Agnes is a 51-year-old widow with hypertension who received a
diagnosis of type 2 diabetes a decade ago. She has been worried
about her diabetes since then because she has not been able to
gain complete control over it. Her glycated
hemoglobin level was 7.0% for 1 year but
gradually increased to 9.0%.
What is glycated hemoglobin?
What would be the level of glycated hemoglobin in someone who doesn't have diabetes? Would you say that Agnes' diabetes is under control?
For the past 2 years, she has been taking metformin. She is maintaining her weight at 165 pounds (75 kg), but she is not able to lose weight.
Agnes' hypertension is well controlled with an angiotensin-converting-enzyme inhibitor; she also takes a statin. Her most recent laboratory tests showed a glycated hemoglobin level of 8.0%. You advise her that she'll need an additional drug to reach the goal of 7.0%.
Agnes hates needles and won't use insulin. Her sister, who also has diabetes, was using [the sulfonylurea drug] glipizide but had episodes of hypoglycemia while taking that drug, including one episode that resulted in an auto accident.
What effect do sulfonylurea drugs have that improves glycemic control?
Why does this drug cause hypoglycemia?
Agnes needs another medication, along with the metformin she already takes, in order to improve her glycemic control. Because she is concerned about hypoglycemia, a potential option would be one of the incretin-based therapies. There are two types of incretin-based drugs: GLP-1 agonists and DPP-4 inhibitors (sometimes referred to as "gliptins").
Incretin-based therapies increase insulin secretion. Why is there less risk of hypoglycemia?
GLP-1 agonists are similar in structure to native GLP-1 so that they bind and activate the GLP-1 receptor. How do DPP-4 inhibitors work?
Agnes has had trouble losing weight, and GLP-1 agonist drugs have been shown to help patients lose weight. Why might a DPP-4 inhibitor be a better choice for Agnes?
Agnes has also heard about a new class of diabetes drugs that works by eliminating excess glucose through the urine. She wants to know about the safety of the newer drugs.
The new class of diabetes drugs that Agnes is referring to are the SGLT2 inhibitors. SGLT2 inhibitors block glucose reabsorption in the kidney.
What type of protein is SGLT2?
Do you think an SGLT2 inhibitor would promote weight gain or weight loss?
Either a DPP-4 inhibitor or an SGLT2 inhibitor seems a reasonable
choice for Agnes since she prefers an oral medication, and is
frightened by the possibility of hypoglycemia. The first DPP4
inhibitor was approved in 2006. Several large studies have shown
that DPP-4 inhibitors are safe and do not increase the risk for
cardiovascular disease. The first SGLT2 inhibitor was
approved by the FDA in May of 2013. In fact, when this paper
was published in October 2013, the journal invited readers to
participate in a poll and about 75% chose a DPP-4 inhibitor as the
drug that they would recommend to Agnes.
What if Agnes and her doctor were trying to decide what new drug
to add in 2024? There are now 5 FDA-approved SGLT-2
inhibitors. They are generally safe, with the main adverse
effect being an increased risk of genitourinary infections.
For Agnes back in 2013, the two advantages for choosing an SGLT2
inhibitor would be that the drug might help her lose weight and
reduce her blood pressure. Various studies since the FDA
approval of SGLT2 inhibitors have been undertaken to investigate
their cardiovascular safety and effectiveness. These studies
have shown that treatment with SGLT2 inhibitors reduces the risk
of cardiovascular disease and slows the progression of diabetic
kidney disease. So if Agnes and her doctor were making this
decision in 2022, they might well choose an SGLT2 inhibitor.
What is another oral drug (approved in 2019) that might be a good option for Agnes in 2024?
We discussed SGLT2 inhibitors in the fall; you can remind
yourself about their mechanism of action at this web
page.
The above case is taken from a paper in the "Clinical Decisions" series in the New England Journal of Medicine. If you are interested in reading further, the reference is:
(2013) Glycemic Management in a Patient with Type 2 Diabetes New England Journal of Medicine 369: 1370-1372 (link)