Tackling type 2 diabetes-associated cardiovascular and renal comorbidities: a key challenge for drug development

KEYWORDS:

• Type 2 Diabetes mellitus
• cardiovascular diseases
• renal diseases, pharmacotherapy
• T2DM comorbidities
• hypoglycemic agents

1. Introduction

Diabetes mellitus type 2 (T2DM) is a global health condition affecting millions of people worldwide. T2DM is associated with ineffective insulin action caused by either insulin resistance or defective insulin molecule [1,2]. Many people with T2DM are likely to have one or more of the other components of metabolic syndrome, which includes overweight, hypertension, obesity, and dyslipidemia [3]. T2DM, in addition to the other conditions that make up the metabolic syndrome, is a common modern-day plague, which continues to rise across all populations worldwide. The prevalence of metabolic syndrome was over 33% in a large cohort of people in the US. This number increased to more than 50% in people aged 60 years and above [4]. Other reports showed that the prevalence rate of metabolic syndrome in Turkey is more than 35% [5]. This combination of abnormal metabolic parameters increases the risk of cardiovascular diseases by several folds and predisposes the patient to other arrays of illnesses including cancer, osteoarthritis, and many others [6]. The different components of the metabolic syndrome of which T2DM is a major part increase the risk of cardiovascular and renal diseases. It is well known that dyslipidemia increases the prospect of developing atherosclerosis, which will reduce perfusion to and from the extracellular matrix. A combination of reduced perfusion due to arterial plaques and angiopathy, low-grade inflammation, oxidative stress, and disruption of the renin-angiotensin system [2,7] significantly increases the risk of cardiovascular diseases. In a large study involving 4.5 million T2DM patients, the prevalence of cardiovascular diseases was as high as 32% [8]. One of the most severe complications of T2DM is microangiopathy [1]. Microvascular disease involving the capillaries of the renal glomerulus occurs in about 40% of the patients with T2DM [9]. The mechanisms by which T2DM causes renal disease are similar to those for cardiovascular diseases. Many studies have shown that in addition to T2DM-induced angiopathy, hypertension is equally an important risk factor for chronic renal disease [10]. The etiology of cardiovascular and renal comorbidities in T2DM patients appears to be very similar. In fact, the result of a recent study showed that cardiorenal comorbidity is present in more than 65% of all T2DM patients [11]. Since the factors leading to T2DM-induced cardiovascular and renal complications are similar, tackling these comorbidities can be achieved with the same set of drugs.

2. Methods

Several databases including PubMed, Scopus, Science Direct, Diabetes UK, and the American Diabetes Association were used to retrieve data for the review. T2DM, cardiovascular, renal, comorbidities, antidiabetic drugs were used as keywords. The search strategy is provided in Figure 1.

Figure 1. A schematic chart of the search strategy. The search using the following items was assembled and processed for the review

3. Epidemiology and burden of diabetes mellitus

A 2019 report put the number of people living with DM across the globe at 463 million [12]. This number will likely increase by 51% to a staggering 700 million by the year 2045 [12]. All of these show that the burden of T2DM on individuals, family, and the society is extremely heavy and will continue to be so for the foreseeable future. The financial burden is also unimaginable because an astronomical amount of money (760 billion USD) was spent on the management of DM in 2019 alone [13]. The potential increase in the number of people with DM and the multiple nature of the causes of T2DM pose a challenge for researchers looking for the best and optimal way to treat T2DM and its associated cardiovascular and renal complications. Many of these cardiovascular and renal comorbidities develop on the ground of microvascular lesions as observed in nephropathy and macrovascular derangement in ischemic coronary heart disease, and myocardial infarction [14].

4. Cardiovascular comorbidities of diabetes mellitus

Many studies have shown that DM is a risk factor for cardiovascular diseases (CVD). CVD including heart failure is twice as common in people with T2DM compared to the general population [15]. Many studies have claimed that even relatively, small increases in blood glucose level raise the risk of CVD exponentially [15]. Cardiovascular co-morbidity of T2DM develops in part from the ramifications of DM-induced hyperglycemia. Hyperglycemia facilitates the production of reactive oxygen species, which in turn causes severe structural alterations in the myocardium [16]. These myocardial anomalies include but not limited to mitochondrial lesions, interstitial fibrosis, apoptosis, structural changes in the proteins regulating Ca²⁺ signaling, vascular lesions, and many others [17]. The repercussions of these hyperglycemia-induced lesions include cardiomyopathy, coronary heart disease, hypertension, atherosclerosis, and disturbances in heart rhythm in humans [15] and in animal models of DM [18].

5. Renal comorbidities of diabetes mellitus

DM is the most common cause of chronic kidney disease (CKD), which is manifested in the form of reduced glomerular filtration rate coupled with the increased urinary secretion of albumin [19]. CKD may in turn lead to kidney failure and the development of other severe morbidities such as cardiovascular disease [20]. The structural changes induced by DM and the subsequent functional decline in the kidney results from blood vessel lesion and increased deposition of extracellular matrix in the mesangium. These changes coupled with the release of inflammatory cytokines, such as TNF-α, IL-1, IL-6, and IL-18 [21] contribute to the rapid progression of diabetic nephropathy.

In a study of more than 687,000 patients with DM, more than 18% developed cardio-renal complication within 4 years of follow-up [22]. Other studies showed that as many a 40% of people with T2DM have CKD [23].

6. Diabetes mellitus and NAFLD

In addition to cardiorenal comorbidities, nonalcoholic liver disease (NAFLD) is common in patients with T2DM. NAFLD is the most prevalent type of liver disease and a risk factor for liver failure [24]. At least 34% of newly diagnosed T2DM patients has NAFLD, and almost 100% of these patients will have NALFD within 6 years after the onset of T2DM [25]. A reduction in the severity of NAFLD mitigates the severity of T2DM [26]. How is NAFLD associated with cardiovascular disease? Several reports have shown that NAFLD, like other components of the metabolic syndrome, poses a severe risk for developing cardiovascular complications, especially in T2DM patients [26]. The etiology of NAFLD-induced cardiorenal complications is still elusive, but it is tempting to speculate that fatty liver, a hepatic sign of the metabolic syndrome may contribute to the release of inflammatory cytokines, dysregulation of factors (hepatocytes produce all coagulation factors except the von Willebrand Factor) responsible for blood homeostasis. A defective coagulation system could lead to micro-thrombosis and eventual risk of developing myocardial infarction and other cardiovascular diseases. NAFLD is also an independent and severe risk factor for chronic renal disease [27]. The mechanism by which NAFLD induces chronic kidney disease is similar to that by which it induces cardiovascular diseases. Many reports showed that NAFLD releases inflammatory cytokines and uric acid and activates the renin–angiotensin system [28]. Therefore, a reduction in the signs of NAFLD could reduce the impact of cardiorenal comorbidities in T2DM patients.

7. Management of DM

Since the etiopathogenesis of T2DM is multifactorial, the approach to managing the disease will take different approaches even though targeting of specific lesions, such as angiopathy, may be similar. Indeed, lifestyle modifications such as increased physical activity and low carbohydrate diet can reduce weight, blood glucose, and the severity of cardiovascular as well as renal comorbidities [29]. Unfortunately, lifestyle regimen may not be enough to reduce blood glucose level and HbA1c to the optimal level, and the need to use therapeutic agents becomes even more crucial. Many anti-diabetic drugs or their combinations are currently used to lower hyperglycemia, with little or no emphasis on how they project on cardiovascular and renal co-morbidities in T2DM patients. Drugs that have been used to treat T2DM include the following: sulfonylureas (glyburide, glimepiride, glipizide), biguanides (metformin), inhibitors of α-glucosidase (e.g. acarbose, miglitol, voglibose), thiazolidinediones (e.g. rosiglitazone, pioglitazone), meglitinides, dipeptidyl peptidase 4 inhibitors (e.g. dutogliptin, vildagliptin, sitagliptin, saxagliptin, denagliptin), GLP-1RA (e.g. liraglutide, exenatide, albiglutide) [30,31], and the newly approved SGLT inhibitors (e.g. canagliflozin, dapagliflozin, empagliflozin) [32].

8. Effect of anti-diabetic drugs on cardiovascular and renal co-morbidities

8.1. Sulfonylureas

Azoulay and Suissa [33] reported that sulfonylureas (SU) are associated with cardiovascular disease and mortality in five of the six studies completed with no bias [33,34]. Other studies showed that the blood level of SU increases in patients with CKD, thereby increasing the risk of developing hypoglycemia when compared with metformin [35]. In contrast, some reports indicate that SU has a strong ability to reduce HbA1c in DM patients [36]. The risk of the cardiovascular or renal event was almost the same in a large cohort of patients (>23,000) taking either SU + metformin or DPP4 inhibitor + metformin. However, the risk of hospitalization for heart failure was higher in the DPP4 inhibitor + metformin group when compared to the SU + metformin group [37]. The CAROLINA trial, which compared, over a period of 6.3 years, the effect of the DPP-4 inhibitor, linagliptin with that of glimepiride, a sulfonylurea on the risk of cardiovascular diseases, body weight gain, and hypoglycemia, showed that the two drugs have similar efficacy in reducing the risk of major adverse cardiovascular events (MACE). However, glimepiride is thrice more likely to cause hypoglycemia compared to linagliptin [38] (Table 1)

Table 1. Effect of antidiabetic drugs on the heart and kidney

Antidiabetic drug	Mechanism of action	Effect on cardiovascular system	Effect on kidney	Ref.
Sulfonylureas	Stimulate insulin release via effect on K+ channel beta cell	Mortality from IHD is significantly higher in DM patients taking SU compared to metformin.	Increased risk of hypoglycemia in patients with CKD	[33–38]
Biguanides (metformin)	Reduce hepatic gluconeogenesis	Protective	Cannot be used in DM patients with eGFR of less than 30 mL per min per 1.73 ^m2. Risk of LA, otherwise it is protective.	[22,31,39]
Alpha-glucosidase	Prevents breakdown of carbohydrates in the GIT	No significant effect on cardiovascular morbidities	Should not be given to patients with advance CKD	[40–43]
Thiazolidinediones	Stimulate PPAR-γ to enhance carbohydrate metabolism	Increased risk of heart failure	Improved renal outcome	[44–47]
Meglitinides	Block K^+ channel	Did not significantly reduce CV outcomes	No significant effect, and risk of hypoglycemia is increased	[48,49]
DPP4i	Inhibitdegradation of incretins	No significant effects on CV outcome	Reduced risk of hHF (except saxagliptin)	[50–53]
GLP-1RA	Increase beta cell mass and insulin sensitivity, satiety and reduce gastric emptying	Significant cardiovascular protection	Significant renoprotection	[54–57]
SGLT2i	Block reuptake of glucose from renal tubules	Potent cardioprotective effect	Significant renoprotection	[32,59–67]

DPP4i: dipeptidyl peptidase-4 inhibitors; GLP-1RA: glucagon-like peptide-1 receptor agonists; SGLT2i: sodium–glucose co-transporter 2 inhibitors; eGFR: estimated glomerular filtration rate; CV: cardiovascular; hHF: hospitalization for heart failure; CKD: chronic kidney disease; LA :lactic acidosis; GIT: gastrointestinal tract; PPAR-γ: proliferator-activated receptor gamma; IHD: ischemic heart disease; DM: diabetes mellitus.

8.2. Biguanides (metformin)

Many studies have shown that metformin has a protective cardiovascular effect [22,31]. Data from the UKPDS 34 showed that metformin significantly reduced T2DM-related end-point by more than 21% and myocardial infarction (MI) by 33%. The ability of metformin to reducing the risks of MACE is significantly greater than that of SU [39]. In a reevaluation of the UKPDS by Petrie et al. [22], metformin reduced the risk of all macrovascular endpoints including cardiac infarction, sudden cardiac death, pectoral angina, central and peripheral vascular disease by as much as 30% [22]. This effect is more pronounced in overweight compared to lean T2DM patients. Metformin prevents cardiovascular complications in T2DM patients because of its anti-atherogenic, anti-inflammatory, and anti-oxidative effects, and its ability to improve microcirculation [22].

The renoprotective ability of metformin is currently disputed but most studies suggest a protective effect on the kidney [22]. The disadvantage of metformin vis-à-vis renal disease is that it cannot be administered to patients with an eGFR of less than 30 mL/min/1.73 m². A clinical trial [RenoMet] looking at the effect of metformin on renal outcomes will be completed in the fourth quarter of 2021 (Table 1).

8.3. Inhibitors of α-glucosidase (e.g. acarbose, miglitol, voglibose)

The STOP-NIDDM multicenter, 3-year trial, where more than 1,400 subjects participated, reported that acarbose reduced the risk of major cardiovascular events (myocardial infarction, hypertension) by 34–49% [40]. Furthermore, in the MeRIA7 (Meta-analysis of Risk Improvement under Acarbose) study, reports showed that the administration of acarbose significantly reduced the risk of any cardiovascular events by 35% and myocardial infarction by 64% [41].

In contrast, the Acarbose Cardiovascular Evaluation trial on 6,522 patients from 176 hospital centers concluded that acarbose did not significantly modify major cardiovascular events in this cohort of Chinese patients [42]. In addition, the blood level of α-glucosidase inhibitors increases in severe renal disease prompting a recommendation by the National Kidney Foundation that alpha-glucosidase inhibitors should be used with care in patients with end-stage CKD and dialysis [43] (Table 1).

8.4. Thiazolidinediones (e.g. rosiglitazone, pioglitazone)

The DREAM trial, which followed more than 5,000 people over a period of 3 years, concluded that rosiglitazone has renoprotective capacity but increases the risk of heart failure [44]. In contrast, the meta-analysis of 26 studies involving 19,645 subjects showed that pioglitazone was able to significantly decrease the risks for major adverse cardiovascular events (MACE), especially, stroke and myocardial infarction but did not reduce the risk of hospitalization for heart failure [45]. The MACE reduction was more prominent in patients with previous CVD [45]. This observation corroborates those reported by the DREAM investigators in 2008 [44]. In agreement with the DREAM study, the report of Zhou et al. [45] showed that pioglitazone possesses a robust renoprotection, irrespective of the stage of kidney disease. The controversy is further punctuated by the outcomes of the 10-year follow-up of the PROactive trial. The trial showed that pioglitazone did not significantly reduce the risk of MACE, including MI, stroke, and peripheral vascular disease, compared to placebo [46]. The CHICAGO study, on the other hand, showed that pioglitazone is superior to glimepiride (a sulfonylurea) in reducing the progression of carotid intima-media thickness in T2DM patients [47]. Pioglitazone also performed better than glimepiride in lowering hypertension, and in increasing the level of HDL cholesterol [47] (Table 1).

8.5. Meglitinides

The NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial showed that there were no significant improvements in cardiovascular outcomes in patients taking nateglinide and valsartan [48]. A more recent retrospective study, looking at the data of 132,737 patients, concluded that meglitinides are inferior to DPP4i, SGLT2i, and GLP-1RA when it comes to the reduction of MACE, especially when used in combination with metformin [49] (Table 1).

8.6. Dipeptidyl peptidase 4 inhibitors (e.g. dutogliptin, linagliptin, vildagliptin, sitagliptin, saxagliptin, and denagliptin)

CARMELINA, a large trial with almost 7,000 subjects, concluded that linagliptin, a very selective DPP4 inhibitor (DPP4i), did not make any difference on the cardiorenal outcome when compared to placebo [50]. Moreover, reports from the SAVOR-TIMI 53 trial show that other members of the DPP4i family such as saxagliptin increased the risk of cardiac failure or the need for hospitalization for cardiac failure [51]. This outcome becomes worse in patients with CKD and a previous history of heart failure. In contrast, DPP4i such as sitagliptin and anagliptin reduced plasma fatty acid-binding protein 4, a cytokine involved in the development of atherosclerosis, weight gain, and insulin resistance and LDL-cholesterol [52], thereby improving cardiovascular outcomes. In a review of several RCTs (EXAMINE, TECOS, and CAROLINA), it was concluded that DPP4i has no significant effect on MACE. In contrast, GLP-1RA reduced the risk of cardiovascular mortality, non-fatal MI, non-fatal stroke, and HF hospitalization [53]. Since these trials show that different DPP4i acts differentially on cardiorenal morbidities, it is plausible that the effect of DPP4i on cardiorenal morbidities is drug rather than class effect (Table 1).

8.7. GLP-1 receptor agonists (e.g. liraglutide, exenatide, and albiglutide)

REWIND and PIONEER 6 trials show that GLP-1RAs have some benefits in reducing major adverse cardiac events [54]. This group of antidiabetic drugs reduces the rate of hospitalization for heart failure (HF) and a modest benefit on MACE. GLP-1RA also reduces macroalbuminuria without influencing the degree of CKD [54]. Reports from the HARMONY trial showed that albiglutide, when given subcutaneously at a maximum dose of 50 mg/week reduced the risk of non-fatal MI compared to placebo [55]. Unfortunately, the number (24% of 9,463) of subjects who dropped out of the trial was high. In contrast, the EXSCEL study, which examined more than 10, 700 patients with a history of cardiovascular events showed that exenatide given once a week did not significantly reduce the risk of MACE when compared to placebo [56]. However, extracts from many large RCTs such as ELIXA showed that GLP-1RA improves cardiovascular outcomes in T2DM patients more effectively than DPP4i [53]. Analysis of data from the LEADER (Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results) and SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) trials showed that GLP-1RA reduced cardiorenal morbidities and mortality when compared to placebo [57,58] (Table 1).

8.8. SGLT inhibitors

Many clinical trials have reported that SGLT2i either alone or with GLP-1RA has a potent cardioprotective effect and safety even in DM patients with previous CVD [32,59]. Large clinical trials including the CREDENCE clearly showed the benefit of SGLT2i in the amelioration of cardiovascular risks in diabetic patients [60]. Another study investigating the effect of SGLT2i on the diabetic kidney showed that the administration of SGLT2i reduced the impact and severity of kidney complications in diabetic patients [60]. In the EMPA-REG study that examined approximately 7,000 patients, SGLT2i markedly reduced cardiovascular mortality, rate of hospitalization for cardiac failure, and the severity of nephropathy. This empagliflozin-induced reduction in the degree of cardiorenal morbidity and mortality was consistent irrespective of baseline condition [61]. The cardiorenal benefits of empagliflozin (an SGLT2i) were further supported by the results of the EMPEROR-Reduced RCT [62]. The CANVAS (Canagliflozin Cardiovascular Assessment Study) RCT involving more than 10, 000 subjects showed that canagliflozin was able to significantly reduce the severity of cardiovascular comorbidities associated with T2DM. The parameters reduced by canagliflozin include cardiovascular death, nonfatal MI, and stroke, heart failure hospitalization, and renal outcomes such as estimated glomerular filtration rate, kidney replacement therapy, or kidney failure [63]. Similarly, VERTIS, an RCT looking at the effect of ertugliflozin on cardiovascular outcome, showed that ertugliflozin, when given at a dose of either 5 mg or 15 mg/quaque die, reduced the risk of HHF in the more than 8,000 subjects enrolled in the trial [64]. In addition to several clinical trials examining the effect of SGLT2i on cardiovascular risks in T2DM patients, a study on the effect of SGLT2i on T2DM patients with renal co-morbidity was conducted in the DAPA-CKD study [65]. The DAPA-CKD trials concluded that in addition to 29% reduction in the risk of HHF, dapagliflozin ameliorated the risk of death from CKD by 31%, and severe CKD and renal failure by 44% [65]. The renal benefit observed in the DAPA-CKD trials was replicated in the EXSCEL RCT [66]. Reports from the DAPA-HF RCT with more than 4,000 participants support the above findings that dapagliflozin significantly reduced the risk of HHF, cardiovascular mortality, and severe kidney function when compared to placebo [67] (Table 1).

9. Conclusion

The etiology of diabetes mellitus (DM) is multifaceted. This is also true of the large variety of complications caused by DM. Long-term complications of DM are evident in the cardiovascular, nervous, renal, musculoskeletal, and visual systems where they cause severe morbidity. The cardiorenal comorbidities of DM are particularly devastating because cardiovascular complications affect the function of the kidney and vice versa. Since many anti-diabetic drugs have adverse effects on either the heart or the kidney, the choice of therapy in the management of cardiorenal comorbidities becomes very crucial.

10. Expert opinion

Chronic hyperglycemia (HG) is common in people with diabetes. Sustained HG induces oxidative stress, which in turn results in the formation of advanced glycated end-products [2]. All of these factors contribute to the development of micro- and macrovascular complications affecting the heart, central and peripheral nervous systems, kidney, and many other vital organs [2]. Cardio-renal diseases may present as either, preexisting condition or simply as complications of T2DM. Indeed, a large majority of T2DM patients develop cardio-renal complications within the first 4 years of the disease [22]. The approach to treating diseases associated with three different organs, namely, pancreatic islets, heart, and the kidney, is a big challenge because what may be beneficial for one organ may have an adverse effect on the other. The major objective of anti-diabetic drugs is to reduce blood glucose and HbA1c levels, in order to reduce oxidative stress and complications associated with DM. These drugs while efficient as hypoglycemic agents may have adverse effects on cardiovascular events and/or renal function.

While sulfonylureas (e.g. glibenclamide, glimepiride) have been a dependable hypoglycemic agent for more than 70 years, several reports have shown that this group of glucose-lowering agent can make cardiovascular events worse [33,34]. Other reports have suggested that SU should be used with care in patients with CKD because blood SU level increases in subjects suffering from CKD [35–38].

In contrast, the biguanide group of hypoglycemic agent, of which metformin is a key member, is cardioprotective [31]. The renoprotective effect of metformin is controversial, although many reports show that it could protect the kidney [22]. The adverse effect of metformin may be due to the generation of lactic acidosis; however, several studies have shown that lactic acidosis develops post metformin administration if the dose is high or in cases of CKD where renal clearance is limited [68].

Alpha-glucosidase is not a drug of choice in tackling T2DM co-morbidities because the use of α-glucosidase inhibitors is not associated with major cardiovascular events. In addition, it is also not recommended in patients with severe CKD [43]. This is in contrast to thiazolidinediones, with a proven renoprotective effect. Although some thiazolidinediones (rosiglitazone) elevate the chances of heart failure [44], other members of this class of hypoglycemic drugs (pioglitazone) can reduce hypertension and increase HDL cholesterol, but its ability to significantly reduce MACE is controversial [46,47]. The effect of meglitinides and DPP4i on the cardiovascular system is controversial. Some reports indicate that the administration of either meglitinides or DPP4i increases the risk of cardiovascular event [51,69], while other studies indicated that there is no adverse effect [45,50]. In contrast, other DPP4i such as anagliptin and saxagliptin can reduce atherosclerosis, weight gain, insulin resistance, and LDL-cholesterol via reduction in plasma fatty acid-binding protein 4 [52].

In contrast to other hypoglycemic agents, GLP-1RA and SGLT2i can reduce major cardiovascular events, and renal morbidities in T2DM patients even in those with existing cardiorenal diseases [32,54,59].

How do GLP-1RA and SGLT2i work? GLP-1RA such as exenatide delay gastric emptying and decrease the blood level of glucagon, stimulate insulin release and insulin sensitivity, increase satiety, and eventually reduce body weight [70]. On the other hand, SGLT2i prevents the reuptake of glucose from renal convoluted tubules resulting in lower blood glucose and body weight [32]

In the light of the analysis of different hypoglycemic agents, which one(s) of them would be most suitable for the treatment of T2DM in patients with cardiorenal co-morbidities? In my opinion, the agents that would fit into this ‘safe’ agent include GLP-1RA and SGLT2i. Indeed, several large studies such as CANVAS [71], CREDENCE, and EMPA-REG OUTCOME Study have all shown that SGLT2i reduces cardiovascular and renal comorbidities by as much as 38% [32].

How do GLP-1RA and SGLT2i reduce blood glucose level and at the same time be protective against cardiovascular and renal co-morbidities in T2DM patients? The answer to this question could reside in the mechanisms of action of these drugs. They increase the efficiency of insulin and reduce glucose load without affecting receptors (e.g. K⁺ channels) that could be found on the membrane of many different cells. They also reduce hyperglycemia by making sure that excess glucose is not reabsorbed (SGLT2i effect) and by increasing pancreatic beta cell mass [32,70]. Moreover, it has been reported that SGLT2i also stimulates the release of endogenous GLP-1, reduces hypertension, and body weight [32]. The reduction of these factors is beneficial not only for DM patients but for people with cardiorenal comorbidities. Drugs that reduce body weight are beneficial to reducing cardiorenal (HF, progression to end-stage renal disease) complications in obese T2DM patients [72]. SGLT2i is able to slow the progression of CKD by reducing barotrauma and proteinuria, glomerular hyperfiltration, and intraglomerular pressure. Other studies have also shown that SGLT2i can prevent oxidative stress, hypoxia, and fibrosis of renal tubules [73]. Moreover, SGLT2i reduces the activity of the sympathetic nervous system, thereby protecting the vascular system. The euglycemia, optimal blood pressure and lipid profile, and lower body weight induced by SGLT2i have been shown to protect small as well as large blood vessels [73]. Direct cardiac effects of SGLT2i have also been reported. This includes its ability to reduce cardiac hypertrophy, apoptosis of cardiac cells, inflammation of the myocardium, and extracellular matrix remodeling. SGLT2i also enhances bioenergetics and metabolomics of the myocardium [73].

Glycemic variability: Reports have shown that SGLT2i have the ability to prevent glycemic variability [74]. This potential of SGLT2i makes it an ideal class of drugs that could prevent macro- and microvascular complications since it has been shown that glycemic variability measured by visit-to-visit of HbA1c is a good measure of the risks of developing vascular complications [75] in T2DM patients. Indeed, large fluctuations in glucose level is a strong predictor of diabetic retinopathy and neuropathy [75]. Similar vascular events occurring in the retina and perineural capillaries would likely be present in small blood vessels supplying the renal glomerulus and the heart. Therefore, a strict glycemic control is a key to preventing cardiorenal co-morbidities in T2DM patients.

A group of Asian Experts recommends the use of SGLT2i in T2DM patients because of its potential to reduce body weight and visceral adipose tissue. Since most T2DM patients are either overweight or obese, the reduction of adipose tissue is a key element in the prevention of cardiorenal complications of T2DM [76]. Indeed, many extensive cardiovascular outcome trials (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, DAPA-HF, CREDENCE) have reported the benefits of SGLT2i and GLP-1RA in patients with T2DM [73,77]. All of these important observations have prompted the American Diabetes Association and the European Association for the Study of Diabetes to recommend SGLT2i and GLP-1RA as the drugs of choice in tackling the cardiorenal complications of T2DM patients [78].

In conclusion, the ideal drug for the treatment of T2DM patients with cardiovascular and renal comorbidities would likely include GLP-1RA, SGLT2i, as monotherapy, or a combination of both. Metformin could be useful if used in small doses and possibly in combination with GLP-1RA and SGLT inhibitors.

Abbreviations

CKD = Chronic kidney disease	=
CV = Cardiovascular	=
CVD = Cardiovascular disease	=
DM = Diabetes mellitus	=
DPP4i=Dipeptidyl peptidase-4 inhibitors	=
eGFR = Estimated glomerular filtration rate	=
GIT= Gastrointestinal Tract	=
GLP-1RA = Glucagon like peptide 1 receptor antagonists	=
GLUT-4 = Glucose transporter type 4	=
HF = Heart failure	=
HG = Hyperglycemia	=
hHF = Hospitalization for heart failure	=
IHD = Ischemic heart disease	=
IL-1 = Interleukin-1	=
IL-18 Interleukin-18	=
IL-6 = Interleukin-6	=
LA = Lactic acidosis	=
MACE = Major adverse cardiovascular events	=
MI = Myocardial infarction	=
PPAR-γ = Peroxisome proliferator-activated receptor gamma	=
RCTs = Randomized Clinical Trials	=
SGLT = Sodium-glucose co-transporters	=
SGLT2i = Sodium-glucose co-transporter 2 inhibitors	=
SU = Sulfonylurea	=
TNF-α = Tumor necrosis factor alpha	=

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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