Glycemic efficacy

• Biguanides (Metformin:)
  • UKPDS 34[86] studied the effect of intensive glycemic control with metformin in newly diagnosed, overweight people with type 2 diabetes. 1,704 patients who were hyperglycemic after 3 months of diet alone were randomly continued on "conventional" management mainly with diet alone versus metformin. Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (p=0.017), and 36% for all-cause mortality ( p=0.011). In secondary analysis, metformin was compared to those allocated sulfonylureas or insulin for intensive-glucose control. Metformin reduced any diabetes-related endpoint more greatly than sulfonylureas or insulin (p=0.0034), all-cause mortality (p=0.021) and stroke (p=0.032). In an unexpected and unexplained result, early addition of metformin in the sulfonylurea-treated group increased diabetes-related deaths (p=.039), although there was no overall association of metformin plus sulfonylurea with increased death risk. Conclusion was that metformin may be the first-line therapy of choice[86].
  • The Multicenter Metformin Study Group:[90] A randomized trial comparing effect of metformin versus placebo in 289 patients with type 2 diabetes who were moderately obese. After 29 weeks, the metformin group had lower fasting plasma glucose (189 mg/dl versus 244 mg/dl) and hemoglobin A1c (7.1% versus 8.6%) compared to placebo. Combination therapy with glyburide compared to glyburide alone resulted in lower fasting plasma glucose (187 mg/dl versus 261 mg/dl) and HbA1c (7.1% vs 8.6%). However, 18% had hypoglycemia in the combination group, compared to only 2% with metformin alone and 3% with glyburide alone[90].
• Sulfonylureas:
  • First-generation agents: The University Group Diabetes Program:[94] An early and much-debated study of new-onset type 2 diabetes, the UGDP randomized participants to treatment with a first-generation sulfonylurea (SU) (tolbutamide), phenformin or insulin. Found deaths from lactic acidosis in the phenformin group, and slightly but significantly more deaths from cardiovascular disease in the SU group. Serious critiques were leveled regarding methods and conclusions, for instance, by A.R. Feinstein[96]. The UGDP finding of adverse effects of SU have not been confirmed or widely accepted, but continue to prompt a Black Box warning in the package insert. SUs have been used safely in myriad studies since Meinert[94].
  • Glimepiride: In a trial of 304 adults with DM2, glimepiride as monotherapy showed hemoglobin A1c reductions of 1.2, 1.8 and 1.9% at 1mg, 4mg, and 8mg doses, respectively.[89]
  • Glipizide: In a trial of 347 adults with DM2 had hemoglobin A1c reductions of 1.5-1.82% on dose of 5-60mg of extended release glipizide once daily.[87]
  • Glyburide: Randomized 31 patients with type 2 diabetes previously inadequately controlled on diet alone to once-daily NPH insulin or glyburide. Baseline HbA1c ~10% in both groups. After 9 months, HbA1c dropped similarly in both groups by ~3%.[93]
• Insulin
  • Basal insulin
    
    • Meta analyses show similar glycemic efficacy of neutral protamine lispro (NPL), detemir, glargine U100, glargine U300, insulin degludec U100, and degludec U200.
    • Determir has been associated with a more favorable weight gain profile versus all other comparitors and glargine U300 with a more favorable weight profile versus glargine U100.
    • Both glargine U300 and degludec U100 and U200 show lower rates of nocturnal hypoglycemia versus glargine U100, determir, and NPL.[26]
  • Bolus insulin
    
    • Short-acting analogs versus regular insulin
      • Meta analyses of short-acting insulin analogs (aspart and lispro) versus regular insulin in DM1 patients showed lower rates of total, severe, and nocturnal hypoglycemia and lower hemoglobin A1c values.[25]
      • Meta analyses of short-acting insulin analogs versus regular insulin in DM2 patients showed better hemoglobin A1c lowering and self-reported postprandial glucoses, but no change in rates of severe hypoglycemia.[65]
    • Short acting versus ultra fast acting
      • Faster-acting aspart (an ultra-fast-acting analog) showed superior hemoglobin A1c lower at 52 weeks (0.1%) as well as lower 1 hour postprandial glucoses (treatment difference 16.4mg/dl) values versus traditional aspart in DM1 patients.[27]7.23 mg/dL In DM2 patients, hemoglobin A1c changes were non-significant, though the faster-acting aspart group did have lower 1 hour post-prandial glucose values versus aspart (7.23 mg/d).[16]
      • Lispro-aabc (an ultra-fast-acting analog) showed non-inferiority vs standard lispro in hemoglobin A1c reductions, but lower 1 and 2 hour postprandial glucose reductions in both DM1 (27.9mg/dl at 1 hour; 31.1mg/dl at 2 hours)[15] and DM2 (11.9mg/dl at 1 hour; 17.3mg/dl at 2 hours)[11] patients.
      • Technosphere Inhaled Insulin[72][4][42]: Maximum concentrations in the blood occur in 12-15 minutes and duration of effect is about 3 hours. In a trial of 471 DM1 patients, Afrezza was found non-inferior to insulin aspart injections, though the aspart group achieved a greater reduction in HbA1c (0.19% between-group difference, in favor of aspart)[43]. Another efficacy trial in 618 DM2 patients randomized to insulin glargine plus Afrezza or premixed insulin found that Afrezza was non-inferior, though again the HbA1c reduction was greater in the pre-mixed insulin group (between-group difference 0.12%)[57]. Those with preexisting lung disease should not use inhaled insulins, and pulmonary function tests are strongly recommended at baseline, at 6 months, and yearly thereafter.
• Alpha-glucosidase inhibitors
  
  • Acarbose[92]: Randomized 96 patients with type 2 diabetes and dietary failure to acarbose versus glibenclamide versus placebo. After 24 weeks, mean HbA1c dropped by 1.1% with acarbose and 0.9% with glibenclamide compared to placebo. Acarbose also lowered postprandial insulin increase[92].
• Thiazolidinediones (TZDs)
  • Pioglitazone: Randomized 408 patients to placebo or four different doses of pioglitazone monotherapy. HbA1c decreased on average between 1 - 1.6% on the three highest doses of pioglitazone (15 - 45 mg daily) after 26 weeks compared to placebo. The improvement in glycemic control was greatest in those who were treatment naive (HbA1c difference from placebo of -2.55%)[84].
  • Rosiglitazone: In a trial fo 498 adults with DM2, 2-4mg doses of rosiglitazone reduced hemoglobin A1c by 1.2-1.5% vs placebo.[82]
• DPP IV Inhibitors
  
  • Alogliptin: In a trial of 2,639 adults with DM2 and baseline metformin, alogliptin lower hemoglobin A1c by 0.68% and 0.72% for the 12.5mg and 25mg doses.[47]
  • Linagliptin: In a trial of 503 treatment-naive DM2 adults, linagliptin reduced hemoglobin A1c by 0.69% vs placebo.[56]
  • Saxagliptin: In a trial of 338 medication-naive DM2 adults, 2.5-5mg of saxagliptin lower hemoglobin A1c by 0.45-0.63% vs placebo.[68]
  • Sitagliptin (Study 021 Group)[78]: A safety and efficacy trial of sitagliptin as monotherapy in type 2 diabetes. Randomized 741 patients to sitagliptin (100 or 200 mg) or placebo. After 24 weeks, overall significant reductions in hemoglobin A1c in sitagliptin group (100 or 200 mg) of -0.79% and -0.94%, respectively compared to placebo. Hemoglobin A1c lowering effects greatest when baseline hemoglobin A1c >9% (~-1.50%). Sitagliptin was weight neutral, with similar incidence of hypoglycemia and slightly higher GI side effects compared to placebo[78].
  • Vildagliptin[56]: Somewhat poorer compared to other DPP-IV inhibitors, vildagliptin was found to have a decrease in HbA1c of 0.44% versus placebo in a group of 503 DM2 patients. However, it does not require dose adjustments for renal and/or hepatic impairment. It is not currently available in the U.S.
• SGLT2 inhibitors
  
  • Canagliflozin: A trial of 584 treatment-naive adults with DM2 showed a 0.77% and 1.03% reduction in hemoglobin A1c on the canagliflozin 100mg and 300mg doses, respectively. Weight loss of 1.9kg and 2.9kg was seen in the 100mg and 300mg doses, respectively.[55]
  • Dapagliflozin: A trial of 485 treatment-naive adults with DM2 showed a 0.77% and 0.89% reduction in hemoglobin A1c on the dapagliflozin 5mg and 10mg doses, respectively. Weight loss of 2.8kg and 3.2kg was seen in the 5mg and 10mg doses, respectively.[58]
  • Empagliflozin: A trial of 899 treatment-naive (or with preceding washout) adults with DM2 saw a 0.74% and 0.85% reduction in hemoglobin A1c for the 10mg and 25mg doses of empagliflozin, respectively. Weight loss of 2.26kg and 2.48kg was seen in the 10mg and 25mg doses, respectively. [53]
  • Ertugliflozin: A trial of 621 adults with DM2 inadequately controlled on metformin showed a 0.7% and 0.9% reduction in hemoglobin A1c on the ertugliflozin 5mg and 15mg doses, respectively. Weight loss of 1.6kg and 1.7kg was seen in the 5 and 15mg doses, respectively.[28]
  • Sotagliflozin: A dual SGLT1 and SGLT2 inhibitor. In a trial of 299 adults with DM2 showed a 0.52% and 0.92% reducting in hemoglobin A1c on the 200mg and 400mg doses, respectively. Weight loss of approximately 2kg was seen across all doses.[40] While approved for a cardiovascular indication in the U.S. (see below), it is not yet approved for treatment of DM2 in adults in the U.S.
• GLP1RAs
  • Dulaglutide: In the various AWARD trials, 0.75mg and 1.5mg doses of dulaglutide were shown to reduce hemoglobin A1c by 0.78-1.64% vs. various comparitors and placebo.[29] In AWARD 2, weight loss was 1.36kg and 2.29kg for the 0.75 and 1.5mg doses, respectively.[48] The AWARD 11 trial of 1,842 adults with DM2 showed hemoglobin A1c reductions of 1.55%, 1.61%, and 1.72% for the 1.5mg, 3.0mg, and 4.5mg, respecitvely at 52 weeks. Weight loss of 4kg and 4.7kg was seen on the 3mg and 4.5mg doses, respectively.[8]
  • Liraglutide: In a trial of 746 adults with DM2 controlled by either diet/exercise or monotherapy, liraglutide showed a reduction in hemoglobin A1c of 0.84% and 1.14% for the 1.2mg and 1.8mg doses, respectively. Weight loss of 1.85-3.39kg occurred in those on liraglutide therapy.[66]
  • Lixisenatide: A trial of 633 adults with DM2 inadequately controlled on metformin monotherapy showed a 0.79% reduction in hemoglobin A1c for the 20mcg lixisenatide dose during 24 weeks of follow up. Weight loss was 2.96kg.[51]
  • Semaglutide
    • Subcutaneous (sc): In a trial of 388 treatment-naive adults with DM2, semaglutide (sc) showed a 1.45% and 1.55% reduction in hemoglobin A1c at week 30 at the 0.5mg and 1mg doses, respectively. Weight loss was 3.73kg and 4.93kg at the 0.5mg and 1mg doses, respectively[32] Another trial of 961 adults with DM2 on baseline metformin +/- sulfonylurea showed hemoglobin A1c reductions of 1.9% and 2.1% on the 1mg and 2mg semaglutide (sc) doses, respectively. Weight loss was 6.0 and 6.9kg, on the 1mg and 2mg doses, respectively[6]
    • Oral (po): In a trial of 703 treatment-naive adults with DM2, semaglutide (po) showed a 0.9% and 1.1% reduction in hemoglobin A1c at the 7mg and 14mg doses, respectively at 26 weeks. Weight loss was 0.9kg and 2.3kg at the 7mg and 14mg doses, respectively[19]
  • Tirzepatide: In a trial of 478 treatment-naive adults with DM2, tirzepatide showed hemoglobin A1c reductions of 1.87-2.11% at the 5mg-15mg doses during 40 weeks of follow-up. Average weight loss was 7.5-9kg across the dose ranges.[7]

Cardiovascular trials

• Biguanides (Metformin)
  • Data from the United Kingdom Prospective DIabetes Study (UKPDS), designed to investigate intensive versus comventional therapy but also comparing metformin therapy versus sulfonlyurea and/or insulin, showed lower all-cause and CV mortality at the end of the study in the metformin group, with effects that persisted even 10 years after the end of the study, including lower rates of MI and death from any cause at that time.[67] Meta-analyses have shown that compared to sulfonylurea monotherapy, metformin monotherapy is associated with lower all cause mortality (adjusted RR 0.5-0.8) and CV mortality (adjusted RR 0.6-0.9).[33]
• Sulfonylureas
  
  • Prior meta-analyses have shown a potential association with increased risks of CV events and even higher risk of mortality.[31][52] These studies are limited and may instead reflect the CV benefit of metformin rather than an increase CV risk from sulfonylureas.
• Insulin
  • Versus non-insulins
    • Meta-analyses have shown no increase in CV and all cause mortality versus oral hypoglycemics or diet/placebo interventions.[35]
  • Basal versus bolus insulin
    • The HEART2D trial of 1,115 patients enrolled within 21 days after acute myocardial infarction (MI) investigated the difference between basal insulin (NPH vs glargine) targeting pre-prandial glucose goals versus bolus insulin (3 daily mealtime doses of insulin lispro) targeting 2 hour post prandial goals. The trial was stopped after approximately 3 years due to lack of efficacy, with similar rates of the primary CV outcome (CV death, nonfatalMI, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome).[61]

• TZDs
  • Pioglitazone[79]: In the PROActive trial, 5,238 patients with type 2 diabetes and evidence of macrovascular disease were randomized to pioglitazone versus placebo. After an average follow-up of 34.5 months, the primary composite endpoint of all-cause mortality, non-fatal myocardial infarction, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankles was not significantly different between groups. However, the composite secondary endpoint of all-cause mortality, non-fatal myocardial infarction and stroke was 16% lower in the pioglitazone group (p=0.027)[79].
  • Rosiglitazone
    • A meta-analysis of 42 published and unpublished, small and large studies found that use of rosiglitazone was associated with a marginally significant increase in deaths from myocardial infarction (odds ratio=1.43, 95% CI 1.03-1.98; p=0.03) and an increase in death from cardiovascular disease that had borderline significance (odds ratio=1.64, 95% CI 0.98 - 2.74; p=0.06). Immediately controversial.[73]
    • RECORD was a large (n=4,447 patients) randomized trial of the cardiovascular events following addition of rosiglitazone to metformin or sulfonylurea therapy, versus the combination of metformin-sulfonylurea therapy, in type 2 diabetes. After 5.5 years, the study found that rosiglitazone treatment was associated with a significant increase in body weight (~4kg), an increased risk of heart failure (hazard ratio 2.10, 95% CI 1.35 - 3.27) and overall bone fractures (relative risk 1.57, 95% CI 1.26-1.97), mainly among women and primarily in upper and lower limb fractures. However, no overall increase in cardiovascular morbidity or mortality was found with use of rosiglitazone in this study[62].
• DPP IV Inhibitors
  
  • Alogliptin: In a study of 5,380 adults with DM2 and either acute MI or unstable angina requiring hospitalization 15-90 days before trial enrollment showed no increased risk of MACE vs placebo (HR 0.96; P< 0.001 for noninferiority; P = 0.32 for superiority) , but did show a trend towards higher rates of hospitalization for CHF (3.9% vs. 3.3%; HR 1.19; 95% CI 0.90-1.58).[50] In 2016, the FDA issued a label warning for both alogliptin and saxagliptin for an increased risk of CHF admissions.[107]
  • Linagliptin: A trial of 6,979 adults with DM2 at "high CV risk" and "high renal risk" showed similar MACE outcomes wtih linagliptin vs placebo (HR, 1.02; 95% CI, 0.89-1.17; P <  .001 for noninferiority).[17]
  • Saxagliptin: A trial of 16,492 adults with DM2 with either known CVD or risk factors over a mean 2 year follow up showed no increase risk of MACE in the saxagliptin group (HR 1.00; 95% CI, 0.89 to 1.12; P=0.99 for superiority; P< 0.001 for noninferiority).
    However, higher rates of hospitalization for heart failure were seen in the saxagliptin group vs placebo (3.5% vs. 2.8%; HR 1.27; 95% CI, 1.07 to 1.51; P=0.007)[49] Based on this, in 2016 the FDA issued a warning about possible increased risk of CHF from both alogliptin and saxagliptin.[107]
  • Sitagliptin: A trial of 14,671 adults with DM2 and estalbished CVD showed no increased risk of MACE vs placebo (HR 0.98; 95% CI, 0.88 to 1.09; P< 0.001) and no increased risk of CHF hospitalizations (HR 1.00; 95% CI, 0.83 to 1.20; P=0.98).[41]
• SGLT2 Inhibitors
  
  • Canagliflozin:
    • ASCVD: The CANVAS trial of 10,142 adults with DM2 and high CV risk (most wtih established CVD) showed a significant reduction in MACE for canagliflozin vs placebo (HR 0.86; 95% CI 0.75-0.97; P = < 0.001 for noninferiority and < 0.02 for superiority). However, there was an increased risk of amputation seen in the canagliflozin group (HR 1.97; 95% CI, 1.41 to 2.75).[30] Based on this data, canagliflozin received an FDA indication to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease.[100]
    • CHF: In the CREDENCE trial of 4,401 adults with DM2 and CKD with macroalbuminuria, there was a lower risk of hospilization for heart failure in the canagliflozin group (HR 0.61; 95% CI, 0.47 to 0.80; P< 0.001), but this trial was not primarily designed for evalution of CHF benefit.[23]
  • Dapagliflozin:
    • ASCVD: In the DECLARE-TIMI 58 trial of 17,160 adults with DM2 who had or were at risk for ASCVD (only about 40% with established CVD) showed no increased risk in MACE in the dapagliflozin group vs placebo (HR 0.93; 95% CI, 0.84-1.03; P =0.17).[24]
    • CHF
      • Reduced EF: In the DAPA-HF trial of 4,744 adults with DM2 and CHF with class II-IV NY Heart Association HF and EF ≤40% showed that the primary outcome (composite of CV death or hospitalization for worsening HF) occurred signifcantly less in the dapagliflozin group (HR 0.74; 95% CI, 0.65 to 0.85; P< 0.001).[18]
      • Preserved EF: The DELIVER trial of 6,263 adults (about 45% of whom had DM) with HF and an EF of >40% showed the primary endpoint (composite of CV death or hospitalization for worsening HF) occurred significantly less in the dapagliflozin group (HR 0.82; 95% CI, 0.73 to 0.92; P< 0.001), with similar results in those with and without DM2.[2]
    • As a result, dapagliflozin received an FDA indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure and to reduce the risk of hospitalization for heart failure in adults with DM2 and either established cardiovascular disease or multiple cardiovascular risk factors.[101]
  • Empagliflozin:
    • ASCVD: The EMPA-REG trial of 7,020 adults with DM2 and high CV risk (most with established CVD) showed a significant reduction in MACE for empagliflozin vs placebo (HR 0.86; 95% CI, 0.74 to 0.99; P=0.04 for superiority).[39]
      • Based on these data, empagliflozin received an FDA indication to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease.[102]
    • CHF:
      • Reduced EF: The EMPOROR-Reduced Trial of 3,730 adults (50% of whom had DM2) with class II-IV heart failure with EF ≤40% showed that the primary endpoint (composite of CV death or hospitalization for worsening HF) occurred significantly less in the empagliflozin group (HR 0.75; 95% CI 0.65-0.86; P< 0.01), with similar results in those with and without DM2.[12]
      • Preserved EF: The EMPOROR-Preserved Trial of 5,988 adults (50% of whom had DM2) with class II-VI heart failure and EF >40% showed that the primary endpoint (composite of CV death or hospitalization for worsening HF) occurred significantly less in the empagliflozin group (HR 0.79; 95% CI 0.69-0.90; P< 0.01), with consistent results in those with and without DM2.[5]
      • As a result, empagliflozin received an FDA indication to to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure.[102]
  • Ertugliflozin:
    • ASCVD: The VERTIS CV trial of 8,246 adults and atherosclerotic CV disease showed no increased risk in MACE in the ertugliflozin group vs placebo (HR 0.97; 95% CI, 0.85 to 1.11; P< 0.001 for noninferiority).[13]
    • CHF: The ertugliflizon group did have a reduced liklihood of first hospitailzation for heart failure (HR, 0.70; 95% CI, 0.54–0.90; P=0.006), regardless of previous heart failure diagnosis, though the trial was not designed to primarily evaluate CHF outcomes.[10]
  • Sotagliflozin:
    • ASCVD: The SCORED trial of 10,584 adults with DM2, CKD (GFR 25-60 ml per minute per 1.73 m²), and risk factors for CV disease showed a significant reduction in MACE (HR 0.84; 95% CI, 0.72 to 0.99).[3]
    • CHF: The SCORED trial showed a significant reduction in the primary endpoint of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure (HR 0.74; 95% CI, 0.63 to 0.88; P< 0.001). [3]
      The SOLOIST-WHF trial of 1222 adults with DM2 who were recently hospitalized for heart failure showed a significant reduction in the primary endpoint of deaths from CV causes and hospitalizations and urgent visits for heart failure (HR 0.67; 95% CI, 0.52 to 0.85; P< 0.001).[9]
    • Sotagliflozin currently has an FDA indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with either heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors.[103]
• GLP1RAs
  • Dulaglutide: In the REWIND trial of 9,901 adults with DM2 and either CV disease or risk factors (approximately 68.5% had risk factors only), dulaglutide showed a significant reduction in MACE (HR 0·88, 95% CI 0·79–0·99; p=0·026), with similar results in those with and without known CV disease at baseline.[22] Because of this, dulaglutide received an FDA indication to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular
    disease or multiple cardiovascular risk factors.[102]
  • Liraglutide: In the LEADER trial of 9,340 adults with DM2 and high CV risk (most with established CVD) liraglutide showed a significant reduction in MACE (HR 0.87; 95%CI, 0.78 to 0.97; P=0.01 for superiority) for the liraglutide group.[34] Because of this, liraglutide received an FDA indication to reduce the risk of major adverse cardiovascular events in adults with type2 diabetes mellitus and established cardiovascular disease.[104]
  • Lixisenatide: In the ELIXA trial of 6,068 adults with DM2 with history of MI or hospitalization for unstable angina in the preceding 180 days, there was no increased risk for MACE in the lixisenatide group (HR 1.02; 95% CI, 0.89 to 1.17).[44]
  • Semaglutide
    • Subcutaneous: In the SUSTAIN 6 trial of 3,297 adults with DM2 and high CV risk (most with established CVD), semaglutide (sc) showed a significant reduction in MACE (HR 0.74; 95% CI, 0.58 to 0.95; P=0.02 for superiority).[37] Because of this, semaglutide (sc) received an FDA indication to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease.[105]
    • Oral: In the PIONEER 6 trial of 3,183 adults with DM2 and high CV risk (most with established CVD), there was no increased risk of MACE in the semaglutide (po) group (HR 0.79; 95% CI, 0.57 to 1.11; P< 0.001 for noninferiority).[20]
  • TIrzepatide: Currently has a CV outcome trial in progress.

Renal trials

• SGLT2 inhibitors
  
  • Canagliflozin
    • The CREDENCE trial of 4,401 adults with DM2 and CKD (GFR 30-90 and albumin/creatinine 300-5000mg/g) showed that the primary outcome (a composite of progression to ESRD, doubling of serum creatinine level, or death from renal or CV causes) occurred less in the canagliflozin group (HR 0.70; 95% CI, 0.59 to 0.82; P=0.00001).[23]
    • As a result, canagliflozin received an FDA indication to reduce the risk of ESRD, doubling of serum creatinine, CV death, and hospitalization for HFin adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria.[106]
  • Dapagliflozin
    • The DAPA-CKD trial of 4,304 adults (67% with DM) with CKD (GFR 25-75 and urinary albumin/creatine 200-5,000mg/g) showed that the primary outcome (a composite of sustained decline in GFR >=50%, ESRD, or death from renal or CV cause occured less in the dapagliflozin group (HR 0.61; 95% CI, 0.51 to 0.72; P< 0.001).[14]
    • As a result, dapagliflozin received an FDA indication to reduce the risk of sustained eGFR decline, ESRD, CV death, and hospitalization for HF in adults with CKD at risk of progression.[101]
  • Empagliflozin
    • The EMPA-KIDNEY trial of 6,609 adults (46% with DM) with CKD (GFR 20-45, urinary albumin/creatinine >200mg/g) showed that the primary outcome (composite of progression to ESRD, sustained decrease in GFR ≥40% from baseline, or death from renal or CV causes) occurred less in the empagliflozin group (HR 0.72; 95% CI, 0.64 to 0.82; P< 0.001).[1]
  • Ertugliflozin
    • Though no specific renal outcomes trial has yet been performed, the VERTIS CV trial showed a non-significant difference in the renal composite outcome of death from renal causes, renal replacement therapy, or doubling of serum creatinine level (HR 0.81; 95.8% CI, 0.63 to 1.04).[13]
  • Sotagliflozin
    • Though no specific renal outcomes trial has yet been performed, the SCORED trial of 10,584 adults with DM2, CKD (GFR 25-60) and risks for CV disease, showed a non-significant difference different in the renal composite outcome of first sustained decrease of ≥50% in GFR, long-term dialysis, renal transplant, or sustained GFR < 15 (HR 0.71; 95% CI 0.46-1.08).[3]