The SGLT2 Inhibitors

The SGLT2 inhibitors are the newest class of drugs used to treat people with diabetes.

They work by inhibiting reabsorption of sugar from the kidneys by the SGLT2 transporters.

Since these transporters account for 90% of sugar reabsorption, their blockage results in significant loss of sugar in the urine. This is especially important in people with Type2 diabetes as they have an increased capacity to reabsorb glucose via these transporters.

The effect is independent of insulin.

Clinically, this results in lower sugar levels in the blood, both before and after meals. The average HA1c reduction is 0.7-1.2% in studies ranging from 4-90 weeks.

HA1c lowering capabilities are similar to, or superior to, sitagliptin (Januvia). Reductions in fasting glucose are greater with the SGLT2's.

Because calories are being lost as increased amounts of sugar are excreted in the urine (50 grams of glucose in the urine is equivalent to 200 calories), the drugs are also associated with weight loss.

Weight loss averaged ~ 5 pounds at 12 weeks.

In 12 month trials, reported weight loss ranges from 6-10 pounds.

Small, but clinically significant reductions in blood pressure (~ 5 mm Hg systolic) are also seen with the SGLT2 inhibitors, presumably due to both fluid loss and weight loss. Uric acid levels may also decline.

Slight increases in LDL-cholesterol and HDL-cholesterol levels have been reported. Studies are underway to determine their clinical significance.

SGLT2 inhibitors currently available include canagliflozin (Invokana), dapagliflozin (Farziga), and empagliflozin (Jardiance).

Clinical efficacy and side effects are similar with some studies suggesting modestly greater imporvements in blood pressure and weight with canagliflozin.

All are once daily oral formulations, taken before the first meal.

Much interest and excitement regarding the SGLT2 inhibitors followed the presentation of data from the EMPA-REG OUTCOME study at the EASD 2015 meeting.

In that study, people with Type 2 diabetes and heart disease received Jardiance. The use of empagliflozin resulted in a 38% relative risk reduction in heart-related deaths and a 32% relative risk reduction in all-cause deaths.

This is the first time a diabetes drug showed improved outcomes in people with high risk heart disease. 

Subsequent trials have reported heart related benefits with Cangliflozin (the CANVAS trial) and dapagliflozin (the DECLARE-TIMI trial).

The class appear to exert their greatest benefit on heart failure related events, but will also reduce the incidence of atherosclerotic heart related events.

Emapgliflozin (Jardiance) appears to have a modestly greater impact on CV outcomes and all cause mortality compared with cangliflozin (Invokana).

Mutliple recent clinical trials suggest that this class of drugs has kidney protective benefits in people with type 2 diabetes with and without baseline kidney dysfunction.

The most common side effects of the SGLT2 inhibitors are genital yeast infections (10% of women and 4% of men), presumably due to increased concentration of sugar in the urine. Most of the genital infections in men occur in men who aren't circumcised. Increased risk of urinary tract infections has not been reported in all trials.

Some people note increased urination.

Canagliflozin (Invokana) has been associated with a modestly increased risk of fracture and amputations in some, although not all, studies. 

Since insulin secretion isn't increased, and reabsorption is only inhibited when blood sugar levels are 90 mg/dl or more, hypoglycemia (low blood sugar) is rare when the SGLT2 inhibitors are used alone.

Symptoms of volume depletion may occur (dizzy with standing).

This is seen most often in people 65 years or older, people who are dehydrated or being treated with fluid pills (diuretics), and/or people with underlying kidney dysfunction.

High potassium levels have been reported, most often in people taking blood pressure medications that block the renin-angiotensin system.

The efficacy of SGLT2 inhibitors is greatest in people with healthy kidneys. If your kidneys aren't filtering normally, enough sugar won't be filtered to allow the drugs to have a significant impact on reabsorption. The drugs are not toxic to the kidneys.

SGLT2 inhibitors should not be used in people with significantly reduced kidney function (i.e. those with GFR's <30 ml/min).

Diabeteic ketoacidosis (DKA) without markedly elevated blood glucoses was reported in 9 people with Type 1 and Type 2 diabetes in a study published online in the June 15, 2015 issue of Diabetes Care. 

This report followed a report of 101 cases of DKA in people with Type 2 diabetes published in a worldwide review by the European Medicines Agency, and a warning by the FDA in May 2015 regarding 20 reports of DKA. Most of these were in people with Type 2 diabetes. 

As with all medications, discuss the pros and cons of treatment with your physician before beginning therapy.

We have participated in many of the pivotal SGLT2 inhibitor studies.

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