Treatment: Best Practices
Diet and Nutrition
Regular monitoring of blood sugar levels is important in order for your diet to be an effective treatment method. External factors such as illness, stress, physical activity, and hormone fluctuations can change blood sugar levels unpredictably. Monitoring these blood sugar levels can help you make adjustments to your diet accordingly.
Nutritionists commonly recommend diets that center around high-fiber and low-fat, which include fruits, vegetables, whole grains, lean meats, poultry, fish, and nonfat dairy. When establishing a diet it is important to consider the glycemic index, a measure of how quickly a particular food causes a rise in blood sugar levels. Foods with low glycemic indexes raise blood sugar levels slowly, thus they make it easier to stabilize your blood sugar levels in your target range. Typically, foods with low glycemic indexes are high in fiber.
Exercise is extremely important in controlling blood sugar levels. It lowers HbA1c (hemoglobin A1c), a standard measure of blood sugar control, and increases sensitivity to insulin. Checking blood sugar levels before, during and after exercise will show how your body responds to exercise. The Mayo Clinic outlines some general guidelines on blood sugar levels 30 minutes before exercising:
● Lower than 100 mg/dL (5.6 mmol/L): blood sugar may too low to exercise. Eat something before you begin.
● 100 to 250 mg/dL (5.6 to 13.9 mmol/L): this is a safe blood sugar range.
● 250 mg/dL (13.9 mmol/L) or higher: take caution, may be at risk for ketoacidosis (excess ketones) which indicates the body does not have enough insulin to control blood sugar levels.
● 300 mg/dL (16.7 mmol/L) or higher: blood sugar is too high to exercise. Definitely risking ketoacidosis.
Commonly Prescribed Drugs
Type II Diabetes can’t be treated with diet and exercise alone. The drugs below are commonly prescribed in adjunct:
● Metformin: the most commonly prescribed drug for treating type II diabetes in overweight or obese people. It is taken orally and works by suppressing glucose production in the liver, decreasing intestinal absorption of glucose, and increasing peripheral uptake and utilization of glucose. The drug was developed in the early 1950’s so its effects are well known and documented. Correct use of metformin yields very minimal side effects. Patients with gestational diabetes (high glucose levels during pregnancy) should avoid metformin unless it is clearly necessary. Side effects include upset stomach, nausea, flatulence, and in rare cases lactic acidosis (lower blood pH).
● Pioglitazone: this drug acts to stimulate nuclear receptor peroxisome proliferator-activated receptor gamma (PPRA-G). This receptor regulates fatty acid storage and glucose metabolism. When used clinically, pioglitazone reduces insulin resistance in the liver, increases the use of insulin-dependent glucose, decreases withdrawal of glucose from the liver, and reduces quantity of glucose in the bloodstream. Side effects include: fluid retention (may result in congestive heart failure), mild weight gain, cold like symptoms, headache, and muscle pain. It is sold under the name Actos in the US.
● Sitagliptin: marketed under the name Januvia. It is an enzyme inhibitor of dipeptidyl pepidase-4 (DPP-4), a major enzyme involved in glucose metabolism. DPP-4 metabolizes incretins, hormones that increase insulin secretion in pancreatic cells. By inhibiting this enzyme, incretin levels increase, insulin levels increase and glucagon secretion is suppressed. Sitagliptin is commonly prescribed with metformin and they are marketed together in an oral form called as Janumet. The benefit of sitagliptin is fewer side effects, particularly less weight gain and hypoglycemia.
● Saxagliptin: very similar to sitagliptin and works by the same mechanism. It was developed in 2009 and sold under the name Onglyza. Side effects include cold like symptoms, stomach pain and headaches. More serious side effects include severe pain in upper stomach, fast heart rate, swelling in hands and feet, and easy bruising or bleeding.
● Repaglinide: an antidiabetic drug which stimulates insulin secretion from the pancreas. The mechanism involves a binding event to ATP-dependent potassium channels on the pancreatic cell membrane. This causes buildup of potassium in the intracellular space and changes the electric potential to positive. This opens voltage gated calcium channels, which causes an influx of calcium to the intracellular space, which increases the secretion of insulin. This drug is sold on the market under the name Prandin. Serious side effects include: seizures, severe stomach pain, pale/yellow skin, dark colored urine, red skin rash, and flu like symptoms. Less serious side effects include: cold like symptoms, diarrhea, nausea, back pain, dizziness, blurred vision, joint pain, temporary hair loss.
● Nateglinide: very similar to repaglinide and belongs to the same class of drugs called meglitinides. It is sold under the name Starlix and works by the same mechanism as repaglinide, and extent of insulin secretion is dependent on glucose levels. It has the same side effects as repaglinide but can also cause jaundice (yellowing of the skin or eyes).
● Sulfonylurea: act by the same mechanism as repaglinide. There are 13 drugs in this class of drugs. They all have the same phenylsulfonylurea backbone, but have two variable regions which distinguish each from one another. Side effects include: weight gain, upset stomach, and headache. Should not be used during pregnancy.
● Exenatide: a glucagon-like peptide-1 agonist (GLP-1) that is administered via subcutaneous injection. GLP-1 alone is responsible for the secretion of insulin in a diabetic state. Clincal use of GLP-1 fails because of the short half-life in vivo. Exenatide is an analog that is 50% similar to GLP-1 and has a longer half-life. In addition, exenatide is resistant to degradation by DPP-4, suppresses glucagon release, slows gastric emptying, subtlety reduces appetite (slight weight loss), and reduces liver fat content. Doses and frequency of doses vary, however a once-weekly injection was approved in January of 2012 under the name Bydureon. The twice a day form is named Byetta and must be injected before the patient’s first and last meal. Severe side effects include: swelling of the thyroid, trouble breathing, urinating less, weight gain, drowsiness, confusion, mood changes, upper stomach pain, vomiting, and low blood sugar. Less serious side effects include: nausea, upset stomach, diarrhea/constipation, weight loss, itching or hard lump at injection site.
● Liraglutide: similar to exenatide and works by the same mechanism. Be weary of this drug since there are concerns centered around cases of C-cell carcinoma (medullary thyroid cancer). Patients using liraglutide showed slightly increased levels of the biomarker of this cancer. This drug is sold under the name Victoza and is only prescribed if the benefits will outweigh the potential risks of the cancer. Side effects are the same as exenatide.
● Canagliflozin: the most recently drug approved by the FDA on March 29, 2013. Canagliflozin is the first drug in a class called sodium-glucose co-transporter 2 inhibitor (SGLT2). The drug is marketed under the name Invokana and works by blocking the reabsorption of glucose by the kidney, allowing it to be excreted, thus lowering blood glucose levels. It has been found to be safe and effective when taken with other diabetes medications such as metformin, sulfonylurea, pioglitazone, and insulin. Common side effects include: urinating more than usual, nausea, and constipation.
Insulin therapy is usually a treatment directed at patients with type I diabetes. But when the drugs above fail to control blood sugar levels, combination with insulin therapy has been shown to be beneficial for patients with type II diabetes. Insulin can be administered in a variety of ways including: subcutaneous injection, via insulin pump, inhalation, transdermally, orally, and in the extreme case by pancreatic transplant. In addition, there are several types of insulin that vary in their pharmacodynamic properties. Depending on patient needs, a medical professional will prescribe insulins that act quickly or slowly. Some available types are: insulin lispro (Humalog), aspart (Novolog), glargine (Lantus), detemir (Levemir), and isophane (Humulin N, Novolin N). The main issue with insulin therapy is that the dosage and timing must be correctly chosen. This is difficult to do since blood sugar levels can be somewhat unpredictable depending on diet, exercise, and food composition. A professional will be able to provide an insulin strategy.
A new class of drug called glucokinase activators (GKA) are being researched for treating type II diabetes. As its name suggests, these drugs work to activate glucokinase, an enzyme involved in glucose metabolism. Diabetic patients tend to show less glucokinase function than normal. By activating the enzyme in a diabetic patient, glucose can be correctly metabolized and uptaken by the liver. The pharmaceutical giant Eli Lilly had done trials on their GKA, but the phase I trial was terminated due to non-clinical safety findings. However, a pharmaceutical company in India called Cadila is current running safety and efficacy trials on their novel GKA by the name of ZYGK1. The trial is incomplete and the end date is not specified.
This drug is a GLP-1 receptor agonist produced by Eli Lilly, similarly to exenatide. However in recently completed phase III trials, dulaglutide performed better than exenatide, metformin and sitagliptin in reducing HbA1c. For a diabetic adult, the goal is to lower HbA1c to less than 7 percent. Dulaglutide did this with only a 1.5 mg dose. In addition, trial patients saw significant weight loss when compared to competing GLP-1 agonists. It proved to be quite safe in trials. Only nausea was reported as a side effect.
Merck and Pfizer have agreed to collaboratively develop and commercialize ertugliflozin, a SGLT2 inhibitor. This drug has recently completed its phase II trial and is ready to go into phase III. Ertugliflozin is rumored to be the best in the SGLT2 inhibitor drug class, given the reputation of these two companies. It will be competing against Eli Lilly/Boehringer-Ingelheim’s empagliflozin (filed NDA) and Bristol-Myers-Squibb/AstraZeneca’s dapagliflozin (phase III).
GlaxoSmithKline Investigational Drugs
GSK has several type II diabetes drugs in development. A compound called 1070806 is a IL monoclonal antibody that is still being used in phase II trials, treating obese patients with type II diabetes. They have also developed a SGLT1 inhibitor combined with an ileal bile acid transport inhibitor called 1614235+2330672 that has entered phase I trials. This type of drug seems to be a novel diabetes treatment, since bile acid transporters are not used in other antidiabetic drugs. Finally, GSK has also developed an investigational GLP-1 agonist called albiglutide and have submitted their IND (Investigational New Drug) application in January of 2013. Although there are many GLP-1 agonists available on the market, there is potential for improvement, especially in reducing side effects.
Researchers at North Carolina State University have developed an innovative way to deliver insulin. Their smart sponge is an injectable sponge derived from chitosan, a polymer found in crustaceans. The sponge surrounds an insulin core. When blood sugar levels rise, chemical reactions cause units of the sponge to become positively charged. The units repel each other, allowing insulin inside the core to enter the blood. When glucose levels drop, the units lose their positive charge and come back together to seal the insulin in. In addition, chitosan can be absorbed by the body, mitigating long term health problems associated with the polymer. Studies have been shown to be effective in mice, 2 days per smart sponge. Human trials have not yet been approved, but this method allows the body to dose itself, which is novel compared to other delivery systems.
Verva Pharmaceuticals has developed an insulin sensitizer called VVP808. It is meant to be taken as a supplement to current antidiabetic drugs. The active ingredient of VVP808 is methazolamide, a drug that was previous used to treat glaucoma. Verva Pharmaceuticals discovered its antidiabetic properties and have completed a phase II trial. VVP808 performed well in the trial, lowering HbA1c levels as well as increasing weight loss in some patients.
Centers of Excellence
● University of California, San Francisco Diabetes Center
● Joslin Diabetes Center (affiliated with Harvard Medical School) – Boston, MA
● Baylor College of Medicine – Houston, TX
- Dr. Lawrence Chan is the Chair for Diabetes Research and is renowned for pioneering novel therapies.
● University of Birmingham Centre for Endocrinology, Diabetes, and Metabolism – Birmingham, UK
● University of Copenhagen Centre of Inflammation and Metabolism – Copenhagen, Denmark
● University of Sydney Medical School – Sydney, Australia