We’ve recently looked at the GLP-1 (glucagon-like peptide) drug injections that stimulate the body’s insulin releasing ability as an adjunct to metformin. The American Diabetes Association gave particular attention to that add-on drug in its 2018 edition of the Practice Standards, due primarily to the cardiovascular health benefits shown in clinical trials.
A feature making these medicines particularly attractive to users, quite aside from their effectiveness as balanced sugar response agents, has been the introduction of longer acting formulations delivered by prefilled injector pen which have simplified the injection routine and cut dosing frequency from twice daily with AstraZeneca’s Byetta in 2005 to once weekly with Eli Lilly’s Trulicity in 2014, and arriving soon at your druggist, Novo Nordisk’s Ozempic. Sanofi also has its entrant in the weekly injection category, efpeglenatide, in Phase III clinical trials in 2018.
In 2016, Intarcia took its implantable GLP-1 infusion technology, still in investigational use, known as Medici™ to the Food and Drug Administration for clearance, hoping to further improve user experience by stretching the dosing interval out as long as three years. We followed our GLP-1 article with a review of the drug-specific and patient-centered considerations weighing in favor or against adopting add-on drugs, like SGLT-2 drugs to divert glucose at the kidneys, and a note on the need to keep an eye out for renal complications.
Rounding out our review of the American Diabetes Association 2018 Practice Standards for T2D drug therapy is some more about SGLT-2’s and about other speciality medications that you may introduce to your pharmacologic regimen to fine-tune your glycemic control.
The drug-specific and patient-specific factors described in our earlier coverage become a bit nuanced here. Agonist drugs, or those that stimulate metabolic response, working in combination with inhibitor drugs, or those that interrupt and suppress metabolic response, go to work at differing times and sites in the digestive system.
SGLT-2 Inhibitors
Let’s take a look at the drug-specific and patient-specific factors and consider the appropriateness of adding an SGLT-2 (sodium glucose co-transporter) inhibitor drug. In this case you would be adding a drug meant to interrupt or prevent the absorption of glucose and rid the system of it rather than to lower its concentration as it circulates in the blood and metabolizes.These tablet drugs, listed below with patient information, work by inhibiting the transport of glucose at the kidneys:
- Jardiance Eli Lilly/Boeringer Ingelheim empafligozin
- Invokana Janssen (Johnson & Johnson) canagliflozin
- Farxiga AstraZeneca dapafliglozin
- Steglatro Merck/Pfizer ertufliglozin, FDA cleared in December 2017.
There has been in development since 2015 an SGLT-1 drug that has recently reached phase III trials in the InTandem clinical program. Sotagliflozin (Sanofi/Lexicon) is delivered in combination with an SGLT-1, and works to block absorption of glucose in the small intestine. These drugs have investigative FDA clearance for use by T1D patients. And although SGLT-2 class drugs are cleared in the U.S. only for T2D therapy at the present time, researchers have investigated SGLT-2 use since 2016 for T1D patients at low dose with close ketone monitoring to forestall risk of hypoglycemia and kidney complications.
Because these drugs redirect glucose to the urinary system before it can be filtered back to the blood system, they increase urinary output and frequency. Hydration becomes important for avoiding blockage from accumulation of toxins and calcium in the urinary tract and the bladder. Clinical trial and adverse event reports of urgency, discomfort, inflammation and infection are not uncommon. In some patients who have established lower limb bone density or circulatory loss there has been shown a statistically significant risk of amputation.
DPP-4 Inhibitors
These medicines, dipeptydal peptidase inhibitors, enhance the effectiveness of injected GLP-1 and natural GIP (glucagon-inhibiting gut peptide) by prolonging the time within which they can work at balancing sugar and insulin. DPP-4s have been available in the U.S. since April 2007 when Merck’s Janumet received FDA approval. They have been prescribed with comparable success as single agents and in combination with other drugs to treat diabetes. They’re available as metformin and cholesterol fighting (statin) combination drugs as well.
- Januvia Merck sitagliptin
- Galvus Novartis vitagliptin
- Onglyza AstraZeneca saxagliptin
- Trandjenta Lilly/Boeringer Ingelheim linagliptin
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Of the DPP-4 combination drugs listed below, Oseni is the only one known to aggravate risk of heart difficulty. Piolgltiizone may cause fluid retention leading to congestive heart failure, or a lessening of the heart’s blood pumping ability, and so it is not recommended for T2D patients in weakened cardiovascular health.
- Janumet Merck sitagliptin with metformin
- Jentadueto Lilly/ Boehringer linagliptin with metformin
- Kazano Takeda alogliptin with metformin
- Komboglyze AstraZeneca saxagliptin with metformin
- Oseni Takeda alogliptin-pioglitazone,
Juvisync , the combination of sitagliptin and the cholesterol fighter simvastatin (Zocor for example), became available in 2011, the first combination to also provide a lipid control benefit. The manufacturer Merck withdrew the product temporarily from the U.S. market in 2013 for competitive reasons.
Other Strategies
For some patients the best add-on strategy simply may be to try and cut carbohydrates off at the pass by introducing a medication that goes to work before glucose can enter the bloodstream. Alpha-glucosidase inhibitors such as acarbose and miglitol are considered primarily as cardiovascular medications with their treatment benefit coming from inhibiting absorption of glucose, leaving the digestion of fats and proteins unaffected.
Meglinitides, known by their generic names nateginide and repaglinide, prompt the pancreas to initiate short-lived surges of insulin, and so are designed for mealtime glucose control. Their efficacy and potency as a glucose-moderating drug are comparable to metformin. Although they differ in their mechanism of action from metformin, they are often prescribed for metformin users who experience gastric discomfort. Meglinitides are considered a first line therapy alternative.
Thiazolidinones are agonist drugs that lower insulin resistance in tissue, and as an added benefit they lower triglycerides and improve the HDL cholesterol, the good kind. These formulations are marketed in the U.S. as Actos (Takeda pioglitazone) and Avandia (GlaxoSmithKlein rosiglitaone).
A lot to absorb. WIth all the jumbling of same-sounding vowels and consonants, you might feel that you’ve been speed-learning how to conjugate Latin verbs.
Remember, as you consider possible next steps with your physician, that diabetes medications work best for you when you’re keeping fit and keeping to a proper diet.
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