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Where Do SGLT-2 Inhibitors Fit in Diabetes Care?

Various T2 factors create need for multiple treatment options.

Diabetes mellitus affects over 300 million individuals worldwide (an estimated prevalence of 6.9% to 10.2% in Western societies and 3.7% to 7.6% in developing countries).1 Type 2 diabetes (T2DM) accounts for 90% to 95% of the incidence. Up to 75% of adults with diabetes have comorbid hypertension.2 There is significant overlap in underlying risk factors and complications of both conditions, including disorders of microvasculature (e.g., coronary artery disease, myocardial infarction, stroke, congestive heart failure, and peripheral vascular disease) and macrovascular complications (retinopathy, nephropathy, and neuropathy).2 Now we have a new treatment, a first in class that works differently than any other diabetes treatment.

Sodium glucose co-transporter 2 (SGLT-2) inhibitors are a new type of treatment for type 2 diabetes to control hyperglycemia and can also lower blood pressure and reduce weight.

With the treatments we already have, do we really need another treatment for diabetes? Type 2 diabetes is a heterogeneous and progressive disease. It has a multivariable etiopathology, meaning that essentially there are many different factors that contribute to type 2 diabetes to different extents in different individuals, and these play out to a greater or lesser extent as the disease progresses. Therefore, we need different treatments and different combinations of treatments to focus on these different factors at different times as the disease progresses.

If we go back 50 years, you will find that we only had one category of drugs for the treatment of diabetes and that would be sulfonylureas. As of 1995, we had a new treatment come on board, which was metformin. Today we have many possibilities and possible combinations for the treatment of diabetes. With all of the possible treatments being used for glucose control, where can the SGLT-2 inhibitors fit in?

Glycemic control is a major issue in type 2 diabetes. Blood pressure control is very important and lipid control is very important. We now have very good evidence that good glycemic control, especially at the very beginning of type 2 diabetes, after diagnosis, is also very important in the long term. It can reduce the onset and severity of the complications of type 2 diabetes and reduce macrovascular risk — and even help to reduce beta cell apoptosis. Therefore, there is very good rationale for using as many therapies as we need at different times to control hyperglycemia, and new information tells us that “the sooner the better” in controlling blood sugars can be very beneficial.

SGLT-2 inhibitors are a non-insulin-dependent mechanism of action; in principle they should be able to be used at any stage during the natural history of type 2 diabetes. From studies with the drugs that have been looked at in detail to date (dapagliflozin and canagliflozin) and the available data that are coming through with the other flozins (e.g., empagliflozin), we can see a consistent reduction in A1c levels in essentially all of the trials. This is in the region, in most cases, of slightly less than 1%, occasionally a little more. And that is with a baseline of 8% or less being reduced to the 7% level.

The amount of glucose that is being excreted in the urine is on the order of 50-100 grams daily. If you work on the principle of about 4 calories to the gram of glucose, that means that between 200 and 400 calories daily are excreted in the urine, so you might indeed expect there to be a weight loss. Most patients with type 2 diabetes are either overweight or obese, and therefore weight loss would be an advantage. Indeed, this is what we see with that amount of calories being eliminated in the urine — typically somewhere between 2 and 3 kg of weight loss over 6 months. Like the A1c value, the effect appears to carry on and is evident in studies that have been extended to 1 and even to 2 years, and soon we will have data for the 3-year follow-up. We are getting reductions in glucose as well as reductions in weight.

The glucose that is eliminated in the urine is also going to create a small amount of osmotic diuresis in the region of 200-400 mL daily. If you divide that among all of a person’s daily voids, it is a fairly modest and not really noticeable amount. However, it may have an effect within the body. These therapies all seem to reduce A1c, weight, and blood pressure similarly. In individuals who have high systolic blood pressures to start with (blood pressure 140 mm Hg or higher) one might expect to see a 5-mm Hg reduction in systolic blood pressure, and perhaps a 2-mm Hg reduction in diastolic blood pressure. When the blood pressure is at the lower-normal range, one would see very little effect on blood pressure. We don’t see individuals developing hypotension.

So, what do we know in terms of safety and tolerability from the trials? Hypoglycemic risk does not appear to be increased when these agents are used as monotherapy or in combination with agents that don’t cause hypoglycemia. Of course, the risk for hypoglycemia is still present if these agents are combined with drugs that can cause hypoglycemia, such as the sulfonylureas and insulin, but nevertheless, one still sees the glucose-lowering effect irrespective of what other agents are used, whether the SGLT-2 inhibitor is being given as monotherapy or combined with metformin, a sulfonylurea, a dipeptidyl peptidase-4 (DPP-4) inhibitor, or insulin. Hypoglycemic risk appears to be under control. As the blood glucose level falls, the amount of available glucose falls, so the amount that is reabsorbed will tend to fall as the SGLT-2 plus SGLT-1 (which is in the more distal part of the proximal tubule) will be able to reabsorb most of that glucose.

Because the SGLT-2 inhibitors work most of their mechanism in the urine, this also raises the risk for urinary infections. Genital infections such as thrush are more common in patients with type 2 diabetes who have glucosuria. This has been noticed with these agents and so they may not be appropriate for individuals who have a history of these types of events. In most individuals this either doesn’t occur or the infections are mild, and if recognized early, manageable. The same holds true for urinary tract infections. In the trials there was a small increase in the incidence of urinary tract infection with the use of these agents when they cause glucosuria. We have no real evidence of hypotension, and although osmotic diuresis can occur, we have no evidence of dehydration, but of course you would not use these agents in individuals who are already predisposed to a reduction in their fluid volume.

The SGLT-2 inhibitors rely on adequate renal function. They rely on a sufficient glomerular filtration to put glucose into the proximal tubule so its reabsorption can be inhibited. As glomerular filtration declines, the efficacy is likely to decline as well, and for this reason, in individuals who have particularly low glomerular filtration rates, SGLT-2 inhibitor therapy would not be indicated because the efficacy would be inadequate.

Chronic kidney disease is an issue in advancing years in patients with type 2 diabetes, and so that is one of the precautions that needs to be seriously considered when choosing to use this type of therapy. That said, because this type of therapy is non-insulin dependent, it can be used early in the progression of type 2 diabetes as an add-on to the monotherapies that we have available at the moment. If renal function is adequate, one can see the glucose-lowering effect of the drug, either weight-lowering or prevention of weight gain, and perhaps some reduction in blood pressure. In the case of adding this therapy to insulin, it is usually possible to either slightly or considerably reduce the amount of insulin, and certainly to reduce or avoid the need for titrating up the insulin. The SGLT-2 inhibitor should fit as a non-insulin-dependent agent with any other therapies at any stage of disease to help control hyperglycemia, given adequate renal function.

We now have another tool to use to control blood sugars and prevent complications from diabetes.

— Steve Freed, R.Ph., Diabetes Educator, Publisher

  1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diab Res Clin Prac. 2010;87:4-14.
  2. Long AN, Dagogo-Jack S. The comorbidities of diabetes and hypertension: mechanisms and approach to target organ protection. J Clin Hypertens. 2011;13(4):244-251.