Can Newer Anti-Diabetic Therapies Delay the Development of Diabetic Nephropathy?

Type 2 diabetes mellitus (T2DM) is progressive in nature and leads to hyperglycemia-associated microvascular and macrovascular complications. Diabetic nephropathy (DN) is one of the most prominent microvascular complication induced by T2DM and is characterized by albuminuria and progressive loss of kidney function. Aggressive management of hyperglycemia and hypertension has been found effective in delaying the development and progression of DN. Although the conventional antidiabetic treatment is effective in the earlier management of hyperglycemia, the progressive loss of beta cells ultimately needs the addition of insulin to the therapy. The emergence of newer antidiabetic agents may address the limitations associated with conventional antidiabetic therapies, which not only improve the glycemic status but also effective in improving cardio-renal outcomes. Nevertheless, the exact role of these agents and their role in minimizing diabetes progression to DN still needs elaboration. The present review aimed to highlights the impact of these newer antidiabetic agents in the management of hyperglycemia and their role in delaying the progression of diabetes to DN/management of DN in patients with T2DM. Copyright:

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is progressive in nature and leads to hyperglycemia-associated complications such as cardiovascular disorders, microvascular events, and mortality. Diabetes progression involves the deterioration of beta cell functions and the worsening of insulin resistance which accompanied by deterioration of multiple parameters, i.e., glycosylated hemoglobin A1C (HbA1C), fasting plasma glucose (FPG), and postprandial glucose level.[1] T2DM usually develops as a part of wider health problem in the form of metabolic syndrome which comprises of central obesity, dyslipidemia, hypertension and impaired glucose tolerance (IGT). IGT leads to hyperinsulinemia as a compensatory response to the increased insulin resistance in the cells.[2] Furthermore, there are certain other abnormalities which can be associated with diabetes progression such as progression from prediabetes to overt-diabetes, changes in acute insulin response, disease progression that require pharmacological therapy, loss of glycemic control by medication and the decline in the beta cell function that can be measured through homeostasis model assessment along with natural history of obesity or progressive weight gain.[3]

Hyperglycemia, dyslipidemia, genetics, and epigenetic regulation are the main factors associated with the pathophysiology of vascular complications in diabetic patients.[4] Vascular complications are further divided into macrovascular complications, i.e., coronary artery disease and cerebrovascular disease, as well as microvascular complications, i.e., neuropathy, nephropathy, and retinopathy. All these complications are primarily affected by blood sugar levels. An intense control of blood sugar with anti-diabetic agents decreases the onset as well as the progression of diabetic vascular complications.[56] Nevertheless, Barret et al., have further emphasized that hyperglycemia may not be the only factor triggering diabetic vascular complications as other less known factors such as genetic and endogenous protective factors have an important role as well.

Diabetic nephropathy (DN) also known as diabetic kidney disease (DKD) is one of the most prominent and prevalent complication of diabetes. DN is induced by diabetes mellitus and is characterized by the presence of albuminuria and progressive loss of kidney function. The incidence of DN in patients with diabetes lays in the range of 30%–40% in type 1 and T2DM and may be different in different populations.[7] Not all patients with T2DM develop DN, but those who develop DN, the progression is variable. There are two types of risk factors which contribute to the development of DN i.e., modifiable and nonmodifiable risk factors. The modifiable risk factors include hypertension, glycemic control, and dyslipidemia, while the nonmodifiable risk factors consist of age, race, and genetic profile. A further elaborative and conceptual classification of the risk factors can be identified as susceptibility factors comprising of age, sex, race and family history, initiation factors, for example, hyperglycemia and acute kidney injury, and progression factors, for example, hypertension, dietary factors, and obesity. Hyperglycemia and hypertension are the two most established risk factors of DN.[8]

The development of DN and ultimately end-stage renal disease (ESRD) starts with the generation and circulation of advanced glycation end products, glomerular hemodynamic and hormonal changes with the elevation of growth factor resulted from diabetes mellitus. All these changes further lead to the generation of reactive oxygen species (ROS) and the inflammatory mediators which ultimately cause glomerular hyperfiltration, renal hypertrophy, altered glomerular filtration rate (GFR), and clinically manifested as albuminuria and hypertension. Furthermore, major vascular complications such as cardiac diseases and death due to cardiac arrest may happen at any time point throughout the progression of T2DM from diabetes mellitus and early DN.[9] DN is clinically diagnosed based on the estimated glomerular filtration rate (eGFR) level and albuminuria measurements in conjunction with clinical criteria such as duration of diabetes and the presence of diabetic retinopathy.[8] DN is clinically characterized by a consistently elevated albumin in the urine and/or a sustained decline in eGFR <60 ml/min/1.73 m2. Microalbuminuria is defined quantitively as urine albumin excretion (UAE) of 30–300 mg/day, 20–200 μg/min in timed urinary collection, or 30–300 mg albumin/g creatinine in a spot specimen.[10] Urine albumin-to-creatinine ratio (ACR) is the ideal test for albuminuria and should be conducted on a spot sample, preferably in the morning. The eGFR is determined using the serum creatinine concentration. Diabetic patients with microalbuminuria are considered as having incipient nephropathy, whereas their progression to macroalbuminuria is a sign of clinical or overt nephropathy.[11]

PHARMACOLOGICAL MANAGEMENT OF DIABETIC NEPHROPATHY

Although the current oral anti-diabetic agents are effective in the early management of T2DM, the progressive β-cell failure will occur later in time which requires the addition of insulin. These oral anti-diabetic agents effectively lower the glucose concentration and may lower the HbA1c level by 1%–2%, specifically associated with higher initial levels of HbA1c.[12] Certain adverse effects noted to be associated with sulfonylureas are hypoglycemia and weight gain while gastrointestinal disturbances were observed with biguanides and α-glucosidase inhibitors.[12]

The long-term complications of diabetes can be reduced by the attainment and maintenance of near normal glucose profile. As a consequence of declining β-cell function, the glucose level increase over time despite pharmacologic and lifestyle interventions and it becomes difficult to maintain HbA1c target with the conventional anti-diabetic agents.[13] Such instances necessitate either increase in drug doses or the use of combination therapies with other oral anti-diabetics or with insulin.[1415] Currently, there are an increasing trend in the development of newer generation of anti-diabetics. Their ability in controlling the blood glucose and minimizing the progression of diabetes complications are reported in many studies. The present review aimed to highlight the role of newer anti-diabetic agents in management of hyperglycemia and delaying the development of DN in T2DM patients.

Other available pharmacological options (nonanti-diabetics) and their impacts on proteinuria and kidney function are summarized in Table 1.

Table 1

Pharmacological treatment of diabetic nephropathy

Drug(s)	Antiproteinuric	Preserve GFR	Diabetes type
ACEi	++	++	T1/T2DM
ARB	++	++	T2DM
ACEi+ARB	+++	-	T1/T2DM
Aldosterone antagonist	+	?	T2DM
Aldosterone antagonist + ARB/ACEi	+++	?	T1/T2DM
Renin Inhibitor	++	?	T2DM
Renin Inhibitor + ACEi/ARB	+++	-	T2DM
Nondihydropyridine CCB	+	?	T2DM
Nondihydropyridine CCB + ACEi/ARB	++	?	T2DM
Dihydropyridine CCB	-	-	T2DM
Allopurinol	?	??	T2DM
Statin	+	?	T2DM
Vitamin D	+	?	T2DM

Lim, 2014.[16] +: Data exist to indicate benefit, −: Data exist to indicate lack of benefit or harm, ?: Insufficient data for conclusion, possible benefit, ACEi: Angiotensin converting enzyme inhibitors, ARBs: Angiotensin receptor blockers, CCB: Calcium channel blocker, T2DM: Type 2 diabetes mellitus

NEWER THERAPEUTIC OPTIONS

In minimizing the progression of DN, intensive management of hyperglycemia has always been the primary focus. Furthermore, the ongoing research in the field of diabetes has led to understanding novel therapeutic targets, which can effectively help in minimizing diabetes associated complications. The gradual introduction of novel drugs and their role in diabetes associated complications has shown some promising results.[16] These newer agents not only confer their protective effects by their hypoglycemic actions but have also been found to have independent reno-protective effects in T2DM patients. These drugs include, but not limited to peroxisome proliferator-activated receptors (PPAR-γ) agonists, glucagon like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium glucose cotransporter-2 (SGLT2) inhibitors.[17] All these nontypical treatment options need further elaborative trials for finding out whether these agents should be preferred or not over the typical hyperglycemia treatment with sulfonylureas or biguanides. A summary of the reno-protective and anti-diabetic effects of the newer anti-diabetic drugs has been elucidated in Table 2.

Table 2

Summary on the newer oral antidiabetic effects on the progression of diabetic nephropathy

Newer antidiabetic	Reno protective effect			Effect on blood glucose			Vacsulo-protective effects	Anti-inflammatory effect on kidney	Additional effects	References
	Reduction in ACR	Reduction in UAE	Effects on eGFR/CrCL	FBG	HbA1c	Insulin sensitivity
TZDs	.	++	-	++	++	++	++	++	.	Sarafidis et al., 200522
	++	-	.	.	-	++	++	.	.	Imano et al., 199823
	.	++	.	.	.	.	.	.	ET-1ꜜ	Nakamura et al., 200024-26
	.	++	.	++	++	++	.	.	.	Lebovitz et al., 200127
	++	.	.	-	-	.	++	.	BPꜜ	Bakris et al.,200328
GLP-1 Agonists	++	.	+	.	++	.	.	++	BWꜜ, SBPꜜ	Mann et al., 201730
	.	++	.	.	++	.	.	.	BWꜜ	Marso et al., 201632
	+	.	-	++	++	.	.	.	BWꜜ	Davies et al., 201633
	.	++	-	.	.	.	.	++	CV risksꜜ	Giugliano et al., 201934
DPP-4 Inhibitors	.	++	-	.	.	.	.	++	.	Cooper et al., 201539
	.	.	-	-	++	.	.	.	.	Mcgill et al., 201339
	+	.	-	.	++	.	.	++	.	Groop et al., 201740
	-	.	-	.	.	.	.	++	.	Ott et al., 201641
SGLT-2 inhibitors	.	.	-	++	++	.	.	.	BWꜜ, UGEꜛ	Bailey et al., 201013
	.	.	.	++	++	.	.	.	BWꜜ, SBPꜜ	Clar et al., 201245
	++	.	++	-	.	.	.	++	.	Jian et al., 201846
	++	.	++	-	++	.	.	++	BMIꜜ, BPꜜ	Takashima et al., 201847
	++	.	++	-	-	.	.	.	-	Heerspink et al., 201748
	++	.	.	.	++	.	.	.	.	Pollock et al., 201949

++: Significant clinical effects, −: No effects, . : No data available, ꜜ: Decrease, ꜛ: Increase, BW: Body weight, UGE: Urinary glucose excretion, CV: Cardiovascular, BP: Blood pressure, SBP: Systolic BP, ET-1: Endothelin-1, BMI: Body mass index, ACR: Albumin-creatinine ratio, UAE: Urinary albumin excretion, eGFR: Estimated glomerular filtration rate, CrCL: Creatinine clearance, HbA1c: Glycosylated haemoglobin, GLP-1: Glucagon like peptide-1, DPP-4: Dipeptidyl peptidase-4, SGLT-2: Sodium-glucose cotransporter-2, TZD: Thiazolidinediones, FBG: Fasting blood glucose

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS AGONISTS

This class of drug also known as Thiazolidinediones (TZD) has been found to improve insulin action, through activation of PPAR-γ receptors which regulate the genes associated with glucose and lipid metabolism, hence incurring anti-hyperglycemia effects. Furthermore, these antidiabetic agents possess vasculo-protective effects by controlling vascular cell proliferation and migration posttrauma, inhibition of angiogenesis, and improvement in markers of inflammation and fibrinolysis.[1819] PPAR-γ agonists such as pioglitazone and rosiglitazone, have shown antifibrotic and anti-inflammatory effects in the kidneys of diabetic rats in addition to their glucose lowering effects. Furthermore, the addition of rosiglitazone to metformin therapy in T2DM has improved albuminuria and blood pressure (BP), independent of glycemic control.[2021]

A number of small-scale observatory studies were performed to evaluate the effects of TZD in patients with T2DM and/or DN. One such study was performed on 20 diabetic patients with hypertension evaluating the effects of rosiglitazone on urinary albumin excretion (UAE). It has been observed that by the end of the treatment, rosiglitazone was associated with significant reductions in UAE, increase in insulin sensitivity in rosiglitazone arm in comparison to placebo as well as decrease in fasting blood sugar and HbA1c. Furthermore, a small but significant reduction in BP has also been observed in that study. Albumin in the 24-h urine collection had decreased from 22.4 ± 4.6 to 13.8 ± 3.0 mg/day (P < 0.05) and albumin-creatinine ratio (ACR) in the spot specimen had decreased from 20.9 ± 3.8 to 14.0 ± 2.8 mg/g (P < 0.05). No significant changes were observed in renal function with rosiglitazone as the creatinine clearance, blood urea nitrogen, and serum creatinine remained unchanged at the end of the study.[22] Similarly, a study of 30 patients with microalbuminuria in the range of 30–300 mg/g creatinine (ACR), were randomly assigned to metformin or troglitazone group. The study observed no effects on lipid profile, BP, or body mass index in any of the treatment group, although HbA1c was seen to decrease more in the metformin group. There were no significant effects on ACR with metformin, while troglitazone has contributed to 40% reduction in ACR at the 4th week (P = 0.021) and has maintained that level throughout the treatment period. Hence, troglitazone has effectively reduced microalbuminuria in T2DM patients through their vascular effects and by improving insulin sensitivity regardless of their hypoglycemic effects.[23] Similarly, a 3 months trial on the effects of pioglitazone, glibenclamide, and voglibose on UAE was conducted in 45 patients with T2DM. Urinary Endothelin-1 (ET-1) and UAE was measured before and after the commencement of the study. An increase in circulating ET-1 precedes the microalbuminuric phase of renal injury related to diabetes. Pioglitazone but not glibenclamide or voglibose, reduced UAE from 142.8 ± 42.2 to 48.4 ± 18.2 μg/min (P < 0.01) and urinary ET-1 levels from 8.6 ± 1.3 to 3.4 ± 0.5 ng/g UC (P < 0.01). Hence, the results of the study are suggestive of marked improvements in UAE and ET-1 with pioglitazone therapy in T2DM patients with microalbuminuria.[24] Similar results of the effects of troglitazone and pioglitazone on UAE has been observed in multiple studies by Nakamura et al.[2526] In a comparatively larger trial on the effect of rosiglitazone monotherapy, 493 T2DM patients were randomized to rosiglitazone or placebo group for 26 weeks. A marked reduction in HbA1c and FPG were observed in the rosiglitazone group. Similarly, rosiglitazone group has an improvement in insulin sensitivity and a significant reduction in UAE (39%–42%).[27] Another study of 121 T2DM patients to compare the effects of glyburide and rosiglitazone of urinary albumin was conducted in 2003. By week 28th, both the groups showed a significant reduction in ACR by 30% from baseline, but by week 52nd of the treatment, only rosiglitazone group has shown significant reduction from baseline ACR. The results are suggestive of beneficial effects of rosiglitazone on improving renal complications regardless of improvements in FPG or HbA1c. The improvement in UAE and BP may be a consequence of improvement in vascular integrity and tone resulting from rosiglitazone treatment.[28] All these studies are indicative of the beneficial effects of PPAR-γ agonists on the renal outcomes through their vascular effects regardless of much improvement in the glycemic profile. As all the studies are indicative of TZD benefits in improving UAE and insulin sensitivity in patients with microalbuminuria, still their effects in T2DM patients with no microalbuminuria or their role in managing the progression to microalbuminuria would be of interest. Furthermore, the genetic variabilities associated with heritability or familial clustering influencing the emergence of diabetic complications is known and may also be considered in understanding the effects of TZD as their mechanism of action is based on PPAR-γ receptors. Finally, beneficial, widespread use of these agents has been overshadowed by the associated clinical issues such as increased risk of bone disease, heart failure and bladder cancer with pioglitazone and ischemic heart diseases with rosiglitazone, which may need further elucidation.[4]

GLUCAGON LIKE PEPTIDE-1 AGONISTS

Despite the availability of treatment options, the quest in finding effective agents continue to protect against the progression of diabetes and associated complications. GLP-1 agonist also known as incretin mimetics, are among the new available drugs which not only maintain the capacity of β-cells to synthesize and secrete insulin in response to glucose but may also increase β-cell mass (demonstrated in preclinical trials), and suppresses glucagon secretion, all of which help in decreasing glucose levels.[29] Furthermore, there are evidences supporting that GLP-1 analogues may additionally reduce systolic BP and triglyceride levels. This class of drugs has improved renal biomarkers in placebo-controlled studies which exerted an additive effect independent of glycemic control. One such trial was the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, comprising of 9340 T2DM patients with cardiovascular risk who were assigned to either liraglutide or placebo arm. A significant decrease in HbA1c (−0.4%) and body weight (−2.3 kg) were observed in liraglutide group. Furthermore, liraglutide group had comparatively fewer prespecified composite renal outcomes than placebo group, i.e., new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level and an estimated GFR of 45 ml or less per min per 1.73 m2 of body-surface area (hereafter referred to as persistent doubling of the serum creatinine level), the need for continuous renal-replacement therapy ESRD with no reversible cause of the renal disease, or death from renal disease (268 patients [5.7%] vs. 337 [7.2%]; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67–0.92; P = 0.003). Similarly, the new-onset persistent macroalbuminuria occurred in fewer patients in the liraglutide group than in the placebo group (161 patients [3.4%] vs. 215 [4.6%]; HR, 0.74; 95% CI, 0.60–0.91; P = 0.004). In the time-to-event analysis, eGFR declined continuously, but the liraglutide group has shown comparatively slower decline than the placebo group (estimated trial-group ratio at 36 months, 1.02; 95% CI, 1.00–1.03; P = 0.01, corresponding to a 2% less decrease with liraglutide). The urinary ACR increased less in the liraglutide group, yielding a 17% lower urinary ACR at 36 months in favor of liraglutide (estimated trial-group ratio, 0.83; 95% CI, 0.79–0.88; P < 0.001).[30] Even after statistically adjusting of HbA1c level at baseline and during the trial, no changes in the effects of liraglutide on renal outcomes were observed and hence the mechanism by which liraglutide effect the renal outcome is unclear. The effects of liraglutide on renal function may be multifactorial, either the hemodynamic effects or the more prominent effects of GLP-1 analogues on oxidative stress and inflammatory biomarkers associated with albuminuria.[30] These results were consistent with a few others other small scale studies which has shown the benefits of GLP-1 analogue in reducing the risk of albuminuria and improving eGFR.[3132] In contrast, efficacy and safety of liraglutide versus placebo as add-on to glucose-lowering therapy in patients with Type 2 diabetes and moderate renal impairment (LIRA-RENAL) trial, found no effects of liraglutide of eGFR after 26 weeks, although it has demonstrated better glycemic control with little risk of hypoglycemia. No significant effects of liraglutide on renal function (eGFR) although urinary ACR was improved by 17% (but not significant) can be linked to the moderate renal impairment patients, which was the studied population. Further elucidation of liraglutide role in patients of different ages and with no renal impairment may provide better image of the role of GLP-1 analogs in renal outcomes.[33]

The trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes (SUSTAIN-6) of 3,297 T2DM patients with cardiovascular risk, was conducted on patients randomly allocated to either receive semaglutide (at the dose of 0.5 or 1 mg once weekly) or placebo. A significant difference in HbA1c (−0.7% and 1.0%) and body weight (−2.9 kg and −4.3 kg) were observed in 0.5 mg and 1.0 mg semaglutide, respectively, while in the placebo group the HbA1c decreased by −0.4%. The median follow-up of the study was 2 years, and patients treated with semaglutide had comparatively a lower hazard of developing new or worsening nephropathy (HR = 0.64 [0.46–0.88], P = 0.005) than placebo. As demonstrated in LEADER trial, the renal outcomes in semaglutide trial have also shown reduction in newonset macroalbuminuria (semaglutide vs. placebo; 2.5% vs. 4.9%, respectively).[34] In addition, a meta-analysis of seven multinational trials and three secondary analyses had been conducted, comprising 56004 T2DM patients focused on evaluating the role of GLP-1 agonists on cardiovascular and renal outcomes. The GLP-1 agonists consisting of lixisenatide, liraglutide, semaglutide, once weekly exenatide, albiglutide, dulaglutide and oral semaglutide was evaluated. Major cardiovascular risk was reduced by 13% (HR, 0.87; 95% CI, 0.80–0.96; P < 0.011) compared with placebo in the overall analysis. Macroalbuminuria driven reduction in composite kidney outcome was reduced by 17% in GLP-1 group (HR, 0.83 [0.69–1.00]). In current trials of GLP-1 agonist, the reduction in newonset macroalbuminuria was the greatest efficacy outcome, with no effects on the eGFR decline. Most of these outcomes are associated with the improved oxidative stress and the role of GLP-1 agonists on the inflammatory biomarkers, thus minimizing the chances of kidney injury.[34]

There are enough evidence available, favoring the use of GLP-1 agonist in reducing developing or worsening of albuminuria, which is a strong predictor of renal outcomes. As experimental and clinical evidence support the reno-protective effects of GLP-1 agonists, still the underlaying mechanism need further elucidation and further research may help in extending the current knowledge.[35]

DIPEPTIDYL PEPTIDASE-4 INHIBITORS

DPP-4 inhibitors are also among the new class of drugs under critical observation for their role in cardiorenal outcomes. These drugs lower blood glucose levels by raising the half-life of short-lived endogenous incretins, such as GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Experimental results and certain animal models have facilitated the hypothesis that DPP-4 inhibitors may have prominent role in protecting kidney from DN and non-DKDs. In certain DN model, DPP-4 inhibitors have been found to have anti-inflammatory and antiapoptotic effects. For instances, sitagliptin has been found to be effective in the reduction of albuminuria in type 2 diabetes patients independent of HbA1c, while algoliptin has been found to be associated with a reduction in oxidative stress but no positive impacts on renal function.[3637] Individual patient-level data pooled analysis of 13 phase 2 or 3 randomized, double-blind, placebo-controlled, clinical trials of DPP-4 inhibitor linagliptin has supported its role in renal outcomes. The pooled analysis consisted of 5466 treated individuals, out of which 3505 received linagliptin 5 mg/OD, and 1961 received placebo. The primary outcome which is the composite of six (6) kidney disease outcome (i.e., new onset of moderate elevation of albuminuria [ACR >30 mg/g], new onset of severe elevation of albuminuria [ACR >300 mg/g], reduction in kidney function [serum creatinine increase to ≥250 μmol/L], halving of eGFR [loss of baseline eGFR >50%], acute renal failure ascertained from diagnostic codes, or death from any cause) was significantly reduced by 16% in linagliptin treatment as compared with placebo (HR, 0.84; 95% CI, 0.72–0.97; P = 0.02). Furthermore, the hazard of new onset of moderate elevation of albuminuria was reduced by 18% in linagliptin treatment group (HR, 0.82; 95% CI, 0.69–0.98; P = 0.03). The renal effects of linagliptin are in accordance with the data from preclinical trials, which indicates its role in the reduction of UAE, renal fibrosis, oxidative stress, and inflammation biomarkers.[38] Similarly, a study on the long-term safety and efficacy of linagliptin in T2DM patients with renal impairment showed a decrease in HbA1c by −0.76% in linagliptin group and −0.15% in placebo. Both the placebo and linagliptin had little effects on renal function, and no evidence of drug-related renal failure observed. Hence, in T2DM patients with renal impairment, linagliptin provided clinically meaningful improvements in glycemic control, having very low risk of severe hypoglycemia, stable body weight, and no evidence of drug-related renal failure. For evaluating the long-term safety and efficacy of linagliptin in renal outcomes, further investigations are needed.[39] In efficacy, safety and modification of albuminuria in type 2 diabetes subjects with renal disease with linagliptin (MARLINA-T2D) randomized clinical trial, 360 patients were randomly assigned to either linagliptin or to placebo. After 24 weeks of follow-up, the adjusted mean ± standard error difference between linagliptin and placebo in change from baseline in HbA1c was −0.60% (95% CI, −0.78 to −0.43, P < 0.0001). The HbA1c reduction over time from baseline was consistently higher in linagliptin than placebo group. Among individuals with HbA1c of more than 7.0%, at week 24, HbA1c of <7.0% was achieved in significantly more individuals in linagliptin group (36%) than placebo (9.3%) (odds ratio, 6.16 [95% CI, 3.13–12.15]; P < 0.0001). In over 24 weeks, the time-weighted average percentage change in urinary ACR was −11.0% in linagliptin group and −5.1% with placebo. Across the participants in the subgroup, the time-weighted average of percentage change from baseline urinary ACR in linagliptin and placebo was broadly similar. The safety and hypoglycemic effects of linagliptin in this study were almost similar to previous trials, but the study demonstrated no significant effects on albumin-lowering in this short-term trial. The contradictory results may be due to the difference in the trials period. A longer duration of treatment with linagliptin may help in the detection of clinically relevant renal effects, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular hemodynamics.[40] Interesting results from a random clinical study on 62 T2DM patients randomly assigned to linagliptin or placebo, reported that linagliptin treatment for 4 weeks may prevent impairment of renal endothelial function. The associated mechanism in preventing the renal endothelial function was demonstrated in in vitro studies which concluded that DPP-4 was expressed in endothelial cells and that inhibition of DPP-4 reduced the microvascular tone through direct mediation of the nitric oxide system.[41] Similarly, a large-scale study comprising 923,936 T2DM patients out of which 83,638 assigned to DPP-4 inhibitors (75.7% sitagliptin, 14.6% vildagliptin, and 9.7% saxagliptin), were performed to evaluate the risk of acute kidney injury with DPP-4 inhibitors. DPP-4 inhibitors use was significantly associated with a lower risk of incident of acute kidney injury (HR 0.57, 95% CI; 0.53–0.61) and risk of dialysis-requiring acute kidney injury (HR 0.57, 95% CI 0.49–0.66). The study suggested DPP-4 inhibitors as a class of hypoglycemic agent with reno-protective effects and associated with a reduced risk of mild or severe acute kidney injuries in T2DM patients. DPP-4 inhibitors render their effects by suppressing the inactivation of GLP-1 and it could retard the progression of DKD by ameliorating inflammation and fibrosis and improving endothelial functions. Furthermore, DPP-4 is widely distributed in endothelial and epithelial tissues, including renal proximal tubular epithelia, podocytes, mesangial cells, and pre-glomerular vascular smooth muscle cells, and its inhibition has a direct impact on preserving the kidney function.[42] A recent clinical trial of cardiovascular and renal microvascular outcome study with linagliptin, was conducted with the aim to evaluate the long-term impact of linagliptin on renal and cardiovascular outcomes in T2DM patients. The multi-national randomized, placebo-controlled trial was conducted in 605 clinics of 27 countries comprising of 6991 T2DM patients. The study reported that 8.8%–9.4% of patients on linagliptin treatment showed better kidney outcomes. In another published work of the same trial with 6979 T2DM patients, no significant impact of linagliptin on baseline eGFR or urinary ACR was observed.[43] Finally, the results of Cardiovascular Outcome study of linagliptin (CAROLINA) versus glimepiride were presented, showing no significant difference in cardiovascular outcomes between the two treatment groups, although linagliptin shows comparatively a lesser risk of hypoglycemia and weight gain. It is irrefutable that DDP-4 inhibitors play antifibrotic role in the kidney of diabetic patients through complex interconnected molecular pathways. The mechanism of kidney fibrosis is a multifactorial and complex process as several cell types such as kidney fibroblasts, tubular epithelial cells, mesangial cells, podocytes, pericytes, vascular smooth muscle cells, and endothelial cells are involved in producing excess extracellular matrix.[44]

The role of DPP-4 inhibitors in improving renal function has widely been discussed in the available literature. Still, there exists a gap in understanding its impact in minimizing the progression in patients at risk of developing kidney disease. Multiple trials conducted on the effects of DPP-4 inhibitors evaluated their effects on kidney secondary to cardiovascular effects. Primary outcomes analysis and the impact of combination therapy needs further elucidation through long-term clinical trials.

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the most recent developed oral hypoglycemic agents act by reducing glucose reabsorption and promote urinary glucose excretion, resulting in lower level of hyperglycemia in T2DM patients. SGLT2 is expressed almost entirely in the renal proximal tubules, hence selective inhibition of this protein leads to renal glucose excretion and reduction of plasma glucose levels without influencing other metabolic processes. Along with their hypoglycemic effects, these drugs have shown impressive results in renal and cardiovascular safety and efficacy. Canagliflozin, dapagliflozin, and empagliflozin have been recently approved for use in the USA, Europe, and certain other countries.[45] The effect of SGLT-2 inhibitors dapagliflozin, was studied in a multicenter, double-blind, placebo-controlled trial of 546 T2DM patients who had inadequate glycemic control with metformin. These patients were randomly assigned to either placebo (137 patients) or to any of the three doses of dapagliflozin (2.5 mg, 5 mg, and 10 mg OD), to evaluate baseline HbA1c changes at 24 weeks. The mean HbA1c differences at 24th weeks were: Placebo (−0.30%), dapagliflozin 2.5 mg (−0.67%), dapagliflozin 5 mg (−0.70%) and dapagliflozin 10 mg (−0.84%). No significant difference was observed in the hypoglycemic symptoms in both placebo and dapagliflozin groups. Urinary glucose excretion increased with dapagliflozin, and a significant reduction in body weight was also observed at 24 weeks. Hence, the addition of dapagliflozin to metformin can improve the glycemic profile of patients who are not responding to metformin only treatment.[13] Similarly, a systematic review of 8 trials, 7 assessed dapagliflozin and one assessed canagliflozin, was published in 2012, focusing on the clinical effectiveness and safety of SGLT-2 inhibitors. In comparison to placebo, dapagliflozin decrease HbA1c by-0.54% (weighted mean difference, 95% CI, 0.67–0.40), but no difference was observed when compared to glipizide. Furthermore, when compared with sitagliptin, a slightly more reduction of HbA1c was observed with canagliflozin (up to -0.21%). In addition, both canagliflozin and dapagliflozin were associated with weight loss, i.e., -1.81 kg with dapagliflozin and-2.3 kg with canagliflozin in comparison to placebo. Furthermore, the long-term trial extension is suggestive of maintained effects over time.[45] A study of 126 T2DM patients with DN was conducted, aiming at investigating the effects of dapagliflozin in these patients by randomly assigning them to dapagliflozin or control (insulin only). No significant difference was observed (P > 0.05) on the basis of FPG, while GFR was significantly improved in the SGLT-2 inhibitor treatment group in comparison to control (P < 0.05) during the follow-up period of 1 year. Moreover, the study demonstrated the effects of dapagliflozin on the plasma level of ROS, which are considered highly toxic to renal tubular epithelial cells and renal tubular endothelial cells. The plasma level of ROS was significantly reduced in the treatment group in comparison to the control group. In conclusion, the study has demonstrated the efficacy of dapagliflozin in improving renal function, although no effects were observed on FPG.[46] Similar results were observed in a study on Japanese T2DM patients, where canagliflozin was associated with the reduction in urinary ACR and improved eGFR in comparison to the control group. It was concluded that, canagliflozin can effectively decrease the progression of kidney disease and can help in reduction of albuminuria and tubulointerstitial markers in diabetes patients with chronic kidney disease (CKD).[47] On the effects of canagliflozin on kidney outcomes, a clinical trial of 1450 T2DM patients already on metformin was conducted. The patients were randomly assigned to canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride up-titrated to 6–8 mg. The study aimed at observing the changes in eGFR and albuminuria over 2 years of follow-up. The eGFR was observed to decline for 3.3 ml/min per 1.73 m2/year (95% CI, 2.8–3.8) with glimepiride. Besides canagliflozin 100 mg was associated with the eGFR reduction of 0.5 ml/min per 1.73 m2 per year (95% CI, 0.0–1.0), and the subjects in canagliflozin 300 mg group had eGFR declines of 0.9 ml/min per 1.73 m2 per year (95% CI, 0.4–1.4) (P < 0.01 for each canagliflozin group vs. glimepiride). In the subgroup analysis of patients with baseline ACR ≥30 mg/g, urinary ACR decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P = 0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P < 0.001) than with glimepiride. The HbA1c changes were the same for all the groups and therefore, canagliflozin confer reno-protective effects independent of its glycemic effect. SGLT2 transported blockade leads to inhibition of sodium and glucose reabsorption which increase the delivery of glucose and sodium in the distal tubule and the juxtaglomerular apparatus causing increase in glomerular perfusion. Furthermore, feedbacks signals are generated which results in afferent arteriolar vasoconstriction along with an acute fall in glomerular perfusion and pressure. The resulting diminished extracellular plasma volume and BP causes a reduction in atrial natriuretic peptide secretion which has an important role in reducing intraglomerular pressure. Clinically these effects manifested as an acute reduction in eGFR and albuminuria which are seldom observed with other class of hypoglycemic agents. Thus, SGLT2 inhibitors specifically alter renal hemodynamic and reduce intraglomerular pressure, which could be expected to translate into improved long-term kidney outcomes.[48] The Delay of IGT by a Healthy Lifestyle Trial (DELIGHT) randomized, double blind, placebo-controlled trial demonstrated the effects of dapagliflozin alone or with combination of saxagliptin on glycemic control in patients with T2DM. The study comprised of 1187 T2DM patients from 116 centers across 9 countries. The follow-up period was 24 weeks, and at the end of study, the difference in mean urinary ACR changes from baseline were-21·0% (95% CI-34·1 to -5·2; P = 0·011) for dapagliflozin and -38.0% (-48·2 to -25·8; P < 0·0001) for dapagliflozin plus saxagliptin. At the 24th week, a significant reduction in HbA1c as compared to placebo was found (−0·58% [-0·80 to -0·37; P < 0·0001]) in the study. Hence it was concluded that, dapagliflozin alone or with saxaglitpin when given in addition to angiotensin-converting enzyme inhibitor or angiotensin receptor blockers can potentially decrease the progression of kidney disease in T2DM patients and moderate to severe CKD.[49] Similar results with canagliflozin were observed in Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation (CREDENCE) trial, which recruited 4401 T2DM patients with stage 2 or 3 CKD and albuminuria. The trial was terminated earlier on the advice of data and safety monitoring committee as pre-specified efficacy was achieved at scheduled interim analysis. The study observed reduced kidney failure and cardiovascular events in canagliflozin group in comparison to placebo at median follow-up of 2.62 years.[50] In addition to CREDENCE trial, certain other trials for empagliflozin (EMPA-KIDNEY), for sotagliflozin (SCORED), and for (DAPA-CKD) are in progress for evaluating the efficacy of these agents in kidney outcomes. Based on the available evidences of SGLT-2 inhibitors unique role in renal effects, DAPA-CKD and EMPA-KIDNEY planned to recruit participants with T2DM and without diabetes, which will provide important information on the potential renal benefits in both population.[51]

Improvement in eGFR decline, reduced progression of albuminuria, improvement in adverse renal endpoints and reduction in all-cause mortality along with cardiovascular benefits were demonstrated in the available literature associated with SGLT-2 inhibitors use, but there are certain evidence regarding the increased risk of genital infections with the use of SGLT-2 inhibitors and a probable increase in urinary tract infection, which may be associated with the increase urinary glucose excretion, ultimately contributing to the proliferation of fungi and other microorganisms in the genitourinary tract, leading to increased risk of genital infections and poor clinical outcomes.[45152] Hence, the use of these agents in the earlier stages of natural history of nephropathy need to be determined. Furthermore, lacking in head-to-head studies of all the novel agents in minimizing the risk of progression or their effects on HbA1c in different population need to be done, for availing clear evidences of their safety and efficacy.

Limitations

The present review focused only on the larger trials evaluating the effects of the newer agents on kidney function in diabetic population. Diabetes mellitus is complicated in nature and can lead to multiple associated complications; hence, all the factors should be considered when formulating therapeutic strategy for diabetic patients.

CONCLUSION

The complex nature of diabetes and its associated complications always render difficulties in formulating management plans. At present, available therapeutic approaches targeting overt hyperglycemia, though efficient in the early stages, may have limited effects on the disease progression. Introducing the newer available anti-diabetics may help in minimizing diabetes-associated complications as these drugs have demonstrated good effects on glycemic control, along with preserved beta-cell function and improving insulin sensitivity. Better glycemic effects along with cardio-renal protective outcomes are the mainstay of the newer available drugs which may need further elucidation by incorporating novel research approaches (Pharmacometrics approaches). Furthermore, larger trials with longer duration may further effectively elucidate the benefits of these agents, which may help in decision making associated with the treatment strategy adopted in the earlier stages of the disease.

Financial support and sponsorship

Acknowledgement to “Ministry of Higher Education Malaysia for Fundamental Research Grant Scheme with Project Code: FRGS/1/2020/STG03/USM/02/2.

Conflicts of interest

There are no conflicts of interest.