Drug Therapies for Diabetes

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1		Itamar Raz	--	3949	2024-01-03 03:11:26

This entry is adapted from the peer-reviewed paper 10.3390/ijms242417147

The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight.

T2DM disease management combination therapy SGLT-2I GLP1 RA

1. Introduction

The last decade has seen the advent of new medications for lowering blood glucose levels. These medications also exhibit a remarkable capacity to alleviate cardiovascular risk factors. These drugs demonstrate a significant ability to reduce the rates of cardio-renal events in patients with diabetes, as well as in individuals without the disease ^[1].

These medications have shifted the focus of cardiologists, nephrologists, and healthcare professionals towards preventing cardio-renal events, partially at the expense of focusing on the importance of maintaining near-normal blood glucose levels ^[1]^[2]^[3]. Simultaneously, several influential studies have highlighted the crucial role of maintaining optimal blood glucose levels for preventing both microvascular and macrovascular complications. These studies raise the fundamental question of whether a 7% hemoglobin A1c (HbA1c) level is an adequate goal or whether we should strive for the normalization of blood glucose levels ^[4]^[5].

These studies have also prompted discussions about the early administration of drugs in patients with diabetes, potentially as combination therapies, and their possible role in the management of diabetes and newly diagnosed diabetes ^[6]. The introduction of these new medications has led to inquiries regarding the role of older drugs in diabetes management and whether discontinuing some of them may be warranted due to the associated potential for harm ^[5]^[7].

2. Metformin

Sixty years after it was introduced into the diabetes pharmacopeia, metformin remains a cornerstone in the treatment of type 2 diabetes and is recommended as the primary oral drug of choice for the management of T2DM across all age groups ^[8]. The well-known advantages of this agent include its glucose-lowering efficacy, ease of combination with almost any other glucose-lowering agent, and its low cost. Metformin is well-tolerated, has only mild side effects, carries a low risk of hypoglycemia, and provides modest body-weight reduction ^[9]^[10].

Metformin, the first-line medication for treating type 2 diabetes, has complex and not yet fully elucidated mechanisms of action that extend beyond its traditionally understood effects on glucose regulation in the liver. While early evidence highlighted the liver as a primary site of action, recent studies indicate a more multifaceted process involving other body areas, such as the gastrointestinal tract, gut microbiota, and tissue-resident immune cells. Its effects seem to differ based on dosage and treatment duration. While the drug was initially thought to primarily affect hepatic mitochondria, new research suggests a novel target at low concentrations, possibly at the lysosome surface. This research suggests a new mode of action. Amidst ongoing debates and the complexity of available information, recent discoveries suggest that the impact of metformin extends beyond liver functions, involving the gut microbiota and immune-system modulation. The drug’s effects could thus potentially expand its use to conditions beyond diabetes ^[11].

A recently published meta-analysis suggested that metformin may protect the cardiovascular system. It also noted that not only could the drug be used more widely to improve kidney function, but that it could contribute to kidney protection. Data also indicate that metformin may reduce the risk of neurodegenerative conditions, and trials are ongoing to directly evaluate the drug’s anti-neoplastic properties ^[12]. Regarding dementia, a meta-analysis demonstrated that diabetic patients treated with metformin had a significantly lower prevalence of cognitive impairment (odds ratio = 0.55, 95% CI 0.38 to 0.78). Furthermore, the incidence of dementia was also significantly reduced in this group (hazard ratio = 0.76, 95% CI 0.39 to 0.88) ^[13].

Regarding the anti-neoplastic properties of biguanides, metformin has emerged as a promising candidate for anticancer treatment. Accumulating epidemiological, preclinical, and clinical evidence have provided support for the utilization of metformin as a therapeutic agent in cancer ^[14]^[15]. There are over 50 recent or active clinical trials investigating the use of metformin for human malignancies. Of particular significance is its ability to reduce circulating insulin levels, which may have significant implications for the treatment of malignancies associated with hyperinsulinemia, such as breast and colon cancers. Furthermore, metformin may exert direct inhibitory effects on cancer cells by targeting the signaling pathway of mammalian target of rapamycin (mTOR) and interfering with protein synthesis ^[15]. Two studies investigated the effects of metformin administered over periods of three to six months to women who had completed chemotherapy and radiation treatment for breast cancer. The first study focused on women with plasma insulin levels of at least 45 pmol/L. This selection criterion was based on earlier research that had identified these women as being at a heightened risk for breast cancer. In this study, metformin was shown to reduce circulating insulin levels by 22.4% (p = 0.024) ^[16].

The second study involved women with elevated testosterone levels and compared metformin doses of 1000 mg/day and 1500 mg/day. The higher dose was found to significantly lower serum testosterone levels and the free androgen index compared to the lower dose. These findings highlight the potential of metformin to reduce serum markers associated with an increased risk of breast cancer ^[16].

In terms of the impact of metformin on cardiovascular disease, a meta-analysis of 13 trials (which included 2079 individuals with T2D who were allocated to metformin and a similar number to the comparison groups of diet and lifestyle changes or placebo) yielded favorable results for the prevention of myocardial infarction/ischemic heart disease. However, no effect reached statistical significance, mainly due to the absence of high-quality evidence ^[17]. The “UKPDS” study included 4075 early diagnosed diabetic patients randomly assigned to either a healthy-lifestyle intervention or healthy-lifestyle intervention with ADD. Among 342 obese diabetic patients that was randomized to metformin therapy, there was relative risk reduction (RRR) of −32% for diabetes-related endpoints, −42% for diabetes-related deaths, −39% for myocardial infarction, and −36% for overall mortality ^[18].

Furthermore, a recent clinical trial presented promising findings regarding long Corona virus disease (COVID). Outpatient treatment with metformin reduced the incidence of long COVID by 40% compared with placebo ^[19].

Despite extensive, long-standing experience with the clinical use of metformin, its mode of action is still not fully understood ^[8].

Notwithstanding the significant benefits of metformin, its high efficacy, and its low risk of side effects, there is increasing consensus that other approaches may be more appropriate as a first line of treatment for some patients ^[20].

3. Thiazolidinediones

Thiazolidinediones (TZD) work by binding to the peroxisome proliferator-activated receptor gamma (PPAR-γ) in the cell nucleus. This binding modulates gene expression involved in glucose and lipid metabolism, enhancing insulin sensitivity in muscle, fat, and liver cells. The primary advantages of TZD include improved glycemic control by reducing blood sugar levels, potential preservation of pancreatic beta cell function, and in some cases, positive impacts on lipid profiles, cardiovascular health, and the reduction of inflammation ^[21]. On the other hand, treatment with pioglitazone can increase the risk for weight gain, peripheral and retinal edema, dyspnea, hospitalization for heart failure (HHF), and bone fractures, mainly in women ^[22].

The PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial presented promising data regarding the beneficial effects of pioglitazone. The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. The results presented a significant decrease in fatal/nonfatal MI (excluding silent MI) [HR = 0.77; 95% CI 0.60–1.00; p = 0.046] and the composite of cardiovascular death, MI (excluding silent MI), and stroke (HR = 0.82; 95% CI 0.70–0.97; p = 0.020) ^[23].

In contrast, a meta-analysis published in 2022 that examined the effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes found that pioglitazone did not significantly affect major adverse cardiovascular events (MACE), all-cause mortality, or HHF (MH–OR: 0.90, 95% CI 0.78–1.03, 0.91, 95% CI 0.77–1.09) and (MH–OR: 1.16, 95% CI 0.73–1.83), respectively) ^[24]. The IRIS (Insulin Resistance Intervention after Stroke) trial was a multicenter, double-blind trial that randomly assigned 3876 patients who had recently suffered ischemic stroke or transient ischemic attack to receive either pioglitazone or a placebo. Among the patients who received pioglitazone, the risk of stroke or myocardial infarction was lower than it was among those who received the placebo (HR 0.76, 95% CI, 0.62–0.93; p = 0.007)) ^[22]. Pioglitazone has positive effects in nonalcoholic steatohepatitis (NASH) in both diabetic and non-diabetic patients ^[25]. In 2006, a randomized control trial with 55 patients presented proof of concept that pioglitazone plus diet, as compared with diet plus placebo, normalized liver aminotransferase levels, as it decreased plasma aspartate aminotransferase levels by 40% vs. 21% (p = 0.04), decreased alanine aminotransferase levels by 58% vs. 34%, (p < 0.001), decreased hepatic fat content by 54% vs. 0% (p < 0.001), and increased hepatic insulin sensitivity by 48% vs. 14% (p = 0.008) ^[26].

A meta-analysis that evaluated the effects of thiazolidinediones for the treatment of patients with prediabetes or T2DM combined with Nonalcoholic fatty liver disease (NAFLD) found that pioglitazone significantly improved insulin sensitivity and the results of liver histology. Additionally, it significantly reduced fasting blood glucose, glycosylated hemoglobin, plasma AST, ALT, and other liver biological indicators ^[27].

In 2012, the American Association for the Study of Liver Disease (AASLD) added pioglitazone as a treatment option for patients with biopsy-proven NASH ^[28].

4. Dipeptidyl Peptidase-4 Inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are common oral anti-hyperglycemic agents that are widely used worldwide. DPP-4 is an important modulator of the incretin system. DPP-4 inhibitors increase the concentrations of both active incretin hormones. They affect levels of GLP-1 by removing the N-terminal His7Ala8 from the active form of GLP-1 and glucose-dependent insulinotropic polypeptide ^[29]. Blocking incretin degradation with DPP4-i allows postprandial insulin release. The first DPP4-i, sitagliptin, received U.S Food and Drug Administration (FDA) approval in 2006. Extensive data from major clinical trials present the benefits of DPP4-i, such as lowering of HbA1c levels and reductions in inflammation and adipocyte size ^[29]. Some DPP4-i, like sitagliptin and saxagliptin, did not increase risk of major adverse cardiovascular events in diabetic patients with known cardiovascular disease ^[30]^[31]. In the SAVOR trial, saxagliptin increased the risk for HHF. Similar non-significant results were demonstrated in the EXAMINE trial ^[32], although the reason is currently unknown ^[31]^[33]. Therefore, the FDA does not recommend saxagliptin or alogliptin for patients with HF. DPP4-i may also decrease renal microalbuminuria. The SAVOR-TIMI53 trial presented positive renal outcomes with saxagliptin, which reduced the development and progression of microalbuminuria in patients with diabetes ^[31]^[34]. DPP4-i are known to be weight-neutral and carry a very low risk of hypoglycemia. Concerns were raised about possible risks for pancreatic cancer, neuroendocrine tumors, and pancreatitis with DPP4-i treatment. However, in 2014, the FDA and the European Medicines Agency (EMA) announced they could not establish a clear relationship between DPP4-i and pancreatitis or pancreatic cancer ^[35].

5. Sulfonylureas

Sulfonylureas lower blood glucose levels by increasing insulin secretion in the beta cells by blocking the KATP channels. They also limit gluconeogenesis in the liver. Sulfonylureas decrease the breakdown of lipids to fatty acids and reduce clearance of insulin in the liver ^[9].

Sulfonylureas are assessed as having high efficacy in lowering blood glucose levels but lack a durable effect and is associated with weight gain and hypoglycemia ^[9]^[20]. Use of sulfonylureas or insulin for early intensive blood glucose control significantly decreased the risk of microvascular complications, underscoring the importance of early and continued glycemic management ^[36].

At the same time, due to their glucose-independent stimulation of insulin secretion, sulfonylureas are associated with an increased risk of hypoglycemia ^[9]. Moreover, concerns about their cardiovascular safety have been raised in several retrospective studies, suggesting a greater risk of cardiovascular disease in patients treated with some of the sulfonylureas that prevent the preconditioning ischemia in the heart ^[37].

Nonetheless, sulfonylureas such as gliclazide and repaglinide do not block NA+/K+ ATPase in the heart vessels, and were not shown to increase cardiovascular events or mortality. ^[38].

Because novel glucose-lowering agents are available, because sulfonylureas carry the risk of hypoglycemia and weight gain, and because the effects of sulfonylureas decline over the long term, sulfonylureas should not be considered as first- or second line. Their use should be considered in patients who are not well-controlled with metformin, and for whom SGLT-2i, GLP1 RA, and DPP-4i are contraindicated or not tolerated, unavailable, or unaffordable. The expert opinion consensus panel published in Diabetes, Obesity and Metabolism in 2020 advised including sulfonylureas as a third-line treatment option ^[39]. A quadruple treatment combination therefore would include metformin, SGLT-2i, GLP-1RA, and sulfonylureas to provide additional decreases in HbA1c, mainly to achieve microvascular protection ^[39].

6. Glinides

Glinides, also known as meglitinides, are insulin secretagogues that depolarize pancreatic β-cells and consequently increase insulin release. Glinides include the drugs repaglinide and nateglinide ^[40]. Glinides and sulfonylureas differ in structure, yet both stimulate insulin secretion through distinct β-cell receptors ^[8]. When used as monotherapies, they exhibit similar clinical efficacy ^[41].

Glinides are rapid-acting, prandial glucose regulators that, unlike sulfonylureas, have a short duration of action. These characteristics render them effective in mitigating postprandial hyperglycemia when they are administered along with meals and are especially advantageous for individuals with inconsistent mealtimes ^[42]. Glinides are useful in patients with chronic kidney disease, as they are predominantly metabolized by the liver and therefore may be a useful alternative to metformin in this population ^[43].

In a Cochrane review of 15 trials that assessed the effects of glinides in patients with T2DM, both repaglinide and nateglinide led to reductions in HbA1c levels. Repaglinide resulted in a decrease of 0.1% to 2.1% in HbA1c, compared to 0.2% to 0.6% for nateglinide. Repaglinide was comparable to metformin in its effectiveness in reducing HbA1c levels, but nateglinide was not ^[44]. Combination therapy with metformin and glinides may improve glycemic control compared to metformin monotherapy ^[45].

Hypoglycemia is one of the major concerns associated with the use of glinides. Nevertheless, most episodes are mild to moderate and do not require assistance. Severe hypoglycemic episodes are rare but may occur; thus, glucose monitoring is important when treatment is initiated until safety is established ^[44]^[46]. Hypoglycemic events appear to be more common with sulfonylureas compared to glinides, and both can lead to weight gain ^[46].

Long-term studies investigating the effect of glinides on cardiovascular outcomes or mortality in patients with T2DM are lacking, and there is no compelling evidence that glinides increase cardiovascular risk ^[44]^[47]. Glinides are mostly used as an additional hypoglycemic agent for patients who fail to achieve their glycemic targets with metformin, but they are also useful as monotherapies when metformin or sulfonylureas are contraindicated.

7. Alpha-Glucosidase Inhibitors

Polysaccharides and disaccharides undergo enzymatic cleavage by alpha-glucosidase to monosaccharides in the upper intestine. Alpha-glucosidase inhibitors reversibly inhibit the enzymatic cleavage of complex carbohydrates to simple absorbable sugars, thereby reducing post-prandial hyperglycemia with no risk of hypoglycemia, subsequently reducing HbA1c ^[48].

In 1999, acarbose (Precose), an alpha-glucosidase inhibitor, was the first drug of this type approved by the FDA. In a multicenter, double-blind, placebo-controlled trial published in 1995, three doses of acarbose (100, 200, and 300 mg three times daily) were compared with placebo. After 16 weeks of treatment, acarbose-treated patients had significant reductions in mean HbA1c levels of 0.78%, 0.73%, and 1.10% (relative to placebo) in the 100 mg, 200 mg, and 300 mg groups, respectively. Gastrointestinal side effects (e.g., abdominal pain, flatulence, and diarrhea) and elevated serum transaminase levels were reported more frequently by the patients treated with acarbose than by those who received the placebo ^[49].

Acarbose can be an option for diabetic patients with constipation. Note that in the case of hypoglycemia in patients with concurrent treatment with acarbose, glucose/dextrose-only solutions are recommended.

8. Glucagon-like Peptide-1 Receptor Agonists—GLP 1 RA

GLP-1 RA has an excellent effect on the cardiovascular system and the brain, but its effects on heart failure and kidney failure are controversial. GLP-1 is a peptide hormone with multiple effects, including increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent matter. Additionally, GLP-1 delays gastric emptying and increases satiety. Currently, there are multiple options for the use of GLP-1RA, which has substantial HbA1c-reduction properties ^[50]. In addition to their significance as glucose-lowering agents, GLP-1RAs present encouraging characteristics, including anti-inflammatory and anti-obesity properties, protective effects on the lungs, and a positive influence on the composition of the gut microbiome ^[51].

Nevertheless, GLP-1RAs are associated with common adverse gastrointestinal effects, which affect more than a third of patients ^[50].

The recently published STEP 1 (Semaglutide Treatment Effect in People with Obesity) ^[52], STEP 2 ^[53], STEP 3 ^[54], and STEP 4 ^[55], trials demonstrate the tremendous impact of weekly GLP-1RA treatment with semaglutide on weight loss and cardiovascular risk factors. The results of the trials led to the conclusion that 2.4 mg semaglutide once a week provides impressive weight loss and improvement in cardiovascular risk factors. It is approved for chronic weight management in adults with Body Mass Index (BMI) ≥ 30 kg/m² or BMI ≥ 25 kg/m² with concomitant conditions such as T2D, hypertension, or hyperlipidemia ^[56]. Additional metabolic benefits included improvements in liver fat content and reduced visceral and subcutaneous abdominal adipose-tissue volumes ^[20].

GLP-1RAs have additional benefits on blood pressure, with significant decreases in systolic blood pressure among hypertensive patients. Diastolic blood pressure is affected less. However, a significant increase in heart rate of 2–4 beats per minute has also been observed ^[57]. Furthermore, a meta-analysis published in November 2022 indicates an increased risk of both all thyroid cancer and medullary thyroid cancer associated with the use of GLP-1 RA, particularly after 1–3 years of treatment ^[58].

Cardiovascular outcome trials (CVOT) showed that treatment with GLP-1RA is associated with significant cardiovascular benefits ^[59].

In August 2023, Novo Nordisk disclosed the headline findings of the SELECT cardiovascular outcomes study. This double-blind trial investigated the use of subcutaneous, weekly 2.4 mg semaglutide in addition to standard care for the prevention of MACE over a period of up to five years, compared to a placebo. The study involved 17,604 adults ages 45 years or older who were diagnosed with overweight or obesity and established cardiovascular disease but who had no previous history of diabetes. The trial successfully met its primary objective by showing a statistically significant 20% reduction in MACE among individuals treated with 2.4 mg semaglutide in comparison to those who received the placebo. Real-world studies investigating cardio-renal outcomes of GLP-1RA suggest that initiation of GLP-1RA was associated with benefits for composite cardiovascular outcomes, MACE, all-cause mortality, myocardial infarction, stroke, cardiovascular death, and peripheral artery disease ^[59]. A study that examined the effects of the use of GLP-1 RA on stroke found that the use of semaglutide reduced the incidence of stroke compared to placebo among people with type 2 diabetes at high cardiovascular risk. This outcome was driven mainly by the prevention of small-blood-vessel blockage ^[60]. It has been shown that GLP 1 reduces proteinuria, but its effect on kidney function is still questionable. Some studies showed that GLP 1 increases cystatin C43, which raises concerns about possible negative renal outcomes ^[61]. Recently, the Icelandic Medicines agency reported about 150 cases of suicidal thoughts and self-injury among people using liraglutide and semaglutide medicines ^[62]. As a result, the EMA’s Safety Committee stated that it will review data on the risk of suicidal thoughts and self-harm as a potential adverse effect of GLP-1 RA use ^[63]. Clinical trials with GLP-1 RA such as SCALE and STEP usually exclude patients with major depressive disorders and previous suicidal attempts; thus, data about the increased risk of self-harm is limited. As of the writing of this research, the researchers did not find compelling evidence in the literature of an increased risk of suicide and self-harm related to GLP-1 RA use ^[52]^[64]. Nonetheless, the EMA review is ongoing, and further recommendations cannot be made on this matter.

Oral GLP-1RA were first introduced in 2019 with oral semaglutide (Rybelsus). When compared with 1 mg subcutaneous semaglutide, there was no significant difference in weight loss and HbA1c at 20 mg and 40 mg doses, with standard escalation. The 2.5 mg, 5 mg and 10 mg groups were all inferior to 1 mg subcutaneous semaglutide in decreasing HbA1c (−0.4%, −0.9%, −1.2% and −1.9%, respectively). The 5 mg and 10 mg doses resulted in body weight decrease of −1.5 kg and −3.6 kg, respectively. Most adverse events are mild, with the most common being gastrointestinal disorders; these results are similar to those seen with the subcutaneous formulation ^[65].

Retatrutide, another novel incretin-mimetic drug, is an agonist of the GLP-1, GIP and glucagon receptors. The Retatrutide Phase 2 trial, published in August 2023, was a phase II, double-blind, randomized, placebo-controlled trial involving 338 non-diabetic adults who had a BMI of 30 or higher, or a BMI of 27 to less than 30 and at least one weight-related condition. Participants were randomized to administration of subcutaneous retatrutide at varying doses (1 mg, 4 mg [initial dose: 2 mg], 4 mg [initial dose: 4 mg], 8 mg [initial dose: 2 mg], 8 mg [initial dose: 4 mg], or 12 mg [initial dose: 2 mg]), or a placebo, weekly, over 48 weeks. At 48 weeks, the least-squares mean percentage weight changes in the retatrutide groups were as follows: −8.7% in the 1 mg group, −17.1% in the combined 4 mg group, −22.8% in the combined 8 mg group, and −24.2% in the 12 mg group, compared to −2.1% in the placebo group. Weight reductions of 5% or more, 10% or more, and 15% or more were observed in 92%, 75%, and 60% of participants receiving 4 mg of retatrutide; 100%, 91%, and 75% for those on 8 mg; 100%, 93%, and 83% for those on 12 mg; and 27%, 9%, and 2% for those receiving placebo. The predominant adverse events in the retatrutide groups were gastrointestinal. These adverse events were dosage-dependent, were mainly of mild to moderate intensity, and were somewhat alleviated with a lower initial dosage (2 mg versus 4 mg) ^[66].

9. Sodium-Glucose Cotransporter Inhibitors (SGLT-2i)

SGLT-2 inhibitors are a class of medications primarily used for managing type 2 diabetes. They provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubules, consequently lowering blood glucose levels. One of the significant benefits of SGLT-2i is their association with weight loss due to the elimination of excess glucose. Moreover, these drugs are associated with consistent reductions in blood pressure. They have a relatively low risk of causing hypoglycemia compared to other diabetes medications, making them a safer option, especially in combination with other anti-diabetic drugs. Beyond their glucose-lowering effects, SGLT-2i exhibit notable cardiovascular benefits, as demonstrated by a reduced risk of heart failure and cardiovascular events. Furthermore, they have shown promise in slowing the progression of kidney disease in diabetic patients. These conclusions are drawn from reliable clinical trials and studies, positioning SGLT-2i as a valuable addition to the management of type 2 diabetes, with potential multifaceted health benefits ^[1]^[9]^[20]^[67]^[68]^[69].

Cardiorenal outcome trials have shown the effectiveness of these drugs in lowering the risk of MACE, HHF, all-cause mortality, and renal deterioration ^[1]^[5]^[20]^[69].

Furthermore, SGLT-2i improve the outcomes of patients with HF or chronic kidney disease (CKD) regardless of whether they have T2DM or not ^[1]^[5]^[69].

SGLT-2i may reduce the risk of cardiovascular death or HHF for both diabetic and non-diabetic patients with HF with reduced ejection fraction (HFrEF) ^[5]^[69].

Additionally, in patients with HF with preserved ejection fraction (HFpEF), SGLT-2i reduce the combined risk of cardiovascular death or HHF and improve symptoms related to HF and physical limitations ^[70]^[71]^[72].

Empagliflozin and dapagliflozin are also associated with an improvement in left-ventricle structure and function in patients with HF, but more information is required to further clarify these effects ^[73]^[74].

In patients with CKD, SGLT-2i use is associated with a reduction in the decline of glomerular filtration rate (GFR), proteinuria, end-stage renal disease, and the risk of death from renal or cardiovascular causes ^[1].

Considering the many advantages mentioned herein, SGLT-2i are recommended as a first-line therapy for T2DM with CVD or renal disease by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) ^[20].

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