Beyond Insulin

What Else Might Help?

Taking insulin by syringe, pen, or pump is necessary for the treatment of all cases of Type 1 diabetes and many cases of Type 2 diabetes. However, being on insulin no longer means that you’ve reached the end of your options for managing your diabetes. A number of other medical treatments can be used safely and effectively along with insulin. Some are oral drugs (pills), while other drugs are taken by injection. Some have been used for decades as treatments for Type 2 diabetes, with benefits for people with Type 1 only recently discovered. And some have just entered the market recently.

If you take insulin, adding a non-insulin treatment may help you improve your blood glucose control and raise your quality of life. Not all treatments discussed in this article are approved by the U.S. Food and Drug Administration for use by people who take insulin. However, many of them have been studied in combination with insulin in clinical studies, and all of them can be prescribed by your doctor if he feels that the benefits outweigh any potential risks. This is called “off-label” prescribing. Some doctors are more comfortable with off-label prescribing than others. The point of this article is to help you know your options so that you and your doctor can have a productive discussion and make an informed decision together.


Getting your health insurance to cover an off-label use of a drug is another story altogether. However, many health plans will cover off-label prescriptions if your doctor makes a strong enough case to the insurance company. Many pharmaceutical companies also offer copay cards that can help offset your out-of-pocket costs for these drugs. Ask your doctor if this option is available for any drug you’ll be taking.

The following are some of the treatments that may be used along with insulin to lower blood glucose.


The first injectable drug other than insulin to hit the market was pramlintide (brand name Symlin), a replacement for the hormone amylin. Amylin is normally secreted by the pancreas along with insulin. People with Type 1 diabetes secrete no amylin at all, and people with Type 2 diabetes usually secrete far too little.

What’s so important about amylin? Plenty. Whereas insulin regulates the removal of glucose from the bloodstream, amylin regulates its entry into the bloodstream. Specifically, it does the following:

• It slows the emptying of the stomach’s contents into the small intestine.

• It blunts the secretion of glucagon by the pancreas, a hormone that signals the liver to release glucose into the blood.

• It enhances satiety (a feeling of fullness) and decreases appetite.

By slowing digestion and minimizing glucagon production after meals just like amylin does, pramlintide can reduce postmeal blood glucose “spikes.” It can also be a valuable weight-loss tool: Users of pramlintide lose an average of more than 6 pounds in the first six months of use, mainly by consuming smaller portions at meals and snacking less often.

Pramlintide is FDA-approved for use by people with Type 1 or Type 2 diabetes who take mealtime rapid-acting insulin. It does not eliminate the need for insulin, but it usually reduces the required doses. It has not been studied or approved for use during pregnancy.

On the downside, pramlintide’s effects last for only about three hours, so it needs to be injected at just about every meal to work throughout the day. It is also slightly acidic, which causes it to sting a bit when injected. This is also why it cannot be mixed directly with insulin in a syringe or other injection device.

The most common side effect associated with pramlintide is nausea. Once a full therapeutic dose is achieved (people starting the drug often begin with smaller doses), mild nausea, sometimes called “sour stomach,” may occur 30–60 minutes after an injection. This nausea tends to last for about 30 minutes, and it usually fades or even disappears entirely after a few weeks as your body becomes acclimated to the drug.

Treating hypoglycemia (low blood glucose) can also be a challenge when using pramlintide, since it slows digestion so much. It is usually necessary to reduce mealtime insulin doses when taking pramlintide to prevent hypoglycemia.

The bottom line is that pramlintide is not for people who take a “casual” approach to diabetes management. It takes effort to use the drug successfully. But once you’re in the swing of using it, the benefits of pramlintide can be significant. Pramlintide is considered the most powerful tool for controlling postmeal blood glucose levels, and it’s very effective at curbing hunger and preventing “grazing” and overeating. However, you must be willing to work through the nausea as well as the process of adjusting your doses of both pramlintide and mealtime insulin.

GLP-1 agonists

Whenever nutrients come in contact with the inner lining of the small intestine, special chemical messengers are secreted by cells of the intestine. One of these chemical messengers is called glucagon-like peptide-1, or GLP-1 for short. As is the case with the hormone amylin, GLP-1 suppresses glucagon production, slows digestion, and decreases appetite. These actions can help people with Type 1 or Type 2 diabetes decrease blood glucose variability (ups and downs) and lose weight. GLP-1 also helps a functioning pancreas release a rapid burst of insulin, a boon for people with Type 2 diabetes who still have fully functioning pancreases. GLP-1 does not carry the risk of hypoglycemia or weight gain when used alone; insulin secretion by the pancreas increases only when the blood glucose level is higher than normal, and it decreases as the blood glucose level approaches normal.

Studies have shown that GLP-1 improves and preserves the health of the pancreas’s insulin-producing beta cells. Since progressive loss of these cells is a hallmark of Type 2 diabetes, GLP-1 treatments hold the potential to halt or reverse this process. For people with Type 2 diabetes, they may reduce or eliminate the need for insulin or oral diabetes drugs. For people with Type 1 diabetes, GLP-1 treatments do not eliminate the need for insulin, but they may reduce a person’s insulin requirements.

GLP-1 agonists are drugs that mimic the effect of GLP-1, with the added advantage that they work for longer than the natural hormone. Currently, three injectable drugs of this type are available: exenatide (Byetta), taken twice daily; liraglutide (Victoza), taken once daily; and extended-release exenatide (Bydureon), taken once a week. Regular exenatide and liraglutide are injected using a pen device, while extended-release exenatide is mixed by the user and injected with a syringe.

GLP-1 agonists are approved to be used alone, or in combination with oral diabetes drugs or basal insulin, for the treatment of Type 2 diabetes. Many people also take a GLP-1 agonist in combination with both basal and mealtime insulins, although this use of the drugs is not FDA-approved and must be recommended by your doctor. While GLP-1 agonists are not FDA-approved for treating Type 1 diabetes, studies have shown that they may have a beneficial effect on the condition. One recent study, for example, showed that exenatide lowered postmeal blood glucose levels in people with Type 1 diabetes, mostly by delaying stomach emptying and suppressing the release of glucose from the liver.

The main side effect associated with GLP-1 agonists is mild nausea during the first few weeks of use. People with gastrointestinal problems or kidney disease are not usually good candidates for using GLP-1 agonists. Also, small studies have suggested a possible link between GLP-1 agonists and pancreatitis (inflamed pancreas).

GLP-1 agonists have the potential to offset many of the factors that contribute to elevated blood glucose levels. Their positive effect on weight loss is unmatched by any other diabetes drug. Individual responses to GLP-1 agonists, however, are highly varied; these drugs work very well for some people, but seem to provide little benefit for others. You can’t know which group you fall into until you give them a try.

DPP-4 inhibitors

As described above, the hormone GLP-1, produced by intestinal cells in response to nutrients, works in multiple ways to help control blood glucose levels, particularly after meals. However, the positive effects of GLP-1 last for only a few minutes, because the hormone is rapidly broken down by an enzyme called DPP-4. The job of a group of drugs known as DPP-4 inhibitors is to keep GLP-1 working longer by preventing DPP-4 from breaking it down. And these drugs accomplish this without requiring an injection.

There are several DPP-4 inhibitors on the market today, as well as a few under development. The currently available drugs include sitagliptin (Januvia), linagliptin (Tradjenta), saxagliptin (Onglyza), and alogliptin (Nesina). Each of these drugs is FDA-approved to be taken alone or in combination with another oral diabetes drug. DPP-4 inhibitors are not FDA-approved to treat Type 1 diabetes, although a 2011 study found that sitagliptin allowed participants with Type 1 to reduce their use of insulin by 10%. While DPP-4 inhibitors have been shown to lower blood glucose without causing hypoglycemia when taken alone, they have not been shown to promote weight loss. DPP-4 inhibitors are not FDA-approved for use with insulin, and if taken with insulin or with an oral drug that carries a risk of hypoglycemia, they may increase this hypoglycemia risk.

Given that they come in pill form, have minimal side effects, and can improve postmeal blood glucose levels, it should be no surprise that DPP-4 inhibitors are growing in popularity. Their blood-glucose-lowering impact is about half of what is typically seen with the injectable GLP-1 agonists, but they can still be quite effective and may be the best choice for some people.


Since being introduced in the United States in 1994, metformin (Glucophage, Glucophage XR, Riomet, and others) has become the most widely prescribed drug for diabetes and one of the most widely used drugs in the world. Metformin does not increase insulin levels and does not carry the risk of hypoglycemia. Instead, it works by reducing the amount of glucose produced by the liver and by sensitizing cells to the effects of insulin; it also tends to suppress appetite. Secondary benefits of metformin may include improvements in cholesterol levels and weight loss. Metformin is often taken in combination with other oral diabetes drugs or insulin, but it can also be effective when used alone. Potential side effects include upset stomach and a rare but serious condition called lactic acidosis in which acid builds up in the blood (particularly when taken by someone with impaired liver function).

Metformin is FDA-approved for the treatment of Type 2 diabetes in people age 10 and older. It is approved for use in combination with other oral diabetes drugs and with insulin in adults age 17 and older. While not FDA-approved to treat Type 1 diabetes, metformin has been widely studied for this purpose. One 2010 review of nine studies found that in people with Type 1 diabetes, metformin was associated with reduced insulin requirements, lower hemoglobin A1c (HbA1c, a measure of long-term blood glucose control), mild weight loss, and improved cholesterol levels.

Because the liver is responsible for releasing glucose during the night, metformin can work quite well for people who are prone to high blood glucose upon waking. It can also reduce the need for basal insulin, which in turn can aid weight-loss efforts. Side effects tend to be minimal compared with those of other diabetes drugs. Because of its availability in generic form, metformin provides great value for its cost.

Thiazolidinediones (TZDs)

TZDs are a group of drugs that work to improve insulin sensitivity at the cellular level. Pioglitazone (Actos) and rosiglitazone (Avandia) are the two currently available TZDs in the United States. Both have been linked to an increased risk of congestive heart failure in people already at high risk for heart disease, so careful monitoring by your doctor is required if you take one of these drugs.

TZDs can be an effective tool for reducing insulin requirements in people who are highly insulin resistant and require very large insulin doses to control their blood glucose levels. However, the high cost of these drugs and their potential side effects make them undesirable to many people and deter most doctors from prescribing them. Besides, it has been shown that similar benefits can be achieved by exercising regularly and/or losing weight.

SGLT2 inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a fairly new class of drugs, the first of which, canagliflozin (Invokana), was approved by the FDA in March 2013 to treat Type 2 diabetes, and the second, dapagliflozin (Farxiga), was approved in January 2014. SGLT2 inhibitors are oral drugs that change the way the kidneys filter glucose from the bloodstream.

Ordinarily, the kidneys act like a dam for glucose, keeping glucose in the bloodstream from “spilling over” into the urine, up to a blood glucose level of approximately 180 mg/dl. When a person’s blood glucose level exceeds 180 mg/dl or so, some of the glucose in the blood is eliminated in the urine. SGLT2 inhibitors work by preventing the kidneys from reabsorbing glucose, essentially “lowering the dam” to allow glucose to spill into the urine starting at a blood glucose level of approximately 80 mg/dl.

SGLT2 inhibitors have been shown to lower HbA1c and fasting glucose levels in people with Type 2 diabetes. They also tend to reduce body weight and systolic blood pressure. Canagliflozin can be taken by itself or in combination with insulin, metformin, pioglitazone, or sulfonylureas (a class of oral drugs that increase insulin secretion by the pancreas).

By causing more glucose to be lost in the urine, SGLT2 inhibitors increase the frequency and amount of urination, both during the day and sometimes also at night. Having more glucose in the urine also increases the risk of urinary tract infections; however, extra fluid intake and good hygiene can help reduce this risk. People on tightly regulated insulin programs may find that after starting to take an SGLT2 inhibitor, both basal and mealtime insulin doses require adjustment to prevent hypoglycemia.

For people struggling to lose weight, SGLT2 inhibitors can be very helpful, since hundreds of calories each day are literally urinated away. This class of drugs can also provide a glucose-stabilizing effect, since higher blood glucose levels lead to more rapid loss of glucose in the urine. However, it is important to weigh these benefits against the more frequent urination, higher infection risk, and greater potential for hypoglycemia that come with these drugs.

Know your options

Managing diabetes is a complex business. Multiple hormones and processes are involved in regulating blood glucose levels, so it may be unrealistic to expect that insulin, alone, can do this job fully and successfully. For evidence that multiple hormones and processes are important, look no further than the biotech companies working to develop an artificial pancreas. To develop a device that successfully measures and regulates blood glucose levels on its own without human input, most companies are testing combinations of drugs and hormones that such a device could use, not just insulin.

Whether you want to reduce your risk of hypoglycemia by using less insulin, are struggling to control your hunger and lose weight, or simply seek improved blood glucose control, many options beyond insulin are available that may help you manage your diabetes better. Work with your doctor to weigh the pros and cons of each treatment you may be considering. In diabetes, as in life, no single method or path is right for everyone, so do what you can to find the one that’s right for you.