August 2013 Issue

Shifting Directions — Learn About a New Diabetes Drug That Targets the Kidney to Improve Blood Glucose Control
By Constance Brown-Riggs, MSEd, RD, CDE, CDN
Today’s Dietitian
Vol. 15 No. 8 P. 34

According to the American Association of Clinical Endocrinologists (AACE), more than 60% of patients with diabetes don’t reach hemoglobin A1c targets, increasing their risk of potentially life-threatening complications. However, new advances in understanding the kidney’s role in glucose homeostasis have helped identify innovative treatments, such as canagliflozin (INVOKANA), which may address many of the shortcomings of conventional drugs.

Canagliflozin received FDA approval in March and represents a paradigm shift from conventional type 2 diabetes therapies. It’s the first in a new class of medications called sodium glucose-limiting cotransporter 2 inhibitors (SGLT2) that target the kidney as a means of glycemic control with the added benefits of reducing body weight and systolic blood pressure.1 The drug is available for use in the United States to improve glycemic control in adults with type 2 diabetes.2

The rapid pace of research on new medications for treating diabetes can be challenging for dietitians and diabetes educators who want to give their patients the most accurate, up-to-date, evidence-based information. This article will provide a brief history of SGLT2 inhibitors, insight into the role of the kidney in glucose homeostasis, and canagliflozin’s mechanism of action, indication, efficacy, safety, and nutrition implications. Meal-planning tips for conventional antihyperglycemic medications also will be discussed.

Historical Perspective
Canagliflozin is the first SGLT2 inhibitor approved by the FDA but not the first to be identified. “The first SGLT inhibitor to be identified was phlorizin, an O-glucoside analog first extracted from the root bark of an apple tree in 1835,” says Jimmy Ren, PhD, therapeutic area lead in metabolics and medical affairs at Janssen Pharmaceuticals.

Phlorizin inhibited both SGLT1 (found primarily in the gastrointestinal tract) and SGLT2.3 “However, due to its low bioavailability and high susceptibility to degradation, phlorizin didn’t progress to clinical trials,” Ren explains.
Nonetheless, SGLT inhibitors remained a focus of clinical research in the management of type 2 diabetes over the past two decades, ultimately leading to the development of phlorizin analogs. The current analogs canagliflozin and dapagliflozin, available in European markets, have better bioavailability and selectivity than phlorizin.3

Kidneys at the Epicenter of Glucose Control
The kidneys probably are best known for their role in fluid and electrolyte balance. However, they’re now understood to play an essential role in glucose homeostasis and hyperglycemia. There are three mechanisms by which the kidney regulates glucose balance: It releases glucose into circulation via gluconeogenesis, uptakes glucose from circulation to satisfy energy needs, and causes glucose reabsorption in the proximal tubule.4 

Each day the kidneys filter approximately 180 g of glucose, virtually all of which is reabsorbed into the bloodstream.1 Glucose reabsorption takes place through two sodium glucose cotransporters, SGLT1 and SGLT2, located within the proximal tubule of the nephron. SGLT2 is the most prevalent and functionally important SGLT in the kidney,3 accounting for approximately 90% of filtered glucose reabsorption in the nephrons. SGLT1, found primarily in the gastrointestinal tract, but also in the proximal tubule, is responsible for reabsorbing the remaining 10% of glucose in the nephrons.3

When glucose levels exceed the capacity for renal glucose reabsorption, glucose is excreted via the urine. The plasma glucose concentration at the time this occurs is called the renal threshold for glucose.4 In people with type 2 diabetes, the renal threshold increases, causing more glucose to be reabsorbed before glucose is excreted, contributing to the worsening of hyperglycemia. This is where canagliflozin comes in.

Canagliflozin
Canagliflozin reduces blood glucose by acting on the kidneys as a “glucuretic” to promote the loss of glucose via the urine. Canagliflozin “selectively inhibits SGLT2, thereby lowering the renal threshold for glucose and promoting renal glucose excretion,” Ren says. So what historically has been viewed as a sign of poorly controlled diabetes—glucose in the urine—is now a desired outcome of canagliflozin and an actual measure of efficacy.

“Since this drug causes glycosuria [glucose in the urine], there will be a need to reeducate patients that glycosuria is a sign that this medication is working rather than a sign of poor diabetes control,” says Linda Delahanty, RD, chief dietitian and director of nutrition and behavioral research at the Massachusetts General Hospital Diabetes Center who also coauthored Beating Diabetes.

In clinical trials, when used as monotherapy, canagliflozin at 100- and 300-mg doses reduced A1c by 0.91 and 1.16 percentage points, respectively, compared with placebo.1 This is significant because research studies show that every percentage point drop in A1c can lower the risk of diabetes complications by 40%.1

In addition to improved glycemic control, both doses of canagliflozin produced significant reductions in body weight and systolic blood pressure. “In patients with type 2 diabetes, approximately 80 g/day of glucose was lost in urine during INVOKANA treatment,” Ren says, which translates to approximately 300 kcal lost per day.

For the majority of type 2 diabetes patients who are overweight, this is welcome news. In contrast to insulin, 100 mg of canagliflozin was shown to promote a 2.2% (1.9 kg) dose-dependent weight loss in clinical trials; 300 mg was shown to promote a 3.3% (2.9 kg) dose-dependent weight loss. Unlike canagliflozin, sulfonylureas and thiazolidinediones all lead to weight gain. In addition, systolic blood pressure decreased by 3.7 and 5.4 mm Hg with the 100- and 300-mg doses of canagliflozin, respectively.1

However, as with many diabetes therapies, canagliflozin isn’t without potential side effects. The most common are vaginal yeast infections, urinary tract infections, and frequent urination.2 Because canagliflozin is associated with a diuretic effect, it can cause low blood volume leading to orthostatic or postural hypotension, a sudden drop in blood pressure on standing.2 This may result in symptoms such as dizziness or fainting and is most common in the first three months of therapy.2 Patients on low-sodium diets will have a higher risk of dehydration.1

Dietitians will need to be particularly vigilant in assessing and monitoring patients who are taking diuretics, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers, and those who already may show evidence of dehydration. “I would prioritize messages of adequate hydration, reduced calories, and weight loss first,” Delahanty says. “After monitoring serum potassium, blood pressure, and assessing usual dietary intake, I’d tailor any education on sodium or potassium accordingly.”

Canagliflozin also can have a negative impact on LDL cholesterol levels as evidenced in clinical trials. “The mean reported changes in LDL levels with this medication [canagliflozin] were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8%) with the 100-mg and 300-mg doses, respectively,” Delahanty says. “I’d assess each patient’s LDL level before and after starting the drug and tailor the degree of emphasis on therapeutic lifestyle changes for disorders of lipid metabolism accordingly.”

Because canagliflozin’s mechanism of action is independent of insulin secretion, it has the potential to be effective in patients with new-onset type 2 diabetes and those with long-standing diabetes, across the spectrum of beta-cell function.5 

The drug was studied as a stand-alone therapy and in combination with other type 2 diabetes treatments, including metformin (Glucophage), glimepiride (Amaryl), pioglitazone (Actos), and insulin. Canagliflozin shouldn’t be used to treat people with type 1 diabetes; who have increased ketones in their blood or urine, known as diabetic ketoacidosis; or severe renal impairment, end-stage renal disease, or who are patients undergoing dialysis.1

Food doesn’t affect canagliflozin’s absorption; however, based on its potential to reduce postprandial glucose excursions due to delayed intestinal glucose absorption, it’s recommended that patients take canagliflozin before the first meal of the day.1

Meal Planning Considerations
Nutrition professionals agree that medical nutrition therapy including physical activity is the cornerstone of type 2 diabetes management. However, the progressive nature of type 2 diabetes usually requires the addition of one or more glucose-lowering medications and eventually insulin.

Dietitians and diabetes educators play a major role in educating patients about when and how to take their diabetes medications. They also provide guidance on how to prevent or minimize adverse effects of medications. The following is a brief overview of the currently available classes of diabetes medications and meal planning strategies for each.

Sulfonylureas
Sulfonylureas lower blood glucose by stimulating insulin secretion from the beta cells of the pancreas.6 To minimize episodes of hypoglycemia, dietitians should encourage patients to maintain carbohydrate consistency from meal to meal and snack to snack. Patients on sulfonylureas require a fixed mealtime schedule.6

Because sulfonylureas are associated with weight gain, energy restriction, reduced fat intake, and regular physical activity should be highly recommended.6

• Glipizide (Glucotrol) should be taken on an empty stomach, 30 minutes before the first meal of the day since food delays its absorption. Glucotrol XL should be swallowed whole, so dietitians should instruct patients not to chew, cut, or crush pills.7

• Glyburide (Diabeta) usually is taken once daily with the first main meal.7

• Glimepiride (Amaryl) is administered as a single dose taken in the morning with breakfast.7

Meglitinides
Meglitinides are similar to sulfonylureas; they stimulate insulin secretion by the beta cells of the pancreas. The major difference between the two is that meglitinides are shorter acting and most effective when taken after meals in the presence of glucose.6 To minimize hypoglycemic episodes, RDs and CDEs should encourage patients to maintain carbohydrate consistency from meal to meal and snack to snack.6

Meglitinides also are associated with weight gain, so dietitians should encourage patients to reduce calorie and fat intake and engage in regular physical activity.6

• Nateglinide (Starlix) is taken one to 30 minutes before meals. RDs should urge patients to omit the dose if they skip a meal.7

• Repaglinide (Prandin) is taken 15 to 30 minutes before meals. Dietitians also should inform patients to omit the dose if they skip a meal.7

Biguanides
Biguanides enhance insulin sensitivity in the muscle. They decrease hepatic glucose production by reducing gluconeogenesis, the formation of glucose from noncarbohydrate sources, and by decreasing glycogenolysis, the breakdown of glycogen to glucose.6 Biguanides have the potential to decrease vitamin B12 and folate absorption, so RDs should monitor B12 and folate levels for changes.6,7 Biguanides aren’t associated with weight gain and actually have the potential to promote slight weight loss.

• Metformin (Glucophage) is the only available biguanide in the United States.6 Like all other biguanides, patients should take metformin with food to reduce gastrointestinal upset.7

Thiazolidinediones
Thiazolidinediones (TZDs) lower blood glucose by increasing glucose uptake in skeletal muscle cells, reducing insulin resistance, and decreasing gluconeogenesis.6 Because TZDs are associated with weight gain and edema, dietitians should monitor their patients’ weight closely at every visit. Energy restriction, reduced fat intake, and regular physical activity can prevent or limit weight gain.6

St John’s wort can interfere with the therapeutic levels of TZDs, so patients should be encouraged to avoid this herb while taking one.7

• Pioglitazone (Actos) and rosiglitazone (Avandia) are the two TZDs currently available. Patients can take TZDs with or without food, but they should take the once-daily dose in the morning.7

Alpha-Glucosidase Inhibitors
Alpha-glucosidase inhibitors (AGIs) are the only medications used to treat type 2 diabetes that don’t specifically target the disease’s pathology. This class of medications works by inhibiting enzymes that digest carbohydrates in the small intestine, thereby delaying carbohydrate absorption.6

• Acarbose (Precose) and miglitol (Glyset) are the two AGIs currently available. Patients should take AGIs with the first bite of every main meal for maximum effectiveness.7 They have no affect on weight, but patients must use oral glucose to treat hypoglycemia. Digestive enzymes should be avoided while taking AGIs because they may reduce the inhibitors’ effectiveness.7

Incretin Mimetics
Incretin mimetics mimic the action of the natural hormones in the gut: glucose-dependent insulintropic peptide and glucagonlike peptide-1 (GLP-1).8 These hormones are released during nutrient absorption and increase insulin in a glucose-dependent manner. They also suppress glucagon secretion, slow gastric emptying, and enhance satiety.8 This class is associated with a modest degree of weight loss over a two-year period.8

Currently, there are two drugs in this class: exenatide (Byetta and Bydureon) and liraglutide (Victoza).

• Byetta is injected twice per day within the hour before breakfast and the evening meal.8

• Bydureon is injected once per week any time, independent of meals.9

• Victoza is injected once per day any time, independent of meals.8

Dietitians should encourage patients to increase fluids and drink sugar-free carbonated beverages to reduce the nausea associated with these medications.

Amylinomimetics
Amylinomimetics counter the effects of an amylin deficiency. Pancreatic beta cells cosecrete amylin with insulin in response to food intake.8 They primarily suppress glucagon release and lower after-meal glucose.

• Pramlintide (Symlin), an injectable, is a synthetic analog of human amylin.8 Patients must inject it separately from insulin. It’s designed to be given with each meal of 250 kcal or more or at least 30 g of carbohydrate.8

DPP-4 Inhibitors
Dipeptidyl peptidase-4 (DPP-4) enzyme inhibitors prevent or slow down GLP-1 degradation. This raises the level of GLP-1 and causes the pancreas to produce more insulin.8 Following are the three available DPP-4 inhibitors:

• Sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta) are taken orally once daily, independent of meals.7 They improve after-meal hyperglycemia and don’t affect weight.7

Insulin
Insulin is responsible for facilitating glucose transport from circulation into muscle and adipose cells, suppressing glucose production in the liver, and regulating cellular glucose, lipid, and protein metabolism.6 Patients on fixed insulin doses will need to maintain carbohydrate consistency meal to meal and snack to snack.6 Patients on flexible insulin regimens may have variable carbohydrate intake and adjust insulin accordingly.6

Insulin is associated with weight gain. Calorie restriction, decreased fat intake, and regular exercise can prevent or limit weight gain. Timing of insulin injections or pump bolus in relation to food varies with insulin type (eg, rapid acting, short acting, intermediate acting, long acting, premixed).7

Patient Education Tips
Because diabetes care largely is based on self-management knowledge and skill, it is as important for patients as it is educators to become knowledgeable about each medication prescribed. The ultimate goal is for patients to know as much as possible about their medication, including the generic and brand name, how it works, side effects, benefits, how much to take, when to take it and how often, effect of missed and delayed doses and instructions for storage, travel, and safety. Research shows that when patients are informed and educated about their medications they have more favorable outcomes. In the words of Elliot P. Joslin, MD, founder of the Joslin Diabetes Center, “The patient who knows the most lives the longest.”

— Constance Brown-Riggs, MSEd, RD, CDE, CDN, is the national spokesperson for the Academy of Nutrition and Dietetics, specializing in African American nutrition, and author of the African American Guide to Living Well With Diabetes and Eating Soulfully and Healthfully With Diabetes.

 

References
1. Media fact sheet: INVOKANA (canagliflozin). Janssen Pharmaceutical Companies of Johnson & Johnson website. http://www.multivu.com/players/English/60562-janssen-invokana/links/60562-K02CAN13156A-INVOKANA-Media-Fact-Sheet.pdf. Accessed May 21, 2013.

2. FDA approves Invokana to treat type 2 diabetes. US Food and Drug Administration website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. March 29, 2013. Accessed May 20, 2013.

3. White JR Jr. Apple trees to sodium glucose co-transporter inhibitors: a review of SGLT2 inhibition. Clin Diabetes. 2010;28(1):5-10.

4. Understanding the role of the kidney in glucose balance. Primary Care Diabetes website. http://pcd-glucose-homeostasis.com/journal/understanding-role-kidney-glucose-balance. November 3, 2011. Accessed May 28, 2013.

5. Janssen Research & Development, LLC Endocrinologic and Metabolic Drugs Advisory Committee. Canagliflozin as an Adjunctive Treatment to Diet and Exercise Alone or Co-Administered With Antihyperglycemic Agents to Improve Glycemic Control in Adults With Type 2 Diabetes Mellitus. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334551.pdf. January 10, 2013. Accessed May 28, 2013.

6. Ross TA, Boucher JL, O’Connell BS. American Diabetes Association Guide to Diabetes: Medical Nutrition Therapy and Education. Chicago, IL: American Dietetic Association; 2005:81-89.

7. Pronsky ZM, Crowe JP.  Food Medication Interactions. 17th ed. Birchrunville, PA: Food Medication Interactions; 2012.

8. Diabetes pharmacotherapy. Academy of Nutrition and Dietetics Nutrition Care Manual website. http://www.nutritioncaremanual.org/content.cfm?ncm_content_id=81035&highlight=
metformin. Accessed May 28, 2013.

9. Medication guide: Bydureon. US Food and Drug Administration website. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM289869.pdf. January 2012. Accessed June 1, 2013.