GLP-1

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.”

“Zepbound,” the newest weightloss drug

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As Zepbound dominates headlines as a new obesity-fighting drug, experts warn that weight loss shouldn’t be the only goal.

A tube with the word Zepbond on it, designed specifically for weight loss.

Zepbound is the newest addition to the weight loss drug arena. In November 2023, it joined the list of obesity-fighting drugs – administered as an injection – to be approved by the U.S. Food and Drug Administration. 

The key to Zepbound’s weight loss potential is its active ingredient, tirzepatide. This is the same active ingredient found in the drug Mounjaro, which is approved to treat Type 2 diabetes. 

The relationship between Zepbound and Mounjaro is similar to two other popular drugs making headlines, Wegovy and Ozempic. Both Wegovy and Ozempic contain the active ingredient semaglutide, with Ozempic approved for the treatment of Type 2 diabetes and Wegovy approved for the treatment of obesity.

Tirzepatide and semaglutide both mimic the digestive hormone GLP-1, which is released by the intestines when we eat to stimulate insulin production and help regulate blood sugar. GLP-1 also suppresses appetite while promoting a sensation of fullness.

Weight loss medications are intended to be used in conjunction with lifestyle changes, such as exercise and a healthy diet. But too often, people view them as a silver bullet for weight loss. And the high price tag and variable insurance coverage for these popular weight loss drugs create a barrier for many people. 

Health risks of obesity

The potential impact of these drugs is staggering, since more than 2 in 5 American adults are obese, according to the National Institutes of Health. 

Obesity is not just an American issue, nor is it going away. The World Obesity Federation estimates that by 2030, 1 in 5 women and 1 in 7 men will be living with obesity worldwide.

Many serious health conditions are associated with obesity, including heart disease, diabetes, high blood pressure, stroke, certain cancers, and osteoarthritis. By treating obesity, a person can reduce or reverse obesity-related disease and improve both their health and quality of life.

However, long-term weight management depends on a number of complex factors. Meal timing and types of foods eaten can affect energy levels, satisfaction and hunger levels. A person’s typical schedule, culture and preferences, activity level and health history must be taken into consideration as well. No single “best strategy” for weight management has been identified, and research indicates that strategies for weight loss and maintenance need to be individualized.

In addition, it is critical to note that research on the long-term effects of these newer weight loss drugs is limited. The available research has focused specifically on weight loss, heart health and metabolism and has found that ongoing use of these new medications is necessary to maintain improvements in weight and related health benefits. 

Common side effects and the emotional toll experienced by those who regain weight once they stop taking the drugs are trade-offs that need to be considered. More research is needed to better understand the long-term impact of both direct and indirect health consequences of taking drugs for weight loss.

It’s not just what you see on the scale

Throughout my years working as a registered dietitian, I have counseled numerous people about their weight loss goals. I often see a hyperfocus on weight loss, with much less attention being placed on the right nutrients to eat.

Societal standards and weight stigma in the health care setting can negatively affect patients’ health and can lead them to obsess about the number on a scale rather than on the health outcome.

Weight loss may be necessary to reduce risks and promote health. But weight loss alone should not be the end goal: Rather, the focus should be on overall health. Tactics to reduce intake and suppress appetite require intention to ensure that the body receives the nutrients it needs to support health.

Additionally, I remind people that long-term results require attention to diet and lifestyle. When a person stops taking a medication, the condition it’s meant to treat can often return. If you stop taking your high blood pressure pills without altering your diet and lifestyle, your blood pressure goes back up. The same effects can happen with medications used to treat cholesterol and obesity.

Nourish your body with nutrients

Despite the prevalence of obesity and the emergence of newer drugs to treat it, 95% of the world’s population doesn’t get enough of at least one nutrient. According to one study, nearly one-third of Americans have been found to be at risk of at least one nutrient deficiency. Additional research indicates that those actively trying to lose weight are more prone to nutrient deficiencies and inadequate intake. 

For instance, a decline in iron intake can lead to iron deficiency anemia, which can cause fatigue as well as an increased risk of many conditions. Adequate intake of calcium and Vitamin D reduce the risk of bone fractures, yet many people get less than the recommended amounts of these nutrients. 

It is true that a healthy body weight is associated with reduced health risks and conditions. But if a person loses weight in a manner that does not provide their body with adequate nourishment, then they may develop new health concerns. For example, when a person follows a diet that severely restricts carbohydrates, such as the ketogenic diet, intake of many vitamins, minerals, phytochemicals – or biologically active compounds found in plants – and fiber are reduced. This can increase risk of nutrient deficiencies and impair the health of bacteria in our gut that are important for nutrient absorption and immune function.

Nutrition recommendations set by the Food and Nutrition Board of the National Academies of Sciences, Engineering, and Medicine and the Dietary Guidelines for Americans provide guidance and resources to help meet nutrient needs to promote health and prevent disease, regardless of the strategy used to lose weight.

Optimizing health

There is no doubt that striving for a healthy body weight can reduce certain health risks and prevent chronic disease. Whether a person strives to maintain a healthy body weight through diet alone or with medications to treat obesity, the following tips can help optimize health while attempting to lose weight.

  1. Adopt an individualized approach to healthy behaviors that promote weight loss while considering personal preferences, environmental challenges, health conditions and nutrient needs.
  2. Focus on nutrient-dense foods to ensure the body is getting required nutrients for disease prevention and optimal function. If medications reduce your appetite, it is crucial to maximize the amount of nutrients in the foods you do consume.
  3. Include exercise in your program. Weight loss as a result of reduced calorie intake can decrease both fat and lean body mass, or muscle. An exercise routine that includes strength training will help improve muscle strength and preserve muscle during weight loss. 
  4. Seek professional help. If you are uncertain about how to adopt an individualized approach while ensuring adequate intake of essential nutrients, talk to a registered dietitian. They can learn about your individual needs based on preferences, health conditions and goals to make dietary recommendations that support health.

How GLP-1s Impact Birth Control

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Because GLP-1 receptor agonists slow down digestion, they may delay the absorption of oral medications like birth control pills, which could affect ovulation and fertility.

As more people begin taking GLP-1 receptor agonists and other incretin-based drugs for glycemic control and weight management, new side effects of these treatments (both good and bad) are emerging. 

Looking at the positives, a large trial of over 17,600 adults found that Wegovy reduced the rate of cardiovascular events, including heart disease and stroke, by 20%. On the negative side of things, the FDA recently updated the label for Ozempic with a warning about intestinal blockages after multiple reports of the rare but severe side effect. 

Now, there is concern about whether GLP-1s may interact with birth control pills. 

Because GLP-1 medicines slow digestion, they may affect the absorption rate of other oral drugs. By slowing the rate at which food travels through your digestive system, they could potentially delay the absorption of the hormones in birth control pills, which could affect ovulation and fertility. 

We spoke with Dr. Claire Meek, a consultant in the diabetes in pregnancy service at Addenbrooke’s Hospital and principal investigator at the Institute of Metabolic Science at the University of Cambridge in the U.K., to explore how GLP-1s affect oral birth control. 

Do GLP-1s impact how well birth control pills work?

Overall, research on GLP-1s and birth control is “very sparse,” Meek said. On one hand, Meek said some studies conducted by drug companies have found no evidence that GLP-1s affect birth control absorption. 

For instance, a 2015 study found that Ozempic (semaglutide) did not affect the levels of oral birth control available in the bloodstream. The study was small (just 43 women) and lasted for about 23 weeks. 

However, Meek said she has received reports from patients about issues with GLP-1s and birth control. Indeed, a 2023 case study described a woman with type 2 diabetes who became pregnant while taking Mounjaro (tirzepatide) and birth control pills. 

The interaction between GLP-1s and birth control is unclear

One key problem is that the process by which GLP-1s reduce the effectiveness of birth control isn’t well understood. It’s possible that the weight loss caused by GLP-1s improves fertility, which leads to higher rates of pregnancy. 

“In the longer term, prolonged use of GLP-1 agonists appears to vastly improve fertility, even in people who previously considered themselves infertile,” Meek said. 

Preliminary research suggests that GLP-1s may improve menstrual regularity and increase fertility rates among people with obesity with hormonal disorders like polycystic ovarian syndrome. 

It’s also possible that GLP-1s directly reduce the absorption of hormonal contraceptives by delaying gastric emptying, as stated on Mounjaro’s drug label.

Meek said it’s important to consider how consistently you’re taking birth control. Oral contraceptives are most effective at preventing pregnancy when taken every day. However, in real life, people may miss a pill here and there. 

One theory is that a missed dose of birth control has different effects depending on your body weight. If you’ve lost a significant amount of weight and you miss a birth control pill, it may have a greater effect on improving fertility than a missed pill would have on someone with a higher body weight. 

“It’s quite possible that missing a dose of birth control is more likely to result in pregnancy when you’re on a GLP-1 agonist, as substantial weight loss with improved glucose levels will improve fertility,” Meek said. 

“It’s a very different situation to missing a dose when you have obesity, insulin resistance, and hyperglycemia, which all reduce fertility,” she added.

Key considerations for taking a GLP-1 and oral birth control

Currently, the drug labels for GLP-1s do not include recommendations regarding birth control pills. 

However, the FDA states that Mounjaro – a dual GIP/GLP-1 receptor agonist – may reduce the efficacy of oral birth control due to delayed gastric emptying. According to the drug label, Mounjaro is most likely to reduce birth control efficacy after the first dose, with this potential side effect diminishing over time.

Monitor side effects

It’s common to experience side effects for both GLP-1s and birth control pills when starting either medication. 

Adverse reactions to GLP-1s tend to be gastrointestinal, including symptoms like nausea, vomiting, and diarrhea. Side effects of birth control include nausea, breast tenderness, headaches, changes in your period, weight gain, and mood changes. 

“Starting a medication, there will be a period (often 2-4 weeks) when you’re getting used to any side effects,” Meek said. “There can be nausea, vomiting, and changes to gut transit, which can influence the absorption of birth control.”

After starting a GLP-1, Meek said healthcare providers should help you monitor side effects. It’s important to recognize that side effects could also arise from interactions between GLP-1s and any medications you take for other conditions.

Call your healthcare provider right away if you experience serious side effects, such as severe stomach pain, chest pain, new or worsening headaches, blurred vision, fever, severe hypoglycemia, or dehydration after starting a GLP-1 or birth control. 

Use additional protection when starting or increasing GLP-1 doses

If you just started taking a GLP-1 and are on birth control pills, you may want to add a second type of contraceptive to prevent pregnancy. 

For instance, Mounjaro’s label recommends that people taking birth control pills “switch to a non-oral contraceptive method, or add a barrier method of contraception for four weeks after initiation and four weeks after each dose escalation.”

While GLP-1 drug labels do not contain specific recommendations about birth control, you may still want to consider extra protection for peace of mind. This could include a birth control injection, implant, patch, vaginal ring, IUD, or condoms. 

Switch to a long-acting reversible birth control

Meek said she encourages planned pregnancies, rather than unplanned pregnancies, for any person with diabetes. 

Diabetes adds another layer of complexity to pregnancy and increases the risk for serious complications, such as high blood pressure, low blood sugar, and life-threatening birth defects for the baby. Therefore, it’s crucial to plan ahead and work on lowering your A1C and increasing time in range before conceiving. 

“In general, people with any type of diabetes who are not planning a pregnancy are recommended to be on long-acting reversible contraception,” Meek said. 

Examples of long-acting birth control options include an IUD or hormonal implant. These methods last for several years, provide excellent protection against pregnancy, and can be removed at any time. 

Can GLP-1s harm a pregnancy?

The drug labels for Ozempic, Rybelsus, Wegovy, and Mounjaro all acknowledge that these medications could potentially impact fertility or harm a developing fetus. 

Meek said there’s not a lot of evidence that GLP-1s cause harm to a fetus, but some animal studies have shown the possibility. 

“We’re still unclear of the risks of GLP-1 agonist use in human pregnancy, and therefore the most cautious approach is to make sure that a GLP-1 is stopped well in advance of trying for pregnancy,” Meek said.

The bottom line on GLP-1s and birth control

Having an individual conversation with your healthcare provider is key to ensure you’re meeting your diabetes and reproductive health goals. 

“I consider GLP-1 agonists a really valuable part of women’s care before and after pregnancy,” Meek said. 

Overall, it’s important to examine risks and benefits for each person individually. It’s also important to consider how risks and benefits may change during transitions from pregnancy prevention and preconception planning to pregnancy and postpartum. 

For anyone with diabetes who is considering becoming pregnant in the future, Meek recommends using preconception care to plan for a healthy pregnancy. Pre-pregnancy services are especially important for people with type 2 diabetes, Meek said, as many have had diabetes for a shorter period and might not know that they’re eligible for such services. 

Ultimately, improving reproductive health for people with diabetes is a matter of “changing conversations to make sure women can access the support and education they need both pre- and post-pregnancy,” Meek said. 

GLP-1s may not raise short-term pancreatic cancer risk for adults with type 2 diabetes

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Key takeaways:

  • No difference in pancreatic cancer risk at 5 to 7 years was observed for adults using GLP-1 receptor agonists vs. basal insulin.
  • Longer-term studies and research examining adults with obesity are needed.

Adults with type 2 diabetes who use GLP-1 receptor agonists do not have an increased short-term risk for pancreatic cancer, according to findings published in JAMA Network Open.

“Our findings provide additional reassurance to physicians prescribing GLP-1 receptor agonists to patients,” Rachel Dankner, MD, MPH, senior researcher in the Gertner Institute for Epidemiology and Health Policy Research at Sheba Medical Center In Israel, told Healio. “We were able to show that the lack of an association between GLP-1 receptor agonists and pancreatic cancer risk over 7 years is independent of important factors like sociodemographic status, ethnic background, age, sex, smoking, BMI or even history of pancreatitis before beginning treatment with these drugs. We also accounted for the history of background diabetes treatment. That means that we minimized the possibility for confounding by indication.”

Rachel Dankner, MD, MPH

Dankner and colleagues conducted a population-based cohort study with data from 543,595 adults aged 21 to 89 years diagnosed with type 2 diabetes (51% women; mean age, 59.9 years). All clinical measures were obtained from the Clalit Healthcare Services database in Israel. Pancreatic cancer diagnoses were collected from the Israel National Cancer Registry. Researchers compared pancreatic cancer risk between adults using GLP-1 receptor agonist and those receiving basal insulin. Participants were followed from 2009 until 2017.

Of the participants, 19.7% used basal insulin and 6.1% used a GLP-1 receptor agonist at some point during the study. During a mean follow-up of 6.1 years, 1,665 adults were diagnosed with pancreatic cancer.

After adjusting for covariates, one defined daily dose of a GLP-1 taken a year before a cancer diagnosis was associated with a lower risk for pancreatic cancer compared with one defined daily dose of insulin (adjusted HR = 0.22; 95% CI, 0.11-0.41). One defined daily dose of a GLP-1 taken 2 to 4 years before cancer diagnosis was also associated with a reduced pancreatic cancer risk than one defined daily dose of basal insulin (aHR = 0.32; 95% CI, 0.13-0.76). No difference in risk was observed between GLP-1 receptor agonists and basal insulin 5 to 7 years before a cancer diagnosis.

Despite the findings, Dankner said providers still need to monitor adults receiving a GLP-1 receptor agonist for pancreatic cancer.

“First, we were only able to provide safety evidence on the first 7 years of GLP-1 receptor agonist use, and there is a need for longer-term use as well, since pancreatic cancer may have a longer latency period,” Dankner said. “In addition, although our analysis emulated a randomized controlled trial and accounted for important confounding factors, we were restricted to the data we had available and there are yet additional factors like alcohol use, which were not available to us. Finally, our study was done on the Israeli population, which is relatively healthy, with low rates of alcohol abuse and relatively healthy dietary habits, so there is room for additional studies like ours on other populations.”

Additionally, Dankner said a similar study should be conducted among people receiving GLP-1 receptor agonists for obesity treatment.

GLP-1s may not raise short-term pancreatic cancer risk for adults with type 2 diabetes

Add topic to email alerts

Key takeaways:

  • No difference in pancreatic cancer risk at 5 to 7 years was observed for adults using GLP-1 receptor agonists vs. basal insulin.
  • Longer-term studies and research examining adults with obesity are needed.

Adults with type 2 diabetes who use GLP-1 receptor agonists do not have an increased short-term risk for pancreatic cancer, according to findings published in JAMA Network Open.

“Our findings provide additional reassurance to physicians prescribing GLP-1 receptor agonists to patients,” Rachel Dankner, MD, MPH, senior researcher in the Gertner Institute for Epidemiology and Health Policy Research at Sheba Medical Center In Israel, told Healio. “We were able to show that the lack of an association between GLP-1 receptor agonists and pancreatic cancer risk over 7 years is independent of important factors like sociodemographic status, ethnic background, age, sex, smoking, BMI or even history of pancreatitis before beginning treatment with these drugs. We also accounted for the history of background diabetes treatment. That means that we minimized the possibility for confounding by indication.”

Rachel Dankner, MD, MPH

Dankner and colleagues conducted a population-based cohort study with data from 543,595 adults aged 21 to 89 years diagnosed with type 2 diabetes (51% women; mean age, 59.9 years). All clinical measures were obtained from the Clalit Healthcare Services database in Israel. Pancreatic cancer diagnoses were collected from the Israel National Cancer Registry. Researchers compared pancreatic cancer risk between adults using GLP-1 receptor agonist and those receiving basal insulin. Participants were followed from 2009 until 2017.

Of the participants, 19.7% used basal insulin and 6.1% used a GLP-1 receptor agonist at some point during the study. During a mean follow-up of 6.1 years, 1,665 adults were diagnosed with pancreatic cancer.

After adjusting for covariates, one defined daily dose of a GLP-1 taken a year before a cancer diagnosis was associated with a lower risk for pancreatic cancer compared with one defined daily dose of insulin (adjusted HR = 0.22; 95% CI, 0.11-0.41). One defined daily dose of a GLP-1 taken 2 to 4 years before cancer diagnosis was also associated with a reduced pancreatic cancer risk than one defined daily dose of basal insulin (aHR = 0.32; 95% CI, 0.13-0.76). No difference in risk was observed between GLP-1 receptor agonists and basal insulin 5 to 7 years before a cancer diagnosis.

Despite the findings, Dankner said providers still need to monitor adults receiving a GLP-1 receptor agonist for pancreatic cancer.

“First, we were only able to provide safety evidence on the first 7 years of GLP-1 receptor agonist use, and there is a need for longer-term use as well, since pancreatic cancer may have a longer latency period,” Dankner said. “In addition, although our analysis emulated a randomized controlled trial and accounted for important confounding factors, we were restricted to the data we had available and there are yet additional factors like alcohol use, which were not available to us. Finally, our study was done on the Israeli population, which is relatively healthy, with low rates of alcohol abuse and relatively healthy dietary habits, so there is room for additional studies like ours on other populations.”

Additionally, Dankner said a similar study should be conducted among people receiving GLP-1 receptor agonists for obesity treatment.

Add topic to email alerts

Key takeaways:

  • No difference in pancreatic cancer risk at 5 to 7 years was observed for adults using GLP-1 receptor agonists vs. basal insulin.
  • Longer-term studies and research examining adults with obesity are needed.

Adults with type 2 diabetes who use GLP-1 receptor agonists do not have an increased short-term risk for pancreatic cancer, according to findings published in JAMA Network Open.

“Our findings provide additional reassurance to physicians prescribing GLP-1 receptor agonists to patients,” Rachel Dankner, MD, MPH, senior researcher in the Gertner Institute for Epidemiology and Health Policy Research at Sheba Medical Center In Israel, told Healio. “We were able to show that the lack of an association between GLP-1 receptor agonists and pancreatic cancer risk over 7 years is independent of important factors like sociodemographic status, ethnic background, age, sex, smoking, BMI or even history of pancreatitis before beginning treatment with these drugs. We also accounted for the history of background diabetes treatment. That means that we minimized the possibility for confounding by indication.”

Rachel Dankner, MD, MPH

Dankner and colleagues conducted a population-based cohort study with data from 543,595 adults aged 21 to 89 years diagnosed with type 2 diabetes (51% women; mean age, 59.9 years). All clinical measures were obtained from the Clalit Healthcare Services database in Israel. Pancreatic cancer diagnoses were collected from the Israel National Cancer Registry. Researchers compared pancreatic cancer risk between adults using GLP-1 receptor agonist and those receiving basal insulin. Participants were followed from 2009 until 2017.

Of the participants, 19.7% used basal insulin and 6.1% used a GLP-1 receptor agonist at some point during the study. During a mean follow-up of 6.1 years, 1,665 adults were diagnosed with pancreatic cancer.

After adjusting for covariates, one defined daily dose of a GLP-1 taken a year before a cancer diagnosis was associated with a lower risk for pancreatic cancer compared with one defined daily dose of insulin (adjusted HR = 0.22; 95% CI, 0.11-0.41). One defined daily dose of a GLP-1 taken 2 to 4 years before cancer diagnosis was also associated with a reduced pancreatic cancer risk than one defined daily dose of basal insulin (aHR = 0.32; 95% CI, 0.13-0.76). No difference in risk was observed between GLP-1 receptor agonists and basal insulin 5 to 7 years before a cancer diagnosis.

Despite the findings, Dankner said providers still need to monitor adults receiving a GLP-1 receptor agonist for pancreatic cancer.

“First, we were only able to provide safety evidence on the first 7 years of GLP-1 receptor agonist use, and there is a need for longer-term use as well, since pancreatic cancer may have a longer latency period,” Dankner said. “In addition, although our analysis emulated a randomized controlled trial and accounted for important confounding factors, we were restricted to the data we had available and there are yet additional factors like alcohol use, which were not available to us. Finally, our study was done on the Israeli population, which is relatively healthy, with low rates of alcohol abuse and relatively healthy dietary habits, so there is room for additional studies like ours on other populations.”

Additionally, Dankner said a similar study should be conducted among people receiving GLP-1 receptor agonists for obesity treatment.

These Medications Might Make Diabetic Retinopathy Worse

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Ksenia Chernaya/Pexels

By Ross Wollen

December 19th, 2022

Diabetic retinopathy is a common complication of diabetes that affects the blood vessels in the retina, the light-sensitive tissue at the back of the eye. If left untreated, diabetic retinopathy can cause severe vision loss or even complete blindness.

The good news is that diabetic retinopathy (DR) can be diagnosed long before it actually begins to impact your vision. The condition is very treatable, and potentially even reversible, especially when caught early.

Doctors have a good understanding of what causes DR: high blood sugar, high blood pressure, and, to a lesser extent, high cholesterol. Diabetic retinopathy is very sensitive to metabolic health, and many of the medications that people with diabetes commonly take can affect its progression and development — for better or for worse.

This article will review the drugs that we know (or suspect) might worsen diabetic retinopathy.

Warning

A quick word of warning: This article shouldn’t be taken as medical advice, and no patient is qualified to decide for themselves whether to avoid any drug listed here. Many of these medications are important for the health of millions of adults, and their benefits may easily outweigh whatever effect they might have on DR.

If you’re concerned that you may be taking a medication that could make your diabetic retinopathy worse, please talk to your doctor. Only a medical professional is qualified to assess the unique totality of your health conditions to recommend medication adjustments.

The Two Diabetes Drugs That (Might) Make DR Worse

Most diabetes drugs have beneficial effects for diabetic retinopathy, slowing its progression and potentially even helping to reverse the damage. Taking your glucose-lowering medications as prescribed by your doctor is absolutely one of the best ways to protect yourself from DR.

There are, however, one and possibly two exceptions to that rule, as described by a recent survey of the topic in the medical journal Eye.

Thiazolidinediones (TZDs)

TZDs have been called “the forgotten diabetes medication.” These pills directly improve insulin resistance, a root cause of type 2 diabetes, but have been deemphasized by authorities due to concerns over harmful side effects, including cardiovascular disease.

Although these drugs are increasingly out of fashion, they are still commonly prescribed. As of 2019, about 8 percent of people with type 2 diabetes used a TZD.

TZDs carry a known risk of diabetic macular edema (DME), an especially damaging form of diabetic retinopathy that affects our keenest vision in the center of our eyesight. TZDs can cause fluid retention, which appears to exacerbate the swelling of blood vessels that characterizes DME. It only happens in a small number of cases — fewer than 3 percent of those that use the drug.

There are now two types of TZDs on the market:

  • Rosiglitazone (Avandia)
  • Pioglitazone (Actos)

Luckily, cessation is associated with rapid eye improvement.

Ozempic

There is some evidence that semaglutide (Ozempic), a GLP-1RA, may increase the incidence of diabetic retinopathy. One of several pivotal studies of semaglutide found an increased risk of DR, and the FDA has reported that a significantly higher percentage of Ozempic users have DR in comparison with users of similar drugs like dulaglutide (Trulicity) and liraglutide (Victoza). The connection is disputed, however, as another large study of semaglutide found no such risk.

Even if the association is real, it’s very possible that your own doctor would conclude that semaglutide is worth the risk. Ozempic is a very effective drug for people with diabetes, typically conferring both rapid glycemic improvements and weight loss.

It seems possible that Ozempic’s effectiveness, in fact, explains its negative effect on the eyes. Contrary to all expectations, rapid improvement in glucose control can actually worsen diabetic retinopathy. This is called “early worsening,” because the eyes will get worse before the major long-term benefits of better blood sugar control become evident.

Experts don’t believe that this is necessarily a reason to avoid Ozempic. A recent discussion of the issue by experts from the American Academy of Ophthalmology suggested that “early worsening” from Ozempic is both “temporary and manageable,” although it does call for increased scrutiny from eye doctors.

Other Drugs With Negative Metabolic Effects

Drugs That Increase Blood Sugar

Some medications are known to cause blood sugar spikes:

  • Steroids, including hydrocortisone and prednisone, can have a dramatic effect on blood sugar. (Steroid creams and inhalers do not have the same effect).
  • Hormonal birth control, including the pill, the shot, the patch, and the IUD
  • Beta-blockers, which are used to treat hypertension, irregular heartbeat, and anxiety
  • Anti-psychotic drugs, which are used to treat schizophrenia and related mental illnesses

If you take any of the above drugs, it might be wise to make sure your main diabetes healthcare provider is aware of it. They may or may not suggest an adjustment.

  • Statins are also associated with rising blood sugar levels — but even taking that factor into account, experts still recommend statins for most adults with diabetes because they reduce the risk of cardiovascular disease.

Finally, if you have advanced diabetic retinopathy that requires treatment, you may be given steroid injections. These drugs can have a powerful anti-inflammatory effect within the eyeball that directly improves DR symptoms, even if they exert a negative effect on insulin sensitivity.

Drugs That Increase Blood Pressure

Hypertension (high blood pressure) is the other big factor that speeds the development and progression of diabetic retinopathy. Accordingly, medications that are known to raise your blood pressure can be considered risk factors for DR.

An incomplete list of some common drugs that can increase blood pressure includes:

  • Pain relievers, including acetaminophen (Tylenol) and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Motrin, Advil) and naproxen (Aleve)
  • Antidepressants, including fluoxetine (Prozac), monoamine oxidase inhibitors, and tricyclic antidepressants
  • Decongestants, including pseudoephedrine (Sudafed, Contac) and phenylephrine (Sudafed PE)
  • Hormonal birth control, including the pill, the shot, the patch, and the IUD
  • Stimulants, such as methylphenidate (Ritalin)

Some supplements, including caffeine and ginseng, can have a similar effect. The Mayo Clinic has a full article on the topic.

Drugs That Increase (Bad) Cholesterol

Experts are very confident that high blood sugar and high blood pressure both lead to diabetic retinopathy. The evidence linking high cholesterol with DR is not quite as strong, although we do know that some cholesterol-lowering drugs (especially fibrates) significantly reduce the incidence of DR.

These are some of the most common drugs that are believed to elevate “bad” cholesterol (LDL and/or triglycerides), which may or may not be risk factors for DR:

  • Steroids
  • Hormonal birth control, including the pill, the shot, the patch, and the IUD
  • Retinoids (used to treat acne)
  • Beta-blockers, which are used to treat hypertension, irregular heartbeat, and anxiety
  • Diuretics

Drugs That Increase Weight

It should be no surprise that weight gain, which is so highly related to the development and progression of type 2 diabetes, is associated with an increased risk of diabetic retinopathy. A 2021 study in Korea found that patients with recent diagnoses of type 2 diabetes that lost 10 percent of their body weight cut their risk of DR in half, whereas those that had 10 percent weight gain tripled their risk.

It’s therefore probably fair to consider any drugs that cause weight gain as potential risk factors for DR.

Some of the most common drugs associated with weight gain include:

  • Tricyclic antidepressants, including amitriptyline (Elavil), doxepin (Silenor), and nortriptyline (Pamelor)
  • Selective serotonin reuptake inhibitors (SSRIs), another type of antidepressant, including escitalopram (Lexapro), paroxetine (Paxil), sertraline (Zoloft)
  • Anti-psychotics, particularly olanzapine (Zyprexa)
  • Anti-seizure medications, including gabapentin (Gralise), pregabalin (Lyrica), and vigabatrin (Sabril).
  • Steroids
  • Beta-blockers
  • Antihistamines

The diabetes medications insulin and sulfonylureas are also associated with weight gain, which is why diabetes authorities have recently begun to prefer other options for glucose control.

Takeaways

Diabetic retinopathy is largely caused by poor metabolic health: high blood sugar, high blood pressure, and possibly high cholesterol. Many prescription medications have undesirable metabolic side effects and can therefore be considered potential contributors to DR.

Furthermore, two types of diabetes drugs in particular are associated with worsening diabetic retinopathy: the family of thiazolidinediones (TZDs), which includes rosiglitazone (Avandia) and pioglitazone (Actos), and semaglutide (Ozempic). Your ophthalmologist should be aware that you are taking one of these drugs, but will not necessarily advise a change, even if you are at high risk of vision loss from DR.

Many of the drugs discussed in this article are vital to the health of millions; therefore, it’s impossible to say whether or not readers should avoid them. As always, the guiding hand of a doctor that understands your unique health status is critical. It’s sometimes up to you to make sure that your various specialists are all on the same page. We encourage you to ensure that your main diabetes care provider and ophthalmologist are aware of every medicine you take.

This article has concentrated on the effects that various medications have on diabetic retinopathy. Medicine, of course, is only one factor of many — diet, exercise, glycemic control, and many other decisions play an immense role in the development and progression of diabetes complications.

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.

GLP-1, SGLT2 combination therapy provides largest weight loss for women with PCOS

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Combination therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor may provide better weight-loss benefits than a single agent for women with polycystic ovary syndrome and obesity, according to study data.

In a randomized, single-blind, 24-week study, participants assigned to dual therapy of 2 mg weekly of the GLP-1 receptor agonist exenatide (Bydureon, AstraZeneca) and 10 mg daily of the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) lost more weight than those taking either agent alone or those receiving dapagliflozin and metformin extended-release (Xigduo XL, AstraZeneca) or phentermine/topiramate extended-release (Qsymia, Vivus).

Weight loss for women with PCOS and obesity
Dual therapy with exenatide and dapagliflozin was associated with greater weight loss in women with PCOS compared with dapagliflozin alone or dapagliflozin with metformin. Data were derived from Elkind-Hirsch KE, et al. J Clin Endocrinol Metab. 2021;doi:10.1210/clinem/dgab408.

“Greater improvements in participants with exenatide plus dapagliflozin may be explained in part by their different, and potentially complementary, mechanisms of action and confirm other studies showing that combining these two agents may exert stronger beneficial effects than each drug alone,” Karen Elkind-Hirsch, MSc, PhD, HCLD, scientific director of research at Woman’s Hospital Research Center in Baton Rouge, Louisiana, told Healio. “These findings, together with the convenience of once‐daily oral dosing and once‐weekly injection, support the use of these medications in this prediabetic population.”Karen Elkind-Hirsch

Elkind-Hirsch and colleagues recruited 119 premenopausal women aged 18 to 45 years with obesity and PCOS and without diabetes to participate in the study. Participants were randomly assigned to one of five therapies: exenatide alone, dapagliflozin alone, dual therapy of exenatide and dapagliflozin, combined dapagliflozin and metformin therapy, or the weight-loss medication phentermine/topiramate extended-release. Clinical, anthropometric and biochemical assessments were conducted at baseline, 12 weeks and 24 weeks.

The findings were published in The Journal of Clinical Endocrinology & Metabolism.

Combination therapy produces greater weight loss

All treatment groups had improvements in fasting glucose, mean glucose, insulin sensitivity and insulin secretion at 24 weeks. Participants receiving combination exenatide and dapagliflozin had a greater reduction in mean blood glucose compared with the dapagliflozin, dapagliflozin and metformin, and phentermine/topiramate extended-release groups (P < .03). Those receiving exenatide or exenatide and dapagliflozin had larger increases in insulin secretion compared with the other three treatment groups (P < .04).

All five treatment groups had reductions in absolute body weight and BMI at 24 weeks, but the exenatide and dapagliflozin group had greater weight loss than those receiving only dapagliflozin or dapagliflozin and metformin (P = .005). Mean weight loss was 6.9% for those receiving exenatide and dapagliflozin therapy and 8% for those receiving phentermine/topiramate extended-release compared with 1.5% for participants receiving only dapagliflozin and 1.7% for those on dapagliflozin and metformin (P < .001).

“Modest weight loss is well known to reduce the risk of future diabetes in individuals with prediabetes,” Elkind-Hirsch said. “Therefore, it cannot be excluded that the modest reduction in body weight contributed in part to the improvement in insulin sensitivity in all groups. While phentermine/topiramate extended-release resulted in consistent significant changes in BMI and waist circumference, only exenatide and dapagliflozin and exenatide alone resulted in significant improvements in insulin secretion as well as mean blood glucose over an oral glucose tolerance test. This finding confirms the beneficial effect of GLP-1 agonists on beta-cell function in this obese prediabetic population.”

Long-term studies needed

Cholesterol, HDL cholesterol, LDL cholesterol and triglycerides-to-HDL ratio did not differ between the two groups. Triglycerides were lower at 24 weeks for the exenatide and dapagliflozin groups compared with phentermine/topiramate extended-release (P < .05). Both systolic and diastolic blood pressure decreased in all treatments at 24 weeks. There were no serious adverse events reported during the trial.

Elkind-Hirsch said the findings are encouraging, but more studies are needed to better establish long-term safety and efficacy of GLP-1 receptor agonists for women with PCOS.

“Future studies should include in their design consideration of the significant number of women with this disorder and the relatively young age of this population,” Elkind-Hirsch said.

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.

Drugs with dual-hormone action gain attention in diabetes field.

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Engineered peptide drugs that simultaneously target two hormone receptors have historically attracted interest among scientists hoping to create new treatments for diabetes. Now, many in the field seem buoyed by new data from a class of diabetes medicines designed to mimic gastrointestinal hormones called incretins, which stimulate insulin release from pancreatic beta cells.

The ‘incretin mimetics’ currently on the market modulate only one receptor. For example, Byetta (exenatide) from California’s Amylin Pharmaceuticals and Victoza (liraglutide) from Denmark’s Novo Nordisk trigger the glucagon-like peptide-1 receptor (GLP-1). To adequately control blood glucose, these drugs are often used at high doses, commonly causing vomiting and nausea. Long-term effects could include increased risk for pancreatitis, pancreatic cancer and thyroid cancer.

The problem is that GLP-1 receptors aren’t confined just to the gut. They’re also found in other tissues, especially the thyroid, pancreas, meninges, kidney and bone. In March, the US Food and Drug Administration began reviewing research linking GLP-1 agonists to increased risk of pancreatitis and precancerous cellular changes associated with pancreatic cancer. And this September, France’s Sanofi withdrew a new drug application in the US for its once-daily injectable GLP-1 agonist lixisenatide owing to concerns over cardiovascular safety.

According to drug developers, drugs that target two receptors simultaneously could provide a solution by more closely approximating the normal physiology lost when type 2 diabetes develops. The hope is to use these drugs at lower doses, decreasing the likelihood for adverse reactions.

Jim Dowdalls / Science Source

Dual fuel: Two-hormone drugs help treat diabetes.

In addition to GLP-1, another endogenous gut hormone is glucose-dependent insulinotropic peptide (GIP), which stimulates postprandial insulin release. Activity of GLP-1 and GIP is thought by some to be impaired in type 2 diabetes. A paper published in late October detailed the effects in humans of a new compound—originally called MAR701 by Indiana’s Marcadia Biotech, which contributed to early development of the compound—that binds and triggers receptors for both GLP-1 and GIP1. It offered data from a phase 2 trial done in collaboration with Roche, the Swiss drug giant, that included 53 patients with inadequately controlled type 2 diabetes.

The trial found a dose-dependent decrease in hemoglobin A1C (HbA1c) in the experimental group, ranging from a decrease of 0.53% to as much as a 1.11% drop; by comparison, the placebo group had an average drop of 0.16%. No participants experienced vomiting, a common side effect of incretin mimetics on the market, and few had nausea. The study also reported that this type of dual agonist lowers blood glucose levels and weight more effectively than single agonists in animal models.

Incredible incretin?

According to study author Matthias Tschöp, scientific director of the Helmholtz Diabetes Center in Munich, the pace of research on engineered peptides for dual-agonist incretin-based therapy has picked up in recent years. Tschöp and his collaborator Richard DiMarchi, a chemist at the University of Indiana in Bloomington, have worked previously on a GLP-1 and glucagon receptor co-agonist, in collaboration with New Jersey–based Merck, and a GLP-1 and estrogen receptor co-agonist, the latter of which showed potential for reversing the metabolic syndrome in rodents2.

Other researchers are in hot pursuit of similar drugs. Scientists at Amylin Pharmaceuticals, which was acquired last year by New York’s Bristol-Myers Squibb, are working on peptide hybrids made of an analog of Byetta linked to davalintide, which mimics amylin, a hormone released from pancreatic beta cells that helps regulate blood glucose levels after a meal3. “The exendin-amylin mimetic peptide hybrids . . . improve glucose tolerance and reduce HbA1c levels in diabetic rodents, coupled with body weight loss that is greater than that achieved by the parent peptides,” says Soumitra Ghosh, senior director of research programs and collaborations at Amylin.

Researchers at the University of Copenhagen and the University of Alberta, in Canada, in collaboration with Denmark’s Zealand Pharma and Germany’s Boehringer Ingelheim, are working on a single molecule that mimics the gut hormone oxyntmodulin, an endogenous peptide hormone with dual GLP-1 and glucagon receptor agonist activity4. The team is in competition with Merck, which has explored oxyntmodulin mimetics, including one called DualAg5.

Some teams are even looking into triple-receptor agonists. Nigel Irwin, a pharmacologist at the Diabetes Research Group at the University of Ulster in Ireland, works with a group focused on preclinical drug discovery of novel peptides for treating metabolic disease and obesity. Irwin’s team published results in late October showing that a hybrid triple agonist, combining the effects of GLP-1, GIP and glucagon, decreased body weight and significantly improved glucose tolerance and insulin sensitivity in mice fed high-fat diets, as compared to conventional antidiabetic agents6. “We also believe that concurrent activation of three receptors will minimize any potential side effects that can occur through over stimulation of a single regulatory peptide receptor,” Irwin explains.