Novel Therapies for Type 2 Diabetes on the Horizon: SGLT2 Inhibitors

Issue 2 – LDL-C and CRP in Clinical Practice: A 2005 Update (PDF), download here

Issue 2 – LDL-C and CRP in Clinical Practice: A 2005 Update

Ronald M. Goldenberg
MD, FRCPC, FACE

Targeting the Kidney for Type 2 Diabetes Management: SGLT2 Inh ibiti on

The traditional management of type 2 diabetes focuses on agents with an insulin-dependent mechanism of action. Now, an emerging approach for managing type 2 diabetes involves pharmacological agents that target the insulin independent action of the renal glucose transporters known as sodium-glucose co-transporter 2 (SGLT2).

SGLT2 inhibition is a novel approach to type 2 diabetes. The normal kidneys reabsorb about 180 g of glucose per day through the proximal tubule of the nephron, with about 90% facilitated via the co-transporters SGLT2 (90%) and SGLT1 (10%). The inhibition of renal glucose reabsorption works to promote renal glucose excretion, resulting in a substantial decrease in blood glucose. Furthermore, the daily 60 – 100 g of glycosuria results in a caloric loss of 240-400 kcal/day and a reduction in body weight.

A large number of SGLT2 inhibitors are in development. In this review, we will discuss canagliflozin and dapagliflozin, the SGLT2 inhibitors with the most clinical data.

Canagliflozin: A1C, BP and Weight Effects

Canagliflozin has been studied in 9 phase 3 trials with over 10,000 subjects. In placebo-controlled studies, canagliflozin has been studied as monotherapy and as add-on therapy.

A1C reductions vs placebo have ranged from 0.6% to 0.9% with canagliflozin 100 mg, and from -0.7% to -1.2% with canagliflozin 300 mg (Figure 1). Canagliflozin led to weight loss and lowered systolic blood pressure (SBP) – weight loss was dose dependent and ranged from 2.7 kg to 3.7 kg, while SBP was typically reduced by 2-7 mmHg across the trials.

“Canagliflozin, in comparison to sitagliptin, led to a further 2.4 kg greater weight loss and a 6 mmHg greater drop in SBP”

Canagliflozin has also been studied in active comparator studies. In a 52-week add-on to metformin trial, canagliflozin reduced A1C by 0.8% to 0.9%. The effect was dose dependent with the 300 mg dose having greater impact than the comparator glimepiride. Compared to glimepiride, canagliflozin was associated with a a significantly lower rate hypoglycemia – about 5% vs 33%, a weight loss difference up to 4.7 kg. Another active-controlled study found canagliflozin 300 mg added to metformin plus sulfonylurea a more effective add-on therapy, leading sitagliptin in lowering A1C (-1.03% vs -0.66%). Canagliflozin, in comparison to sitagliptin, led to a further 2.4 kg greater weight loss and a 6 mmHg greater drop in SBP. In a study in patients with moderate renal impairment, canagliflozin was more effective than placebo in lowering A1C, where there was a -0.33% decrease with 100 mg, and -0.44% with 300 mg. This reduced efficacy in patients with moderate renal impairment is expected, as with impaired renal function there is less filtered glucose, and therefore less glucose reabsorption to be inhibited with an SGLT inhibitor.

Dapagliflozin: A1C, BP and Weight Effects

Dapagliflozin has been studied in over 4,500 patients. Dapagliflozin 10 mg lowered A1C between 0.5% to 1.0% from baseline, vs placebo, and was also associated with a 2 to 3 kg weight loss and systolic BP reduction of 4 to 7 mmHg. An active comparator trial with 2 years of follow-up found dapagliflozin to be more effective than glimepiride (A1C difference -0.18%) as an add-on to metformin, with a 5.1 kg weight-loss benefit and significantly less hypoglycemia (4% vs 46%). In a study in patients with moderate renal impairment (eGFR 30-59ml/min), dapagliflozin did not significantly reduce A1C (-0.44%) compared to placebo (-0.32%). Dapa-gliflozin is not recommended for use in patients with moderate to severe renal impairment (eGFR < 60 ml/min).

Safety Profile of SGLT2 Inhibitors

The most common adverse events related to SGLT2 inhibitor therapy are urinary and genital tract infections. In controlled trials, 8.2% of canagliflozin treated patients developed urinary tract infections compared to 6.7% of patients treated with placebo or comparator agents. In dapagliflozin trials, UTI occurred in 7.7% of patients compared to 6.3% in the placebo treated group. Most UTIs were mild to moderate, and rarely led to drug discontinuation (0.3%).

Vulvovaginal candidiasis developed in about 11% of canagliflozin-treated patients compared to 3.2% of placebo treated patients, and balanitis affected about 4% of canagliflozin-treated patients compared to 0.6% of placebo treated patients. Similarly, genital infections were more likely with dapagliflozin – 8.2% vs 1.3 % in placebo. Adverse events related to reduced intravascular volume (e.g., hypotension) can also occur with SGLT2 inhibitors. Canagliflozin treated patients had about a 4% rate of volume-related adverse events vs 2.4% of comparator treated patients, and dapagliflozin treatment was similarly associated with more frequent volume related events (1%), compared to placebo (0.4%). Finally, in pooled trials with canagliflozin, there was a slight dose-dependent rise from baseline in LDL cholesterol of 0.11 – 0.21 mmol/L. Similar modest LDL-C elevations were seen in dapagliflozin trials. There is no known mechanism for the small rise in LDL-C.

In meta-analyses of SGLT2 inhibitors, there has been no signal for an increase in major cardiovascular events. For canagliflozin, the hazard ratio (HR) was 0.91 (95% CI: 0.68, 1.22), and for dapagliflozin the HR was 0.67 (95% CI: 0.39,1.18) – each agent demonstrating an upper bound of the 95 percent confidence interval for the hazard ratio significantly less than the 1.8 figure recommended by the FDA for drug approval. Ongoing cardiovascular outcome trials with SGLT2 inhibitors will help establish the cardiovascular effects of these agents.

SGLT2 inhibitors have not been shown to be carcinogenic or genotoxic in preclinical studies. There was no increase in benign or malignant neoplasms amongst canagliflozin-treated patients in canagliflozin phase 3 trials. With dapagliflozin, amongst 19 phase 2B/3 trials, there was no difference in overall malignancies between dapagliflozin and control patients. There was, however, a slight but statistically insignificant imbalance in two tumor types. In dapagliflozin treated patients, there were 9 cases of bladder cancer (incidence rate 0.153/100 patient-years) compared to 1 case amongst control patients (incidence rate 0.031/100 patient-years). Half of the bladder cancer cases were diagnosed within one year of study start and 6 of 10 had baseline hematuria, suggesting these tumours were preexisting prior to dapagliflozin initiation and unlikely to be drug related. There were 10 cases of breast cancer (rate 0.370/100 patient-years) in the dapagliflozin group compared to 3 cases in the control group (rate 0.220/100 patient-years). All cases of breast cancer were detected during the first year of drug exposure, making drug-related cancer unlikely. Further data will help to determine if dapagliflozin has any impact on the rates of bladder or breast cancer.

Summary

SGLT2 inhibitors represent novel emerging oral therapies for the management of type 2 diabetes.

They have an insulin-independent mechanism of action, making them useful agents at any stage of type 2 diabetes and in conjunction with various background agents, including insulin. They offer efficacious glucose lowering, with the added benefits of a modest weight loss, lowering of systolic BP and an excellent tolerability profile. They will be a welcome addition to the armamentarium of agents available for managing type 2 diabetes.


eGFR – Practical Meaning in Your Patients’ Renal Function

Patients with kidney disease may have a variety of different clinical presentations. Many patients, however, are asymptomatic and are noted on routine examination to have an elevated serum creatinine concentration or an abnormal urinalysis. Creatinine itself, as a diagnostic marker, may unfortunately be misleading, especially in the elderly, who are forming a growing segment of our practices.

Estimation of the GFR is used clinically to assess the degree of kidney impairment and to follow the course of the disease.

Normal GFR

The glomerular filtration rate (GFR) is equal to the sum of the filtration rates in all of the functioning nephrons; thus, the GFR gives a rough measure of the number of functioning nephrons. The normal value for GFR depends on age, sex, and body size, and is approximately 130 and 120 mL/min/1.73 m2 for men and women, respectively, with considerable variation even among normal individuals.

Estimated GFR

The most common methods utilized to estimate the GFR are:

  1. Measurement of the creatinine clearance
  2. Estimation equations based upon serum creatinine such as
    • the Cockcroft-Gault (CG) equation,
    • the Modification of Diet in Renal Disease (MDRD) Study equations, and
    • the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

Creatinine is derived from the metabolism of creatine in skeletal muscle and from dietary meat intake. It is released into the circulation at a relatively constant rate. Creatinine is freely filtered across the glomerulus and is neither reabsorbed nor metabolized by the kidney. Serum creatinine can only be used to estimate GFR in individuals with stable kid-ney function.

The relationship between GFR and serum creatinine is not linear, but inversely proportional. At high levels of GFR, small changes in the serum creatinine level may reflect large changes in GFR. At low levels of GFR, large changes in the serum creatinine level reflect relatively smaller changes in GFR.

(These equations are available online at –http://www.nephron.com/MDRD_GFR.cgi)

Cautions

  1. Amputees, patients with malnutrition and those with muscle wasting may have lower serum creatinine levels.
  2. Young men and African Americans have higher muscle mass and higher serum creatinine levels at any given level of GFR.
  3. Patients with cirrhosis have artificially lower levels of serum creatinine.
  4. Pearls

    1. MDRD equation underestimates GFR when it is greater than 60 mL/min per 1.73 m2.
    2. Among patients with GFRs greater than 60 mL/min per 1.73 m2, the CKD-EPI equation was associated with less bias, improved precision, and greater accuracy.
    3. CKD-EPI is more accurate than MDRD equation in estimating GFR in the elderly.
    4. CG equation underestimates GFR in obese individuals and overestimates when BMI < 25.
    5. Use 24 Hr creatinine clearance in pregnancy, amputees, cirrhotics and patients with extremes in age and weight.
    6. Use radionuclide kidney clearance scanning for kidney donor evaluation, research or prediction of GFR following nephrectomy.
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