatide, a drug which is a glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist, could be a new promising agent in the treatment of DM. Research studies evaluating the effect of GLP-1 agonists on retinopathy (especially semaglutide) and the rate of pancreatitis are on the way. Other aspects that merit further investigation are, for example, the appropriate duration of their use (especially with respect to the effect on the HbA1c level), their effect on brain natriuretic peptides, and on peripheral arterial disease.

Conclusions

SGLT2 inhibitors and GLP-1 agonists have now become part of the current cardiovascular pharmacology guidelines for the treatment of patients diagnosed with type 2 DM and cardiovascular disease. Therefore, their use should be prioritised based on the patient’s DM profile and cardiovascular risk.