SGLT-2

Could AID Transform Type 2 Diabetes Care?

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While AID has traditionally been used in type 1 diabetes, new data suggests this technology has many of the same benefits in type 2 – namely, improving time in range and A1C while reducing hypoglycemia. Plus, AID dramatically simplifies blood sugar management. 

From continuous glucose monitoring (CGM) to automated insulin delivery (AID) systems, diabetes technologies that began as innovations for people with type 1 diabetes are slowly beginning to reach people with type 2.

For instance, many insurance companies now cover CGMs for people with type 2 diabetes who take insulin as well as those who are not on insulin but have a history of hypoglycemia. And earlier this week, the FDA approved Stelo by Dexcom, a CGM designed specifically for people with type 2 diabetes who are not taking insulin.

However, less progress has been made with reimbursement by insurance companies for AID. Off-label use of AID drew significant attention at the ATTD 2024 conference, with presenters highlighting the benefits for many people with diabetes across a range of settings and systems.

AID improves time in range across different systems and settings

Research shows that AID leads to many of the same benefits in type 2 diabetes as in type 1 diabetes: improved time in range, reduced hypoglycemia, and reduced A1C. Importantly, these benefits were consistent across different study settings and regardless of which AID system was used.

A study of 30 Tandem Control-IQ users with type 2 diabetes found that time in range increased by about 15% from 56% at baseline to 71% at six weeks. This translates to an increase of 3.6 hours per day spent in range.

Dr. Anders Carlson, diabetes medical director at the International Diabetes Center in Minnesota, said this finding is in line with studies in type 1 diabetes as well as the time in target range guidelines for type 1 diabetes.

Outside of clinical trials, research suggests that the benefits of AID extend to people with type 2 diabetes in the “real world.”

In a study presented at ATTD, MiniMed 780G users were able to achieve 71-75% time in range outside of a clinical trial, again meeting the targets for diabetes. “This is really compelling evidence that in a real-world setting, this AID system can work for people with type 2 diabetes,” Forlenza said.

Participants who used the recommended MiniMed 780G settings (i.e. the lowest glucose target) achieved a time in range of 80%.

For Carlson, this finding raises an important question – what are the optimal settings for AID in type 2 diabetes? For instance, since low blood sugar (hypoglycemia) is less of a concern, it may be beneficial to have more aggressive targets from the get-go.

Another study investigated the Omnipod 5 AID system in 24 participants with type 2 diabetes, finding strong improvements in time in range with minimal hypoglycemia. Among those on MDI, time in range increased from 43% at baseline to 58% at six months. Participants on basal insulin only saw even larger improvements in time in range, from 31% at baseline to 65% at six months.

Dr. Anne Peters, professor of medicine at USC, also highlighted reductions in total daily insulin dose among participants on MDI – yet another way in which AID could simplify type 2 diabetes management.

How might combining AID with GLP-1s and SGLT-2s affect glucose levels?

Growing use of GLP-1 receptor agonists, SGLT-2 inhibitors, and diabetes technology poses new questions for the future of diabetes care. That is, how might the combination of technology and medications optimize outcomes for people with type 2 diabetes?

In the Omnipod 5 study, half of the patients were also taking a GLP-1 or SGLT-2. Overall, Omnipod users taking a GLP-1 or SGLT-2 saw greater improvements in time in range compared to those who were only taking insulin. Participants in the GLP-1 or SGLT-2 group saw a 24% increase in time in range from 28% at the start of the study to 62% at eight weeks. Meanwhile, participants not using a GLP-1 or SGLT-2 improved their time in range by 18%, from 35% at baseline to 53% at eight weeks.

Carlson said this finding suggests that combining GLP-1s or SGLT-2s with AID could potentially lead to even better glycemic control than AID alone – though formal studies will be needed to test this hypothesis.

Similarly, Dr. Gregory Forlenza, associate professor of pediatric endocrinology at the University of Colorado, noted the ability of GLP-1s to reduce insulin needs. Combining these powerful medications with AID may help people with type 2 diabetes improve glycemic control and lose weight. It’s possible these improvements could even help people work toward diabetes remission.

What about AID for older adults with type 2 diabetes?

Starting insulin can be challenging for people of all ages, but it can be especially complex for older adults or disabled people with type 2 diabetes who receive home care.

Elderly people have a higher risk of severe hypoglycemia and hypoglycemia or ketoacidosis. Diabetes management for older adults can also be complicated by impaired cognition or dementia, reduced mobility, and difficulty accessing care.

In this context, the CLOSE AP+ study investigated AID assisted by nurses in people with type 2 diabetes unable to manage their own multiple daily injections (MDI) at home. CLOSE AP+ tested Control-IQ technology in 25 participants who had an average age of 70 years.

At 12 weeks, time in range improved significantly, from 37% to 63%. Time below range was less than 1%, while time above range was under 10%. Overall, Reznik highlighted that a majority of participants reached the American Diabetes Association guidelines for older people with diabetes. These guidelines recommend:

  • At least 50% time in range (70-180 mg/dL)
  • Less than 1% time below range (<70 mg/dL)
  • Less than 10% time above range (>250 mg/dL)

It’s also worth noting that participants using Control-IQ technology saw a significant 1.3% reduction in A1C. Over 90% of participants reached an A1C of less than 8% by the end of the trial, without any increase in severe hypoglycemia. Dr. Yves Renzik, professor of endocrinology at CHU Caen Normandy in France, also highlighted high patient confidence and high nurse satisfaction with the AID system in this study.

Ultimately, the CLOSE AP+ study showed that AID can be used safely in people with type 2 diabetes who require home nursing care. This confirms the benefits of AID extend beyond the “standard” person with type 2 diabetes to older adults and people with disabilities.

The bottom line

Numerous presentations at ATTD 2024 demonstrated that AID is safe and effective for people with type 2 diabetes. Both clinical trials and real-world data show that this technology increases time in range and improves A1C while minimizing hypoglycemia.

“I want to emphasize that across a wide variety of real world and clinical trial evidence sets, and across very different AID systems, everyone is either doing a great job hitting a goal for time in range or achieving a massive improvement in glucose control,” Forlenza said. He noted that AID leads to time in range increases of 15% to 24% in people with type 2 diabetes, nearly double the improvements typically seen in type 1 diabetes.

However, several questions remain to be answered regarding optimal settings, bolusing, and the potential of AID when combined with GLP-1s and SGLT-2s. Carlson highlighted the following areas for further research:

  • Are people on MDI the only candidates for AID? Or could AID be used in all people with type 2, regardless of their insulin needs and whether or not they’re meeting glycemic goals?
  • Is previous experience with technology necessary for successful use of AID in people with type 2 diabetes?
  • Does AID help with diabetes self-management (such as carb awareness)?
  • What role will primary care providers provide in supporting AID in this population?

Beyond glycemic data, it’s also important to consider user experience with AID. Overall, the data suggests that people with type 2 diabetes had good satisfaction and confidence in using these systems. Even people who hadn’t previously used diabetes devices reported a positive experience with AID, Peters noted.

“I honestly wasn’t sure my patients would like AID – many were technology-naive people,” Peters said. “But they loved it and they wanted to stay on it because they felt it improved their glycemic control.”

What Are My Choices for Metformin Alternatives?

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Metformin alternatives

While you are likely familiar with metformin and insulin as the two well-known medications for treating type 2 diabetes, many other options are available to help you manage your glucose levels. Here is a rundown of some of the other options that may improve your health and diabetes management.

When you are diagnosed with type 2 diabetes, you will likely hear from your healthcare team that the most common initial treatment regimen consists of some combination of metformin and lifestyle changes to your diet and exercise.

For most people, type 2 diabetes is a progressive disease (this means that without proper treatment it can continue to worsen over time). In addition, some people may have more severe and chronic hyperglycemia for a long time prior to being diagnosed with type 2 diabetes. As a result, you might need additional medications the longer you have diabetes to keep your glucose levels in a healthy range.

Insulin remains the most effective therapy to lower glucose, particularly in comparison to most oral medicines for type 2 (including metformin). Therefore, at the time of diagnosis, if there is evidence of long-standing and persistent hyperglycemia, you may be advised to start insulin, since it is most effective and rapid in its action to lower glucose levels. Once diagnosed, if you are unable to meet your glucose targets (whether that be because your condition has progressed over time, your current medications are not doing enough to lower your glucose, or because you were experiencing significant symptoms), your healthcare team may suggest using insulin.

While these treatments are some of the most well-known, there are many other medications available today for people with type 2. These additional drugs have dramatic effects; many of them can lower your risk for various diabetes-related complications, while still maintaining similar glucose-lowering properties.

“People with diabetes should be aware of their need for different medications based on their risk profiles,” said Dr. Robert Gabbay, chief scientific and medical officer for the American Diabetes Association. “All people with diabetes should also be referred for and receive DSMES, or diabetes self-management education and support, at diagnosis. This gives people the opportunity to engage with a skilled diabetes care and education specialist, ask questions about therapies, and increase awareness.”

As new diabetes drugs continue to receive FDA approval at an unprecedented rate, here is a look at the different types of medications that can improve your health and help you better manage your diabetes. If you are at an increased risk for developing complications, or your glucose levels have not responded well with metformin, talk with your healthcare provider about whether these medications may be a better option.

SGLT-2 inhibitors

SGLT-2 inhibitors are oral medications that can help lower your glucose levels by helping your body remove excess glucose by excreting it in your urine. These drugs can lower A1C levels, and research has shown that they can also slow the progression of kidney disease and protect against heart disease (heart attack, stroke, hospitalization for heart disease and death) and heart failure. However, SGLT-2 inhibitors should not be prescribed to those who have already progressed to stage 4 or end stage kidney disease.

Additionally, unlike other glucose-lowering drugs, SGLT-2s come with a relatively low risk of hypoglycemia. The currently available SGLT-2 inhibitors include Farxiga, Invokana, Jardiance, and Steglatro.

Side effects of taking an SGLT-2 inhibitor may include:

  • More frequent urination
  • Increased risk for urinary tract infections and genital yeast infections
  • Increased risk for kidney damage for those already at advanced stages of kidney disease
  • Increased risk for diabetic ketoacidosis (DKA)
  • Low blood pressure, syncope (loss of consciousness caused by low blood pressure), and dehydration due to volume depletion
  • Invokana, specifically, may increase your risk for amputations, ketoacidosis, and kidney damage beyond that associated with other SGLT-2 drugs.

GLP-1 receptor agonists

GLP-1 receptor agonists are another type of glucose-lowering medication, which can either be taken orally or, more commonly, through a once-daily or once-weekly injection. GLP-1 receptor agonists can lower your A1C levels, and some have been shown to lower your risk for heart and kidney disease as well.

Perhaps most remarkable, however, is that taking a GLP-1 receptor agonist can lead to significant weight loss. If you have struggled with weight management through diet and exercise changes alone, talk with your healthcare provider about starting a GLP-1 receptor agonist. The currently available medications in this class are Adlyxin, Bydureon, Byetta, Ozempic, Rybelsus, Trulicity, and Victoza.

Side effects of taking a GLP-1 receptor agonist may include:

  • Nausea
  • Vomiting and diarrhea (usually decreases over time)
  • Risk for hypoglycemia, if taken in combination with insulin or a sulfonylurea (read below)

DPP-4 inhibitors

DPP-4 inhibitors are a class of drugs that can lower your glucose by inhibiting glucagon release in your body, a hormone that causes your blood sugar to rise. This helps stimulate insulin production and decreases the emptying of your stomach, making you feel more full. Both of these effects help lower glucose levels.  These drugs are taken orally and are often combined with metformin to bolster the glucose-lowering action. When taken with metformin, there is a low risk for low blood sugar with a DPP-4 inhibitor, but taking them with insulin or sulfonylureas can place you at a higher risk.

While they can lower your glucose, DPP-4 inhibitors have not been shown to have the same effects on weight loss and complications as the SGLT-2 and GLP-1 drug classes. Available DPP-4 inhibitors include Januvia, Nesina, Onglyza, and Tradjenta.

Side effects include:

  • Gastrointestinal problems
  • Flu-like symptoms
  • Increased risk for pancreatitis

Sulfonylureas (SFUs)

SFUs are a type of glucose-lowering medications that have been around for many years as a treatment for type 2 diabetes. While SFUs are effective at lowering glucose and are available as less expensive generic brands, they significantly increase your risk for low blood sugar and can cause weight gain. Given that other drug classes can lower your glucose and reduce complications without the added risk for hypoglycemia, you may want to discuss these other options with your healthcare provider.

Side effects include:

  • Higher risk for experiencing hypoglycemia
  • Weight gain
  • Hunger
  • Upset stomach

Thiazolidinediones (TZDs)

TZDs are another glucose lowering medication that work by reducing insulin resistance. Similar to SFUs, TZDs are cheaper and come in generic brands but can place users at a higher risk for negative side effects such as weight gain and an increased risk for heart failure. Discuss these risks with your healthcare provider to find the best option for you.

Side effects include:

  • Weight gain
  • Edema, or fluid buildup, usually in your feet, legs, hands, or arms
  • Increased risk for heart failure or experiencing a bone fracture

Combination Drugs

Combination drugs, as the name suggests, combine two or more drugs, usually from different classes, into a single medication. Combination drugs can increase the effectiveness of each individual medication, reduce overall side effects, or decrease the total number of injections or pills in your daily treatment routine. Some currently available combination drugs include Janumet (Januvia + metformin), Kombiglyze XR (Onglyza + metformin extended release), and Synjardy (Jardiance + metformin).

Of course, these different drugs can also be taken as separate doses at the same time, or in combination with your insulin regimen. Layering multiple therapies can alleviate some negative side effects, help lower your glucose more effectively, and help prevent complications at the same time. Combination therapies allow your healthcare provider to develop a much more personal treatment for you.

Cost and access

Depending on your insurance coverage, drug costs are often a factor in determining which treatment you receive. Given how they minimize side effects and protect against complications, GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors are all ideal options, but they tend to be more expensive and aren’t yet available in generic forms in the US.

SFUs, TZDs, and metformin are available in generic brands and are typically much cheaper – but obviously, as is the case with SFUs and the risk of severe hypoglycemia, there may be reasons why these drugs are not preferred. Regardless, all of these medications can help you lower your glucose, so talk with your provider about which treatment fits your budget and insurance coverage.

The bottom line

While metformin and lifestyle modification remain the first-line therapies for type 2 diabetes, as you can see, there are several other medications that you may be able to try before needing to go on insulin. Depending on your risk for developing complications like heart or kidney disease, it’s often more effective to start using a GLP-1 receptor agonist or an SGLT-2 inhibitor before progressing to insulin injections.

This flowchart from the American Diabetes Association details the process for how your healthcare provider makes decisions on which medications may best for each individual. While the chart may seem complex, it illustrates the many different options that might be available to you depending on cost, risk factors, and overall health goals.

“Ask questions,” said Dr. Gabbay. “Have a frank discussion with your diabetes care provider to understand the available options, why a treatment may or may not be for you, and ask questions to understand the treatments you do receive.”

Talk with your healthcare provider about whether you might benefit from one of these drugs. The path from metformin to insulin is by no means direct, and there may be other options that can help you improve your diabetes management.

Two New Drug Classes Tied to Better Survival in Type 2 Diabetes

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Patients with type 2 diabetes who did not achieve adequate glycemic control with metformin had improved survival during follow-up if they received add-on therapy with a sodium-glucose cotransporter 2 (SGLT-2) inhibitor or a glucagon-like peptide 1 (GLP-1) agonist rather than a dipeptidyl peptidase-4 (DPP-4) inhibitor or control (placebo or no treatment), in a network meta-analysis that indirectly compared these three drug classes.

Rates of heart failure and myocardial infarction (MI) were also lower in patients who received SGLT-2 inhibitors rather than controls.

But GLP-1 agonists were associated with a higher rate of (largely gastrointestinal) adverse events leading to withdrawal from the trials.

These findings, by Sean L Zheng, MB, from the National Heart and Lung Institute at Imperial College, London, UK, and colleagues were published April 17 in JAMA.

“Based on these findings, SGLT-2 inhibition and GLP-1 agonists may be preferred over DPP-4 inhibitors as add-on therapies to metformin,”

In fact, “of the three classes tested, SGLT-2 inhibition may be preferred over the incretin-based therapies based on their association with lower mortality and their favorable adverse event profile,” Zheng and colleagues indicate.

However, they caution that SGLT-2 inhibitors were also associated with increased risk of genital infections, and canagliflozin, but not empagliflozin, was linked with a significant increase in lower-limb amputations. So “our analyses do not rule out the possibility of a clinically meaningful safety signal for SGLT-2 inhibitors and amputation,” they warn.

On the other hand, DPP-4 inhibitors were linked with a greater risk of pancreatitis.

Thus, “careful treatment selection may be necessary to minimize these outcomes in at-risk patients,” Zheng and colleagues advise. Moreover, because the network meta-analysis was an observational study, it cannot determine cause and effect, and the findings would have to be confirmed in further research.

Increasingly Prescribed, But Which Drug Class Is Best?

“The three drug classes assessed here are being increasingly prescribed,” for type 2 diabetes, said Zheng in a statement by Imperial College, “yet until now there have been no clinical trials studying how these drugs compare to each other, and which type of drug could be the best option for patients.”

He and his coauthors searched for studies published up until October 2017 and identified 236 randomized clinical trials in 176,310 patients.

There were 65 trials of SGLT-2 inhibitors, 83 trials of DPP-4 inhibitors, and 65 trials of GLP-1 agonists that compared these agents with a control, and 23 studies that directly compared two drug classes.

Zheng and colleagues aimed to investigate the rate of all-cause mortality (the primary outcome) as well as cardiovascular mortality, heart failure, MI, stroke, adverse events, and hypoglycemia, with use of the three drug classes.

Almost half of the patients came from nine cardiovascular outcome trials: EMPA-REG OUTCOME and CANVAS with SGLT-2 inhibitors; ELIXA, LEADER, SUSTAIN-6, and EXSCEL with GLP-1 agonists; and SAVOR-TIMI 53, EXAMINE, and TECOS with DPP-4 inhibitors.

Overall, during follow-up, patients who received an SGLT-2 inhibitor had a 1% absolute lower rate of death and a 0.8% lower rate of cardiovascular death than patients who received control therapy.

Patients who received a GLP-1 agonist, which are subcutaneously injected, had a “more modest” 0.6% lower risk of death and a 0.5% lower risk of cardiovascular death during follow-up than patients who received control therapy.

However, rates of these two outcomes were similar in patients who received a DPP-4 inhibitor or control therapy.

Expressed another way, patients who received an SGLT-2 inhibitor or a GLP-1 agonist were less likely to die of all causes during follow-up than patients who received control therapy (hazard ratio [HR], 0.80 and 0.88, respectively).

Similarly, patients who received an SGLT-2 inhibitor or a GLP-1 agonist were less likely to die of cardiovascular causes during follow-up than patients who received a DPP-4 inhibitor (HR, 0.78 and 0.0.86, respectively).

The researchers acknowledge a limitation is that they assume there are class effects on mortality. But while, for example, all-cause mortality during follow-up was reduced with GLP-1 agonists liraglutide (in LEADER) and semaglutide (in SUSTAIN-6) it was not with lixisenatide (in ELIXA) or exenatide (in EXSCEL).

Also, the trials may have been too short to detect cardiovascular mortality in patients at low cardiovascular risk, and the meta-analysis did not examine how glycemic control affected mortality.

“Crowded Market” of Second-Line Diabetes Drugs

Separately, an analysis of US sales figures for 2017 shows that sales of GLP-1 agonists rose by 32% in 2017 compared with 2016. Sales of SGLT-2 inhibitors grew by 24% during that time, but sales of DPP-4 inhibitors were flat.

The SGLT-2 inhibitor sales were likely boosted on the one hand by a new US indication for empagliflozin (Jardiance, Lilly/Boehringer Ingelheim), that of improving cardiovascular survival, but were probably diminished by a black-box warning mandated by the Food and Drug Administration for amputations for canagliflozin (Invokana, Janssen).

Meanwhile, Zheng and colleagues say their analysis will help inform patient–physician discussions.

“Our hope is that in the crowded market that is diabetes medications, patients and their doctors have the necessary information to allow them to make informed decisions about long-term treatment strategies,” said Zheng.

The study was supported by a grant from the British Heart Foundation.