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Drug Review: Dipeptidyl-Peptidase-4 Inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin)

The four dipeptidyl-peptidase-4 inhibitors available in the U.S. are sitagliptin (sold as Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). Vildagliptin is available in other countries.

Remember that drug names vary by country and manufacturer.  This is a brief drug review; consult your physician or pharmacist for details.

How do they work?

DPP-4 inhibitors decrease both fasting and after-meal blood sugar levels primarily by increasing insulin release from pancreas beta cells.  How they do it is complicated.

First off, you need to know that two gastrointestinal hormones levels—glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide—increase in response to a meal.  These hormones increase insulin secretion by pancreas beta cells, suppress glucagon secretion from pancreas alpha cells after meals, help suppress glucose production by the liver, and improve glucose uptake by tissues outside the liver.  GLP-1 also slows emptying by the stomach and reduces food intake.  All this tends to lower glucose levels after meals.

Did I mention it was complicated?

If we could make these gut hormones hang around longer, their glucose-lowering action would be enhanced.  How can we make them hang around and work longer?  Easy: suppress the enzyme that degrades them: dipeptidyl-peptidase-4.  That’s what DPP-4 inhibitors do.

The small intestine hormone GLP-1 is a major player in normal carbohydrate metabolism.  GLP-1 levels, by the way, are decreased in type 2 diabetes.

For the DPP-4 inhibitors, we have no data on long-term safety, mortality, or diabetic complications.

Uses

Sitagliptin is FDA-approved as initial drug therapy for the treatment of type 2 diabetes, and as a second agent in those who do not respond to a single agent, such as metformin, a sulfonylurea, or a thiazolidinedione.  It can also be used as a third agent when dual therapy with a sulfonylurea and metformin doesn’t provide adequate blood sugar control.

Saxagliptin, linagliptin, and alogliptin are FDA-approved as initial drug therapy for the treatment of type 2 diabetes (in adults) or as add-on drugs for those who do not respond to a single drug, such as metformin, a sulfonylurea, or a thiazolidinedione.  In case you’re wondering, you wouldn’t use several of the DPP-4 inhibitors at the same time.  In the summer of 2012, the FDA approved linagliptin as an add-on drug for type 2 diabetics already taking insulin.  Linagliptin and alogliptin haven’t been studied in nursing or pregnant women; I’m not sure about sitagliptin and saxagliptin in those settings.  Alogliptin is approved for combined use with metformin, pioglitazone, insulin, and perhaps sulfonylureas.

Dosing

The DPP-4 inhibitors are given by mouth.   The usual dose of sitagliptin is 100 mg once daily, with reduction to 50 mg for moderate to severe kidney impairment and 25 mg for severe kidney impairment.  The usual dose of saxagliptin is 2.5 or 5 mg once daily, with the 2.5 mg dose recommended for patients with moderate to severe kidney impairment.  Linagliptin’s dose is 5 mg daily, regardless of liver or kidney funtion.  The alogliptin dose is 25 mg daily, with lower doses for those with kidney impairment.

Side Effects

Generally well-tolerated.  No risk of hypoglycemia when used as the sole diabetes drug.  They do not cause weight gain.  Sitagliptin, linagliptin, and alogliptin might cause pancreatitis.  Alogliptin may cause liver disease or abnormal liver function blood tests. Saxagliptin and alogliptin may increase the risk of heart failure, particularly in those with pre-existing heart or kidney disease.

Don’t use if you have . . .

. . . moderate or severe kidney impairment (sitagliptin) or severe kidney impairment (saxagliptin).
Use sitagliptin or alogliptin with caution and careful monitoring if you have a history of pancreatitis.

Steve Parker, M.D.

Updated April 7, 2016

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Which Drug Is Best for Treatment of Type 2 Diabetes?

Physicians now have an amazing array of drug therapies  for control of type 2 diabetes.  Until now, there has been no consensus as to which drugs to use, and when.

The American Association of Clinical Endocrinologists and the American College of Endocrinology have just issued a joint statement with specific drug recommendations.  Their algorithm is quite detailed.  Here are a few highlights you might not know about:

  • Regular human insulin is not recommended
  • NPH insulin is not recommended
  • The following should be used earlier and more frequently:  GLP-1 agonists (exenatide) and DPP-4 inhibitors (sitagliptin and saxagliptin)
  • sulfonylureas are a lower priority
  • metformin is still a key drug

In the U.S., exenatide is sold as Byetta; sitagliptin is Januvia; saxagliptin is Onglyza; metformin is Glucophage (among others). 

If you have type 2 diabetes and are arguing with your physician about optimal drug therapy, this treatment algorithm may be a helpful tie-breaker. 

Steve Parker, M.D.

Reference:  Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: An algorithm for glycemic controlEndocrine Practice, 15 (2009): 540-559.

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U.S. Food and Drug Administration Approves Saxagliptin (Onglyza) for Type 2 Diabetes

CB107673Yesterday, July 31, 2009, the FDA approved use of saxagliptin, a DPP4 inhibitor, in adults with type 2 diabetes as an adjunct to diet and exercise.  Bristol-Myers Squibb and AstraZeneca will sell the drug under the brand name Onglyza.

The drug’s only competitor in the U.S. market is Merck’s Januvia, which sold over $400 million in the first quarter of this year.

“How does saxagliptin work?”

Incretin hormones influence secretion of insulin and glucagon by the pancreas.  The dipeptidyl peptidase-4 (DPP4) enzyme inactivates these incretin hormones.  Saxagliptin inhibits the DPP4 enzyme, resulting in increased insulin production and decreased production of glucagon. 

“But it causes bad side effects, right?”

No, not that we know of yet.  Overall, incidence of side effects is similar to placebo side effects.  The drug may slightly increase headache, runny nose, and sore throat.  Risk of hypoglycemia is increased minimally, if at all. 

“Can I use Onglyza with my other diabetes drugs?”

It’s FDA-approved for use by itself or in combination with metformin, sulfonylureas, and thiazolidinediones. 

“What’s the dose?”

2.5 or 5 mg by mouth daily, without regard to meals. 

“Is this a tremendous breakthrough in treatment of type 2 diabetes?”

Probably not.  But it’s good to have another treatment option.  And competition among the drug manufacturers tends to bring down prices.   

Steve Parker, M.D.

References: 

Bristol-Myers Squibb.   Press Release from Bristol-Myers Squibb, July 31, 2009.

Goldstein, Jacob.  Saxagliptin approval: Finally, competition for Merck’s Januvia.  WSJ.com Health Blog, July 31, 2009.

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Filed under Drugs for Diabetes