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Inhibiting Kidney Glucose Reabsorption: A Novel Insulin-independent Therapy in Type 2 Diabetes Mellitus

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 15th Annual Canadian Diabetes Association (CDA)/ Canadian Society of Endocrinology & Metabolism (CSEM) Professional Conference and Annual Meeting

Vancouver, BC / October 10-13, 2012

Vancouver - New updated guidelines on the management of type 2 diabetes mellitus are expected early in 2013. A preview of the new guidelines indicates that glycemic targets may be relaxed in select patients and that the individualized treatment approach needs to be encouraged. Development of new agents with novel mechanisms of action could help fulfill the goal of individualized treatment. A new class of oral agents that can reduce HbA1c levels in an insulin-independent manner and induce weight loss through the excretion of glucose into the urine is of great interest. By inhibiting kidney glucose reabsorption, these sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown considerable promise in clinical trials. Some SGLT2 inhibitors also appear effective in patients with moderate renal impairment, an important patient group, especially with longer-standing diabetes.

Chief Medical Editor: Dr. Léna Coïc , Montréal, Quebec

Better Guidance, Better Treatment Tailoring

Individualization appears to be the overarching theme of the new 2013 Canadian Diabetes Association (CDA) clinical practice guidelines, expected to be published in March, 2013. According to Dr. Alice Cheng, Assistant Professor of Endocrinology, University of Toronto, Ontario, and chair of the clinical practice guidelines steering committee, the CDA is revisiting glycemic targets as well as therapeutic choices for patients with type 2 diabetes as recent evidence suggests that at least some patients may be treated to less stringent targets. “For the vast majority of patients, an HbA1c [target] of ≤7% is still going to remain,” she stated, unchanged from recommendations made in 2008.

Also unchanged is an HbA1c target of ≤6.5% for some patients to further lower the risk of nephropathy; a fasting plasma glucose or preprandial plasma glucose of 4.0 to 7.0 mmol/L or a 2-hour postprandial glucose of 5.0 to 10.0 mmol/L. “What has changed is that we have given better guidance as to which patients might have less stringent targets—still the minority of patients—but we have given guidance as to when we can back off a bit and how high we should allow individuals to drift,” Dr. Cheng remarked. The upper ceiling of that drift is an HbA1c of 8.5%, she added.

As Dr. Cheng noted, the diabetes community is now more aware of some of the potential downsides of treating blood sugars aggressively. Certain factors such as biological age, level of function, the presence of comorbidities, short life expectancy and patients who are prone to hypoglycemia or who do not recognize hypoglycemia, may allow physicians to be “a little more lax” in their targets. The new treatment paradigm still identifies metformin as the initial therapy of choice with an option to use it from the point of diagnosis.

For second-line therapy, the committee hopes to provide in the new guidelines more guidance as to what drug to choose and how to make that choice. Any antihyperglycemic agent that has received a notice of compliance by the time the guidelines are being finalized will be included in the 2013 guidelines.

Protecting patients against macrovascular complications remains an important theme in the new guidelines but which group of patients requires protection has been better defined and simplified.

Achieving guideline targets still appear to be elusive for many practitioners. In a survey of primary care practices in 3 provinces, the use of evidence-based medicine was very high in the group overall but achievement of therapeutic targets was disappointing, with only 45% having an HbA1c <7%; 59% an LDL-C <2 mmol/L and <29.6% achieving a blood pressure (BP) of <130/80 mm Hg (Figure 1). “Only 10.1% of patients reached all 3 targets,” Dr. Lawrence Leiter, Professor of Medicine and Nutritional Sciences, University of Toronto, noted, “so target achievement remains poor.”

Figure 1.


Asked to comment on this “action” gap, Dr. Cheng suggested it will require all players to endorse the CDA recommendations to promote change—health care practitioners need to be both aware of and agree to changes; the health care system has to facilitate them and patients have to both agree with the changes and modify their behaviours accordingly. “Ultimately the driver is the patient,” Dr. Cheng emphasized. “If patients come in and start asking: What is my HbA1c? What is my LDL-C? What is my BP? Then we have won. But patients need the tools to self-manage first and we are the facilitators in that process.”

Rationale of SGLT2 Inhibition

As discussed by Dr. Robert Josse, Professor of Medicine, University of Toronto, the kidney plays a key role in glucose homeostasis. “During normal conditions with a normal glomerular filtration rate (GFR), all the glucose is filtered [at the glomerulus] and is reabsorbed,” Dr. Josse explained. Reabsorption of glucose occurs through the action of specialized channels called sodium-glucose co-transporter 2 (SGLT2) and SGLT1, he added. SGLT2 is a high-capacity, low-affinity transporter and facilitates the reabsorption of approximately 90% of all glucose in individuals with normal GFR.

Of the 10% of glucose that escapes reabsorption, the SGLT1 transporter, a low-capacity, high-affinity transporter, “mops up” the rest. The amount of glucose filtered at the glomerulus is based on the plasma glucose concentration and the GFR; provided blood glucose is <10 mmol/L and patients have a normal GFR, “all glucose is reabsorbed,” Dr. Josse reiterated. When blood glucose levels exceed this concentration, “the capacity of the receptors to reabsorb glucose is saturated and glucose is excreted in the urine,” he added.

Clinical studies exploring SGLT2 inhibitors now in development support inhibition of the SGLT2 transporter as a means by which to induce large amounts of glucose to be excreted in the urine. Importantly, reduction in glucose toxicity through SGLT2 inhibition is independent of pancreatic function and of insulin—“these drugs affect the kidney and nothing else,” Dr. Josse emphasized.

Because greater amounts of glucose are excreted in the urine, “you are also losing about 300 to 400 calories/day and over time, weight loss usually occurs.” As speakers here reminded delegates, a substantial proportion of patients do not maintain glycemic goals with metformin monotherapy and a second drug, often a sulfonylurea, is commonly required to achieve adequate glycemic control. The sulfonylureas, however, are associated with weight gain and an increased risk of hypoglycemia. They also tend to lose their effectiveness over time.

Study Findings

A potential alternative to a sulfonylurea could be the SGLT2 inhibitor canagliflozin. Dr. Leiter presented a study of patients on background metformin randomized to either canagliflozin 100 mg (n=483) or 300 mg (n=485) or to glimepiride (n=482) once a day for 52 weeks. Baseline HbA1c levels were 7.8% in all treatment groups.

“The HbA1c came down nicely in all 3 groups,” Dr. Leiter reported. At week 52, the mean reduction in HbA1c from baseline was 0.82% in the 100 mg arm, 0.93% in the 300 mg arm and 0.81% in the glimepiride arm, suggesting that both doses of canagliflozin were non-inferior to glimepiride. Indeed, the 300 mg dose of the SGLT2 inhibitor led to a significantly greater reduction in HbA1c relative to the sulfonylurea, Dr. Leiter noted. The SGLT2 inhibitor also provided consistently lower HbA1c values over 52 weeks than glimepiride.

In terms of body weight, “those on glimepiride gained an average of 0.7 kg over the year, while those on the 2 doses of canagliflozin lost an average of 3.7 kg and 4 kg [100 mg and 300 mg, respectively] and those on the higher dose [of canagliflozin] had a 5.7% reduction in body weight over the year which translated into a 4.7 kg difference between patients on canagliflozin and patients on the sulfonylurea,” Dr. Leiter reported.

There was also a numerically greater reduction in systolic BP of 3 to 5 mm Hg and a 2 to 2.5 mm Hg reduction in diastolic BP relative to patients on the sulfonylurea, he added. The incidence of hypoglycemia was low with both doses of canagliflozin and occurred at a significantly lower rate than that in the sulfonylurea arm. LDL-C went up in all 3 groups although the increase was numerically higher with the SGTL2 inhibitor.

Conversely, “the HDL-C also went up so there were really no big differences between the SGLT2 inhibitor and the glimepiride arms,” Dr. Leiter stated. Nor were there any major differences in any adverse events although rates of genital fungal and urinary tract infections were higher with the SGLT2 inhibitor.

Combination Therapy

In a review of the overall status of SGLT2 inhibitors, Dr. Vincent Woo, Assistant Professor of Medicine, University of Manitoba, Winnipeg, showed data supporting the addition of an SGLT2 inhibitor to metformin, to insulin and both. In one study cited by Dr. Woo, the addition of oral dapagliflozin to metformin resulted in a mean reduction in HbA1c of approximately 0.70% at the end of 24 weeks compared to 0.30% with placebo.

The addition of oral canagliflozin 100 mg to metformin also led to a mean change in HbA1c of 0.76 % at 12 weeks while canagliflozin 300 mg led to a mean reduction of 0.92% at the same timepoint. The mean reduction in HbA1c for placebo in the same study was 0.22% (Figure 2). In triple therapy, the addition of canagliflozin to background metformin plus a sulfonylurea reduced HbA1c by a mean of 0.85% and 1.06% for the 100 mg and 300 mg doses, respectively. In contrast, placebo reduced mean HbA1c by 0.13% (P<0.001)

Even used as monotherapy, canagliflozin 100 mg and 300 mg reduced HbA1c by 0.77% and 1.03% respectively over 26 weeks. Both SGLT2 inhibitors have also been shown to significantly reduce HbA1c when added to insulin. Regardless of whether the SGLT2 inhibitors are used alone or in combination with other antihyperglycemics, they consistently reduce weight by 2.5 to 3.5 kg, with weight loss occurring usually within the 3 months of initiation of treatment after which it tends to plateau, as Dr. Woo noted.

Figure 2.

“The medication works as a mild diuretic as well,” Dr. Woo added, “so there is some reduction in both systolic and diastolic BP but importantly, no increase in heart rate.” Adverse effects consistently include an increased incidence of genital fungal infections and a slight increase in urinary tract infections. However, these infections usually occur as single episodes and infrequently recur.

“There is also a consistently low risk of hypoglycemia,” Dr. Woo added, “and so far there are no safety concerns with any of the SGLT2 agents.”

Renal Impairment

As diabetes progresses, patients are at risk for kidney failure and in the setting of renal insufficiency, some antihyperglycemics need to be used judiciously or avoided. With no consensus yet on the best way to achieve glycemic targets in T2DM patients with renal impairment, Gough et al. reported on a retrospective meta-analysis of 3 clinical trials of the long-acting glucagon-like peptide-1 (GLP-1) agonist liraglutide.

After 26 weeks of treatment, there was no difference in HbA1c response to injections of 1.2 or 1.8 mg doses among patients with normal renal function vs. those with mild (60 to <90 mL/min) or moderate renal impairment (<60 mL/min). However, with the higher dose of the GLP-1 agonist, serum creatinine was significantly lower compared with placebo at week 26. Reduction in serum creatinine with the 1.8 mg dose was also associated with a 38% lower risk of patients being categorized with moderate renal impairment at week 26.

The incidence of major and minor hypoglycemic episodes was low in all treatment groups and was not affected by any degree of renal impairement.

Dr. Jean-Francois Yale, Professor of Endocrinology, McGill University Health Centre, Montreal, Quebec, and colleagues explored the efficacy of SGLT2 inhibition with canagliflozin in patients with moderate renal impairment. They randomized 269 patients with a mean baseline HbA1c of 8.0% and an estimated GFR of 39.4 mL/min/1.73 m2 to canagliflozin 100 mg, 300 mg or placebo. Approximately 75% of the group was already on insulin.

At the end of 26 weeks, HbA1c was significantly reduced by a mean of 0.33% with the 100 mg dose and a mean of 0.44% for the 300 mg dose (Table 1). This compared to a mean reduction of 0.03% for placebo (P<0.05 and P<0.001). Both doses were again associated with a mean weight loss of 1.2 kg and 1.4 kg compared with 0.2 kg weight gain for placebo. Favourable changes in BPs were also observed.

Table 1.

Because most patients were already on insulin, more hypoglycemia at slightly over 50% was observed with both doses of SGLT2 inhibition vs. 36% for placebo. The incidence of urinary tract infections was slightly higher in the active treatment arms as well. However, findings from this study support the efficacy of canagliflozin in the setting of moderate renal impairment, as investigators concluded.

“The only drugs we have that cause weight loss are the GLP-1 receptor agonists and they are given by injection and they cause a lot of nausea at the beginning so there is a lot of teaching involved,” Dr. Yale remarked in an interview. “So with the SGLT2 inhibitors, we have a new class of agents that can induce weight loss while improving glucose control and they do not cause low blood sugar so they are a new class of drugs that we are looking at with interest.”


Guidelines can set therapeutic targets and recommend strategies by which to achieve these targets but it is the patient who has to believe in, and follow, the treatment plan for management to be a success. As a new class of oral agents, the SGLT2 inhibitors may be used either alone or in combination with other agents to further reduce HbA1c and promote weight loss. The fact that some may also be used effectively in moderate renal impairment is an additional benefit, as not all antihyperglycemics are safe or effective in this setting.   

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