Diabetes

The U.K. National Institute for Health and Care Excellence (NICE) has issued new guidance on the combined usage of dapagliflozin and insulin for treating patients with type 1 diabetes inadequately controlled by insulin alone.

In a review of clinical trials, NICE found that dapagliflozin plus insulin conferred small benefits in hemoglobin A_1c, weight loss, and quality of life, compared with insulin alone. These benefits translated to a reduced risk of long-term complications over the lifetime of the patient.

In the new NICE guideline, dual treatment with dapagliflozin and insulin in adults with type 1 diabetes and a body mass index greater than 27 kg/m² is recommended only when they are receiving insulin doses of more than 0.5 units/kg per day; have undergone an evidence-based, quality-assured education program; and are supervised by a physician specializing in endocrinology and diabetes.

Hemoglobin A_1c levels should be assessed after 6 months and at regular intervals after that; if glycemic control is not improved, dapagliflozin should be stopped, as there is an increased risk of diabetic ketoacidosis.

Find the full technology appraisal guidance on the NICE website.

[email protected]

The U.K. National Institute for Health and Care Excellence (NICE) has issued new guidance on the combined usage of dapagliflozin and insulin for treating patients with type 1 diabetes inadequately controlled by insulin alone.

In a review of clinical trials, NICE found that dapagliflozin plus insulin conferred small benefits in hemoglobin A_1c, weight loss, and quality of life, compared with insulin alone. These benefits translated to a reduced risk of long-term complications over the lifetime of the patient.

In the new NICE guideline, dual treatment with dapagliflozin and insulin in adults with type 1 diabetes and a body mass index greater than 27 kg/m² is recommended only when they are receiving insulin doses of more than 0.5 units/kg per day; have undergone an evidence-based, quality-assured education program; and are supervised by a physician specializing in endocrinology and diabetes.

Hemoglobin A_1c levels should be assessed after 6 months and at regular intervals after that; if glycemic control is not improved, dapagliflozin should be stopped, as there is an increased risk of diabetic ketoacidosis.

Find the full technology appraisal guidance on the NICE website.

[email protected]

The U.K. National Institute for Health and Care Excellence (NICE) has issued new guidance on the combined usage of dapagliflozin and insulin for treating patients with type 1 diabetes inadequately controlled by insulin alone.

In a review of clinical trials, NICE found that dapagliflozin plus insulin conferred small benefits in hemoglobin A_1c, weight loss, and quality of life, compared with insulin alone. These benefits translated to a reduced risk of long-term complications over the lifetime of the patient.

In the new NICE guideline, dual treatment with dapagliflozin and insulin in adults with type 1 diabetes and a body mass index greater than 27 kg/m² is recommended only when they are receiving insulin doses of more than 0.5 units/kg per day; have undergone an evidence-based, quality-assured education program; and are supervised by a physician specializing in endocrinology and diabetes.

Hemoglobin A_1c levels should be assessed after 6 months and at regular intervals after that; if glycemic control is not improved, dapagliflozin should be stopped, as there is an increased risk of diabetic ketoacidosis.

Find the full technology appraisal guidance on the NICE website.

[email protected]

Choose your answer in the poll below. To check the accuracy of your answer, see Endocrine Consult: 10 (Safe) Ways to Reduce Patients’ Insulin Costs.

[polldaddy:10400221]

Click on page 2 below to find out what the correct answer is...

The correct answer is d.) 500%

To learn more, see this month's Endocrine Consult: 10 (Safe) Ways to Reduce Patients’ Insulin Costs.

Choose your answer in the poll below. To check the accuracy of your answer, see Endocrine Consult: 10 (Safe) Ways to Reduce Patients’ Insulin Costs.

[polldaddy:10400221]

Click on page 2 below to find out what the correct answer is...

The correct answer is d.) 500%

To learn more, see this month's Endocrine Consult: 10 (Safe) Ways to Reduce Patients’ Insulin Costs.

Choose your answer in the poll below. To check the accuracy of your answer, see Endocrine Consult: 10 (Safe) Ways to Reduce Patients’ Insulin Costs.

[polldaddy:10400221]

Click on page 2 below to find out what the correct answer is...

The correct answer is d.) 500%

To learn more, see this month's Endocrine Consult: 10 (Safe) Ways to Reduce Patients’ Insulin Costs.

Almost a century after its discovery, insulin remains a life-saving yet costly medication: In the past 15 years, prices have risen more than 500%.¹ Patients may ask you why the insulin you prescribe is so expensive, and the complex process for determining drug costs makes it difficult to answer. But the bottom line is, patients need their insulin—and they want it without breaking the bank.

Thankfully, there are several strategies for reducing the cost of insulin. First and foremost, patients must be advised that not taking their prescribed insulin, or taking less insulin than prescribed, is not a safe alternative. An individualized cost-benefit analysis between patient and provider can help to determine the best option for each patient. After working in endocrinology for 5 years, I have learned the following 10 ways to help patients whose financial situations limit their access to insulin.

1 Try older insulins, including mixed insulin 70/30 or 50/50, insulin NPH, or regular insulin. Because the beneficial effects may not be as long lasting with these as with newer insulins on the market, your patient may need to test glucose levels more frequently. Also, insulin NPH and any mixed insulins are suspensions, not solutions, so patients will need to gently roll older insulins prior to use. Those in pen form may also have a shorter shelf life.

2 Switch to a syringe and vial. Although dosing can be less precise, this could be a viable option for patients with good vision and dexterity. This method helps patients save in 3 ways: (1) the insulin is less expensive; (2) syringes generally cost less (about $30 for 100) than pen needle tips (about $50 for 100); and (3) vials of NPH are longer-lasting suspensions that are stable for about 28 days once opened, compared to 14 days for pens.^2-4

3 Switch from a 30- to a 90-day supply of refills. This helps to lower copays. For example, a mail-order program (eg, Express Scripts) that ships from a warehouse typically offers lower pricing than a brick-and-mortar pharmacy with greater overhead. Many of these programs provide 2-pharmacist verification for accuracy and free home delivery of medications at a 10% discount, as well as 24-hour pharmacist access.⁵ The ease of obtaining prescriptions by this method also can help with medication adherence.

4 Patient assistance programs (PAPs) offered by insulin manufacturers can help lower costs for patients who find it difficult to afford their medication. Information on these programs is available on the respective company’s websites, usually in multiple languages (although some are limited to English and Spanish). Patients applying for a PAP must provide a proof of income and adhere to the program’s specific criteria. Renewal is typically required each year.^6-8

5 Copay cards are available to many patients with private insurance and may help make insulin more affordable. Patients may be able to receive a $25 monthly supply of insulin for up to 1 year (specific terms vary). Maximum contributions and contributions toward deductibles also vary by program, so patients need to familiarize themselves with what their particular copay card allows. Generally, copay cards are not a sustainable long-term solution; for one thing, they expire, and for another, emphasis should be placed on affordable medications rather than affording expensive medications.

[polldaddy:10400221]

Continue to: 6 External PAPs for patients on Medicare...

6 External PAPs for patients on Medicare can help lower the costs of prescription medications.⁹ A database of pharmaceutical PAPs is available on the Medicare website.¹⁰ Some PAPs may help patients on Medicare pay through the $5,100 coverage gap or “donut hole”—a term referring to a gap in prescription drug coverage once patients have met their prescription limit (all Medicare part D plans have a donut hole).^11,12 Patients and providers will need to read the fine print when applying for an external PAP, because some have a monthly or one-time start-up fee for processing the paperwork (and note, there is often paperwork for the relief program in addition to the PAP paperwork through the pharmaceutical company).

7 A Program of All-Inclusive Care for the Elderly (PACE) is available in many states; check medicare.gov to see if your state is eligible. For patients 55 and older on Medicare or Medicaid who do not opt for care at a nursing home facility, PACE may be able to provide care and coverage in the patient’s home or at a PACE facility. Services include primary care, hospital care, laboratory and x-ray services, medical specialty services, and prescription drugs. To be eligible for PACE services, the patient must live in the service area of a PACE organization and have a requirement for a nursing home-level of care (as certified by your state).

8 Shop around for the best deal. Encourage your patients to comparison shop for the best prices rather than accepting the first or only option at their usual pharmacy. Different pharmacies offer drugs at lower prices than competitors. Also, continually compare prices at GoodRx or HealthWarehouse.com. The latter—a fully licensed Internet-based pharmacy—sells FDA-approved medications at affordable prices in all 50 states, without the requirement for insurance coverage.

9 Use of a patch pump may be less expensive for patients with type 2 diabetes who are taking basal-bolus regimens. Patches slowly deliver single short-acting insulin (usually insulin aspart or lispro) that acts as a basal insulin, with an additional reservoir for prandial insulin at mealtime and for snacks. As there is a catheter in the patch, patients would not require the use of needles.¹³

10 Try removing mealtime insulin for patients with type 2 diabetes who need minimal mealtime insulin. Clinicians can initiate a safe trial of this removal by encouraging the patient to consume a low-carbohydrate diet, increase exercise, and/or use other noninsulin medications that are more affordable.

Continue to: The affordability of insulins...

The affordability of insulins is a potentially uncomfortable but necessary conversation to have with your patient. Providers are one of the best resources for patients who seek relief from financial difficulties. The recommendations discussed here can help providers and patients design a cost-conscious plan for insulin treatment. Although each recommendation is viable, the pros and cons must be weighed on a case-by-case basis. Providers and patients should also pay attention to the Senate Finance Committee’s ongoing discussions and possible resolutions that could result in lower insulin costs. Until legislation that lowers the prices of insulin comes to fruition, however, providers should continue to plan with their patients on how to best get their insulin at the lowest cost.

Test yourself with the poll here.

Almost a century after its discovery, insulin remains a life-saving yet costly medication: In the past 15 years, prices have risen more than 500%.¹ Patients may ask you why the insulin you prescribe is so expensive, and the complex process for determining drug costs makes it difficult to answer. But the bottom line is, patients need their insulin—and they want it without breaking the bank.

Thankfully, there are several strategies for reducing the cost of insulin. First and foremost, patients must be advised that not taking their prescribed insulin, or taking less insulin than prescribed, is not a safe alternative. An individualized cost-benefit analysis between patient and provider can help to determine the best option for each patient. After working in endocrinology for 5 years, I have learned the following 10 ways to help patients whose financial situations limit their access to insulin.

1 Try older insulins, including mixed insulin 70/30 or 50/50, insulin NPH, or regular insulin. Because the beneficial effects may not be as long lasting with these as with newer insulins on the market, your patient may need to test glucose levels more frequently. Also, insulin NPH and any mixed insulins are suspensions, not solutions, so patients will need to gently roll older insulins prior to use. Those in pen form may also have a shorter shelf life.

2 Switch to a syringe and vial. Although dosing can be less precise, this could be a viable option for patients with good vision and dexterity. This method helps patients save in 3 ways: (1) the insulin is less expensive; (2) syringes generally cost less (about $30 for 100) than pen needle tips (about $50 for 100); and (3) vials of NPH are longer-lasting suspensions that are stable for about 28 days once opened, compared to 14 days for pens.^2-4

3 Switch from a 30- to a 90-day supply of refills. This helps to lower copays. For example, a mail-order program (eg, Express Scripts) that ships from a warehouse typically offers lower pricing than a brick-and-mortar pharmacy with greater overhead. Many of these programs provide 2-pharmacist verification for accuracy and free home delivery of medications at a 10% discount, as well as 24-hour pharmacist access.⁵ The ease of obtaining prescriptions by this method also can help with medication adherence.

4 Patient assistance programs (PAPs) offered by insulin manufacturers can help lower costs for patients who find it difficult to afford their medication. Information on these programs is available on the respective company’s websites, usually in multiple languages (although some are limited to English and Spanish). Patients applying for a PAP must provide a proof of income and adhere to the program’s specific criteria. Renewal is typically required each year.^6-8

5 Copay cards are available to many patients with private insurance and may help make insulin more affordable. Patients may be able to receive a $25 monthly supply of insulin for up to 1 year (specific terms vary). Maximum contributions and contributions toward deductibles also vary by program, so patients need to familiarize themselves with what their particular copay card allows. Generally, copay cards are not a sustainable long-term solution; for one thing, they expire, and for another, emphasis should be placed on affordable medications rather than affording expensive medications.

[polldaddy:10400221]

Continue to: 6 External PAPs for patients on Medicare...

6 External PAPs for patients on Medicare can help lower the costs of prescription medications.⁹ A database of pharmaceutical PAPs is available on the Medicare website.¹⁰ Some PAPs may help patients on Medicare pay through the $5,100 coverage gap or “donut hole”—a term referring to a gap in prescription drug coverage once patients have met their prescription limit (all Medicare part D plans have a donut hole).^11,12 Patients and providers will need to read the fine print when applying for an external PAP, because some have a monthly or one-time start-up fee for processing the paperwork (and note, there is often paperwork for the relief program in addition to the PAP paperwork through the pharmaceutical company).

7 A Program of All-Inclusive Care for the Elderly (PACE) is available in many states; check medicare.gov to see if your state is eligible. For patients 55 and older on Medicare or Medicaid who do not opt for care at a nursing home facility, PACE may be able to provide care and coverage in the patient’s home or at a PACE facility. Services include primary care, hospital care, laboratory and x-ray services, medical specialty services, and prescription drugs. To be eligible for PACE services, the patient must live in the service area of a PACE organization and have a requirement for a nursing home-level of care (as certified by your state).

8 Shop around for the best deal. Encourage your patients to comparison shop for the best prices rather than accepting the first or only option at their usual pharmacy. Different pharmacies offer drugs at lower prices than competitors. Also, continually compare prices at GoodRx or HealthWarehouse.com. The latter—a fully licensed Internet-based pharmacy—sells FDA-approved medications at affordable prices in all 50 states, without the requirement for insurance coverage.

9 Use of a patch pump may be less expensive for patients with type 2 diabetes who are taking basal-bolus regimens. Patches slowly deliver single short-acting insulin (usually insulin aspart or lispro) that acts as a basal insulin, with an additional reservoir for prandial insulin at mealtime and for snacks. As there is a catheter in the patch, patients would not require the use of needles.¹³

10 Try removing mealtime insulin for patients with type 2 diabetes who need minimal mealtime insulin. Clinicians can initiate a safe trial of this removal by encouraging the patient to consume a low-carbohydrate diet, increase exercise, and/or use other noninsulin medications that are more affordable.

Continue to: The affordability of insulins...

The affordability of insulins is a potentially uncomfortable but necessary conversation to have with your patient. Providers are one of the best resources for patients who seek relief from financial difficulties. The recommendations discussed here can help providers and patients design a cost-conscious plan for insulin treatment. Although each recommendation is viable, the pros and cons must be weighed on a case-by-case basis. Providers and patients should also pay attention to the Senate Finance Committee’s ongoing discussions and possible resolutions that could result in lower insulin costs. Until legislation that lowers the prices of insulin comes to fruition, however, providers should continue to plan with their patients on how to best get their insulin at the lowest cost.

Test yourself with the poll here.

Almost a century after its discovery, insulin remains a life-saving yet costly medication: In the past 15 years, prices have risen more than 500%.¹ Patients may ask you why the insulin you prescribe is so expensive, and the complex process for determining drug costs makes it difficult to answer. But the bottom line is, patients need their insulin—and they want it without breaking the bank.

Thankfully, there are several strategies for reducing the cost of insulin. First and foremost, patients must be advised that not taking their prescribed insulin, or taking less insulin than prescribed, is not a safe alternative. An individualized cost-benefit analysis between patient and provider can help to determine the best option for each patient. After working in endocrinology for 5 years, I have learned the following 10 ways to help patients whose financial situations limit their access to insulin.

1 Try older insulins, including mixed insulin 70/30 or 50/50, insulin NPH, or regular insulin. Because the beneficial effects may not be as long lasting with these as with newer insulins on the market, your patient may need to test glucose levels more frequently. Also, insulin NPH and any mixed insulins are suspensions, not solutions, so patients will need to gently roll older insulins prior to use. Those in pen form may also have a shorter shelf life.

2 Switch to a syringe and vial. Although dosing can be less precise, this could be a viable option for patients with good vision and dexterity. This method helps patients save in 3 ways: (1) the insulin is less expensive; (2) syringes generally cost less (about $30 for 100) than pen needle tips (about $50 for 100); and (3) vials of NPH are longer-lasting suspensions that are stable for about 28 days once opened, compared to 14 days for pens.^2-4

3 Switch from a 30- to a 90-day supply of refills. This helps to lower copays. For example, a mail-order program (eg, Express Scripts) that ships from a warehouse typically offers lower pricing than a brick-and-mortar pharmacy with greater overhead. Many of these programs provide 2-pharmacist verification for accuracy and free home delivery of medications at a 10% discount, as well as 24-hour pharmacist access.⁵ The ease of obtaining prescriptions by this method also can help with medication adherence.

4 Patient assistance programs (PAPs) offered by insulin manufacturers can help lower costs for patients who find it difficult to afford their medication. Information on these programs is available on the respective company’s websites, usually in multiple languages (although some are limited to English and Spanish). Patients applying for a PAP must provide a proof of income and adhere to the program’s specific criteria. Renewal is typically required each year.^6-8

5 Copay cards are available to many patients with private insurance and may help make insulin more affordable. Patients may be able to receive a $25 monthly supply of insulin for up to 1 year (specific terms vary). Maximum contributions and contributions toward deductibles also vary by program, so patients need to familiarize themselves with what their particular copay card allows. Generally, copay cards are not a sustainable long-term solution; for one thing, they expire, and for another, emphasis should be placed on affordable medications rather than affording expensive medications.

[polldaddy:10400221]

Continue to: 6 External PAPs for patients on Medicare...

6 External PAPs for patients on Medicare can help lower the costs of prescription medications.⁹ A database of pharmaceutical PAPs is available on the Medicare website.¹⁰ Some PAPs may help patients on Medicare pay through the $5,100 coverage gap or “donut hole”—a term referring to a gap in prescription drug coverage once patients have met their prescription limit (all Medicare part D plans have a donut hole).^11,12 Patients and providers will need to read the fine print when applying for an external PAP, because some have a monthly or one-time start-up fee for processing the paperwork (and note, there is often paperwork for the relief program in addition to the PAP paperwork through the pharmaceutical company).

7 A Program of All-Inclusive Care for the Elderly (PACE) is available in many states; check medicare.gov to see if your state is eligible. For patients 55 and older on Medicare or Medicaid who do not opt for care at a nursing home facility, PACE may be able to provide care and coverage in the patient’s home or at a PACE facility. Services include primary care, hospital care, laboratory and x-ray services, medical specialty services, and prescription drugs. To be eligible for PACE services, the patient must live in the service area of a PACE organization and have a requirement for a nursing home-level of care (as certified by your state).

8 Shop around for the best deal. Encourage your patients to comparison shop for the best prices rather than accepting the first or only option at their usual pharmacy. Different pharmacies offer drugs at lower prices than competitors. Also, continually compare prices at GoodRx or HealthWarehouse.com. The latter—a fully licensed Internet-based pharmacy—sells FDA-approved medications at affordable prices in all 50 states, without the requirement for insurance coverage.

9 Use of a patch pump may be less expensive for patients with type 2 diabetes who are taking basal-bolus regimens. Patches slowly deliver single short-acting insulin (usually insulin aspart or lispro) that acts as a basal insulin, with an additional reservoir for prandial insulin at mealtime and for snacks. As there is a catheter in the patch, patients would not require the use of needles.¹³

10 Try removing mealtime insulin for patients with type 2 diabetes who need minimal mealtime insulin. Clinicians can initiate a safe trial of this removal by encouraging the patient to consume a low-carbohydrate diet, increase exercise, and/or use other noninsulin medications that are more affordable.

Continue to: The affordability of insulins...

The affordability of insulins is a potentially uncomfortable but necessary conversation to have with your patient. Providers are one of the best resources for patients who seek relief from financial difficulties. The recommendations discussed here can help providers and patients design a cost-conscious plan for insulin treatment. Although each recommendation is viable, the pros and cons must be weighed on a case-by-case basis. Providers and patients should also pay attention to the Senate Finance Committee’s ongoing discussions and possible resolutions that could result in lower insulin costs. Until legislation that lowers the prices of insulin comes to fruition, however, providers should continue to plan with their patients on how to best get their insulin at the lowest cost.

Test yourself with the poll here.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

When scientists discovered the band of hemoglobin A_1c during electrophoresis in the 1950s and 1960s and discerned it was elevated in patients with diabetes, little did they know the important role it would play in the diagnosis and treatment of diabetes in the decades to come.^1–3 Despite some caveats, a hemoglobin A_1c level of 6.5% or higher is diagnostic of diabetes across most populations, and hemoglobin A_1c goals ranging from 6.5% to 7.5% have been set for different subsets of patients depending on comorbidities, complications, risk of hypoglycemia, life expectancy, disease duration, patient preferences, and available resources.⁴

With a growing number of medications for diabetes—insulin in its various formulations and 11 other classes—hemoglobin A_1c targets can now be tailored to fit individual patient profiles. Although helping patients attain their glycemic goals is paramount, other factors should be considered when prescribing or changing a drug treatment regimen, such as cardiovascular risk reduction, weight control, avoidance of hypoglycemia, and minimizing out-of-pocket drug costs (Table 1).

CARDIOVASCULAR BENEFIT

Patients with type 2 diabetes have a 2 to 3 times higher risk of clinical atherosclerotic disease, according to 20 years of surveillance data from the Framingham cohort.⁵

Mixed results with intensive treatment

Reducing cardiovascular risk remains an important goal in diabetes management, but unfortunately, data from the long-term clinical trials aimed at reducing macrovascular risk with intensive glycemic management have been conflicting.

The United Kingdom Prospective Diabetes Study (UKPDS),⁶ which enrolled more than 4,000 patients with newly diagnosed type 2 diabetes, did not initially show a statistically significant difference in the incidence of myocardial infarction with intensive control vs conventional control, although intensive treatment did reduce the incidence of microvascular disease. However, 10 years after the trial ended, the incidence was 15% lower in the intensive-treatment group than in the conventional-treatment group, and the difference was statistically significant.⁷

A 10-year follow-up analysis of the Veterans Affairs Diabetes Trial (VADT)⁸ showed that patients who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1,000 person-years than those assigned to standard therapy, but no improvement in median overall survival. The hemoglobin A_1c levels achieved during the trial were 6.9% and 8.4%, respectively.

In 2008, the US Food and Drug Administration (FDA)⁹ mandated that all new applications for diabetes drugs must include cardiovascular outcome studies. Therefore, we now have data on the cardiovascular benefits of two antihyperglycemic drug classes—incretins and sodium-glucose cotransporter 2 (SGLT2) inhibitors, making them attractive medications to target both cardiac and glucose concerns.

Incretins

The incretin drugs comprise 2 classes, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors.

Liraglutide. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial¹⁰ compared liraglutide (a GLP-1 receptor agonist) and placebo in 9,000 patients with diabetes who either had or were at high risk of cardiovascular disease. Patients in the liraglutide group had a lower risk of the primary composite end point of death from cardiovascular causes or the first episode of nonfatal (including silent) myocardial infarction or nonfatal stroke, and a lower risk of cardiovascular death, all-cause mortality, and microvascular events than those in the placebo group. The number of patients who would need to be treated to prevent 1 event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause.⁹

Lixisenatide. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial¹¹ studied the effect of the once-daily GLP-1 receptor agonist lixisenatide on cardiovascular outcomes in 6,000 patients with type 2 diabetes with a recent coronary event. In contrast to LEADER, ELIXA did not show a cardiovascular benefit over placebo.

Exenatide. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL)¹² assessed another GLP-1 extended-release drug, exenatide, in 14,000 patients, 73% of whom had established cardiovascular disease. In those patients, the drug had a modest benefit in terms of first occurrence of any component of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-component major adverse cardiac event [MACE] outcome) in a time-to-event analysis, but the results were not statistically significant. However, the drug did significantly reduce all-cause mortality.

Semaglutide, another GLP-1 receptor agonist recently approved by the FDA, also showed benefit in patients who had cardiovascular disease or were at high risk, with significant reduction in the primary composite end point of death from cardiovascular causes or the first occurrence of nonfatal myocardial infarction (including silent) or nonfatal stroke.¹³

Dulaglutide, a newer GLP-1 drug, was associated with significantly reduced major adverse cardiovascular events (a composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in about 9,900 patients with diabetes, with a median follow-up of more than 5 years. Only 31% of the patients in the trial had established cardiovascular disease.¹⁴

Comment. GLP-1 drugs as a class are a good option for patients with diabetes who require weight loss, and liraglutide is now FDA-approved for reduction of cardiovascular events in patients with type 2 diabetes with established cardiovascular disease. However, other factors should be considered when prescribing these drugs: they have adverse gastrointestinal effects, the cardiovascular benefit was not a class effect, they are relatively expensive, and they must be injected. Also, they should not be prescribed concurrently with a DPP-4 inhibitor because they target the same pathway.

 

 

SGLT2 inhibitors

The other class of diabetes drugs that have shown cardiovascular benefit are the SGLT2 inhibitors.

Empagliflozin. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG)¹⁵ compared the efficacy of empagliflozin vs placebo in 7,000 patients with diabetes and cardiovascular disease and showed relative risk reductions of 38% in death from cardiovascular death, 31% in sudden death, and 35% in heart failure hospitalizations. Empagliflozin also showed benefit in terms of progression of kidney disease and occurrence of clinically relevant renal events in this population.¹⁶

Canagliflozin also has cardiovascular outcome data and showed significant benefit when compared with placebo in the primary outcome of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, but no significant effects on cardiovascular death or all-cause mortality.¹⁷ Data from this trial also suggested a nonsignificant benefit of canagliflozin in decreasing progression of albuminuria and in the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes.

The above data led to an additional indication from the FDA for empagliflozin—and recently, canagliflozin—to prevent cardiovascular death in patients with diabetes with established disease, but other factors should be considered when prescribing them. Patients taking canagliflozin showed a significantly increased risk of amputation. SGLT2 inhibitors as a class also increase the risk of genital infections in men and women; this is an important consideration since patients with diabetes complain of vaginal fungal and urinary tract infections even without the use of these drugs. A higher incidence of fractures with canagliflozin should also be considered when using these medications in elderly and osteoporosis-prone patients at high risk of falling.

Dapagliflozin, the third drug in this class, was associated with a lower rate of hospitalization for heart failure in about 17,160 patients—including 10,186 without atherosclerotic cardiovascular disease—who were followed for a median of 4.2 years.¹⁸ It did not show benefit for the primary safety outcome, a composite of major adverse cardiovascular events defined as cardiovascular death, myocardial infarction, or ischemic stroke.

WEIGHT MANAGEMENT

Weight loss can help overweight patients reach their hemoglobin A_1c target.

Metformin should be continued as other drugs are added because it does not induce weight gain and may help with weight loss of up to 2 kg as shown in the Diabetes Prevention Program Outcomes Study.¹⁹

GLP-1 receptor agonists and SGLT2 inhibitors help with weight loss and are good additions to a basal insulin regimen to minimize weight gain.

Liraglutide was associated with a mean weight loss of 2.3 kg over 36 months of treatment compared with placebo in the LEADER trial.¹⁰

In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6),²⁰ the mean body weight in the semaglutide group, compared with the placebo group, was 2.9 kg lower in the group receiving a lower dose and 4.3 kg lower in the group receiving a higher dose of the drug.

In a 24-week trial in 182 patients with type 2 diabetes inadequately controlled on metformin, dapagliflozin produced a statistically significant weight reduction of 2.08 kg (95% confidence interval 2.84–1.31; P < .0001) compared with placebo.²¹

Lifestyle changes aimed at weight management should be emphasized and discussed at every visit.

HYPOGLYCEMIA RISK

Hypoglycemia is a major consideration when tailoring hemoglobin A_1c targets. In the Action to Control Cardiovascular Risk (ACCORD) trial,²² severe, symptomatic hypoglycemia increased the risk of death in both the intensive and conventional treatment groups. In VADT, the occurrence of a recent severe hypoglycemic event was the strongest independent predictor of death within 90 days. Further analysis showed that even though serious hypoglycemia occurred more often in the intensive therapy group, it was associated with progression of coronary artery calcification in the standard therapy group.²³ Hence, it is imperative that tight glycemic control not be achieved at the cost of severe or recurrent hypoglycemia.

In terms of hypoglycemia, metformin is an excellent medication. The American Diabetes Association²⁴ recommends metformin as the first-line therapy for newly diagnosed diabetes. Long-term follow-up data from UKPDS showed that metformin decreased mortality and the incidence of myocardial infarction and lowered treatment costs as well as the overall risk of hypoglycemia.²⁵ When prescribed, it should be titrated to the highest dose.

The FDA²⁶ has changed the prescribing information for metformin in patients with renal impairment. Metformin should not be started if the eGFR is less than 45 mL/min/1.73 m², but it can be continued if the patient is already receiving it and the eGFR is between 30 and 45. Previously, creatinine levels were used to define renal impairment and suitability for metformin. This change has increased the number of patients who can benefit from this medication.

In patients who have a contraindication to metformin, DPP-4 inhibitors can be considered, as they carry a low risk of hypoglycemia as well. Sulfonylureas should be used with caution in these patients, especially if their oral intake is variable. When sulfonylureas were compared to the DPP-4 inhibitor sitagliptin as an add-on to metformin, the rate of hypoglycemia was 32% in the sulfonylurea group vs 5% in the sitagliptin group.²⁷

Of the sulfonylureas, glipizide and glimepiride are better than glyburide because of a comparatively lower risk of hypoglycemia and a higher selectivity for binding the K_ATP channel on the pancreatic beta cell.²⁸

Meglitinides can be a good option for patients who skip meals, but they are more expensive than other generic oral hypoglycemic agents and require multiple daily dosing.

GLP-1 analogues also have a low risk of hypoglycemia but are only available in injectable formulations. Patients must be willing and able to perform the injections themselves.²⁹

 

 

LOOSER TARGETS FOR OLDER PATIENTS

In 2010, among US residents age 65 and older, 10.9 million (about 27%) had diabetes,³⁰ and this number is projected to increase to 26.7 million by 2050.³¹ This population is prone to hypoglycemia when treated with insulin and sulfonylureas. An injury sustained by a fall induced by hypoglycemia can be life-altering. In addition, no randomized clinical trials show the effect of tight glycemic control on complications in older patients with diabetes because patients older than 80 are often excluded.

A reasonable goal suggested by the European Diabetes Working Party for Older People 2011³² and reiterated by the American Geriatrics Society in 2013³³ is a hemoglobin A_1c between 7% and 7.5% for relatively healthy older patients and 7.5% to 8% or 8.5% in frail elderly patients with diabetes.

Consider prescribing medications that carry a low risk of hypoglycemia, can be dose-adjusted for kidney function, and do not rely on manual dexterity for administration (ie, do not require patients to give themselves injections). These include metformin and DPP-4 inhibitors.

DRUG COMBINATIONS

Polypharmacy is a concern for all patients with diabetes, especially since it increases the risk of drug interactions and adverse effects, increases out-of-pocket costs, and decreases the likelihood that patients will remain adherent to their treatment regimen. The use of combination medications can reduce the number of pills or injections required, as well as copayments.

Due to concern for multiple drug-drug interactions (and also due to the progressive nature of diabetes), many people with type 2 diabetes are given insulin in lieu of pills to lower their blood glucose. In addition to premixed insulin combinations (such as combinations of neutral protamine Hagedorn and regular insulin or combinations of insulin analogues), long-acting basal insulins can now be prescribed with a GLP-1 drug in fixed-dose combinations such as insulin glargine plus lixisenatide and insulin degludec plus liraglutide.

COST CONSIDERATIONS

It is important to discuss medication cost with patients, because many newer diabetic drugs are expensive and add to the financial burden of patients already paying for multiple medications, such as antihypertensives and statins.

Metformin and sulfonylureas are less expensive alternatives for patients who cannot afford GLP-1 analogues or SGLT2 inhibitors. Even within the same drug class, the formulary-preferred drug may be cheaper than the nonformulary alternative. Thus, it is helpful to research formulary alternatives before discussing treatment regimens with patients.

When scientists discovered the band of hemoglobin A_1c during electrophoresis in the 1950s and 1960s and discerned it was elevated in patients with diabetes, little did they know the important role it would play in the diagnosis and treatment of diabetes in the decades to come.^1–3 Despite some caveats, a hemoglobin A_1c level of 6.5% or higher is diagnostic of diabetes across most populations, and hemoglobin A_1c goals ranging from 6.5% to 7.5% have been set for different subsets of patients depending on comorbidities, complications, risk of hypoglycemia, life expectancy, disease duration, patient preferences, and available resources.⁴

With a growing number of medications for diabetes—insulin in its various formulations and 11 other classes—hemoglobin A_1c targets can now be tailored to fit individual patient profiles. Although helping patients attain their glycemic goals is paramount, other factors should be considered when prescribing or changing a drug treatment regimen, such as cardiovascular risk reduction, weight control, avoidance of hypoglycemia, and minimizing out-of-pocket drug costs (Table 1).

CARDIOVASCULAR BENEFIT

Patients with type 2 diabetes have a 2 to 3 times higher risk of clinical atherosclerotic disease, according to 20 years of surveillance data from the Framingham cohort.⁵

Mixed results with intensive treatment

Reducing cardiovascular risk remains an important goal in diabetes management, but unfortunately, data from the long-term clinical trials aimed at reducing macrovascular risk with intensive glycemic management have been conflicting.

The United Kingdom Prospective Diabetes Study (UKPDS),⁶ which enrolled more than 4,000 patients with newly diagnosed type 2 diabetes, did not initially show a statistically significant difference in the incidence of myocardial infarction with intensive control vs conventional control, although intensive treatment did reduce the incidence of microvascular disease. However, 10 years after the trial ended, the incidence was 15% lower in the intensive-treatment group than in the conventional-treatment group, and the difference was statistically significant.⁷

A 10-year follow-up analysis of the Veterans Affairs Diabetes Trial (VADT)⁸ showed that patients who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1,000 person-years than those assigned to standard therapy, but no improvement in median overall survival. The hemoglobin A_1c levels achieved during the trial were 6.9% and 8.4%, respectively.

In 2008, the US Food and Drug Administration (FDA)⁹ mandated that all new applications for diabetes drugs must include cardiovascular outcome studies. Therefore, we now have data on the cardiovascular benefits of two antihyperglycemic drug classes—incretins and sodium-glucose cotransporter 2 (SGLT2) inhibitors, making them attractive medications to target both cardiac and glucose concerns.

Incretins

The incretin drugs comprise 2 classes, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors.

Liraglutide. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial¹⁰ compared liraglutide (a GLP-1 receptor agonist) and placebo in 9,000 patients with diabetes who either had or were at high risk of cardiovascular disease. Patients in the liraglutide group had a lower risk of the primary composite end point of death from cardiovascular causes or the first episode of nonfatal (including silent) myocardial infarction or nonfatal stroke, and a lower risk of cardiovascular death, all-cause mortality, and microvascular events than those in the placebo group. The number of patients who would need to be treated to prevent 1 event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause.⁹

Lixisenatide. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial¹¹ studied the effect of the once-daily GLP-1 receptor agonist lixisenatide on cardiovascular outcomes in 6,000 patients with type 2 diabetes with a recent coronary event. In contrast to LEADER, ELIXA did not show a cardiovascular benefit over placebo.

Exenatide. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL)¹² assessed another GLP-1 extended-release drug, exenatide, in 14,000 patients, 73% of whom had established cardiovascular disease. In those patients, the drug had a modest benefit in terms of first occurrence of any component of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-component major adverse cardiac event [MACE] outcome) in a time-to-event analysis, but the results were not statistically significant. However, the drug did significantly reduce all-cause mortality.

Semaglutide, another GLP-1 receptor agonist recently approved by the FDA, also showed benefit in patients who had cardiovascular disease or were at high risk, with significant reduction in the primary composite end point of death from cardiovascular causes or the first occurrence of nonfatal myocardial infarction (including silent) or nonfatal stroke.¹³

Dulaglutide, a newer GLP-1 drug, was associated with significantly reduced major adverse cardiovascular events (a composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in about 9,900 patients with diabetes, with a median follow-up of more than 5 years. Only 31% of the patients in the trial had established cardiovascular disease.¹⁴

Comment. GLP-1 drugs as a class are a good option for patients with diabetes who require weight loss, and liraglutide is now FDA-approved for reduction of cardiovascular events in patients with type 2 diabetes with established cardiovascular disease. However, other factors should be considered when prescribing these drugs: they have adverse gastrointestinal effects, the cardiovascular benefit was not a class effect, they are relatively expensive, and they must be injected. Also, they should not be prescribed concurrently with a DPP-4 inhibitor because they target the same pathway.

 

 

SGLT2 inhibitors

The other class of diabetes drugs that have shown cardiovascular benefit are the SGLT2 inhibitors.

Empagliflozin. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG)¹⁵ compared the efficacy of empagliflozin vs placebo in 7,000 patients with diabetes and cardiovascular disease and showed relative risk reductions of 38% in death from cardiovascular death, 31% in sudden death, and 35% in heart failure hospitalizations. Empagliflozin also showed benefit in terms of progression of kidney disease and occurrence of clinically relevant renal events in this population.¹⁶

Canagliflozin also has cardiovascular outcome data and showed significant benefit when compared with placebo in the primary outcome of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, but no significant effects on cardiovascular death or all-cause mortality.¹⁷ Data from this trial also suggested a nonsignificant benefit of canagliflozin in decreasing progression of albuminuria and in the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes.

The above data led to an additional indication from the FDA for empagliflozin—and recently, canagliflozin—to prevent cardiovascular death in patients with diabetes with established disease, but other factors should be considered when prescribing them. Patients taking canagliflozin showed a significantly increased risk of amputation. SGLT2 inhibitors as a class also increase the risk of genital infections in men and women; this is an important consideration since patients with diabetes complain of vaginal fungal and urinary tract infections even without the use of these drugs. A higher incidence of fractures with canagliflozin should also be considered when using these medications in elderly and osteoporosis-prone patients at high risk of falling.

Dapagliflozin, the third drug in this class, was associated with a lower rate of hospitalization for heart failure in about 17,160 patients—including 10,186 without atherosclerotic cardiovascular disease—who were followed for a median of 4.2 years.¹⁸ It did not show benefit for the primary safety outcome, a composite of major adverse cardiovascular events defined as cardiovascular death, myocardial infarction, or ischemic stroke.

WEIGHT MANAGEMENT

Weight loss can help overweight patients reach their hemoglobin A_1c target.

Metformin should be continued as other drugs are added because it does not induce weight gain and may help with weight loss of up to 2 kg as shown in the Diabetes Prevention Program Outcomes Study.¹⁹

GLP-1 receptor agonists and SGLT2 inhibitors help with weight loss and are good additions to a basal insulin regimen to minimize weight gain.

Liraglutide was associated with a mean weight loss of 2.3 kg over 36 months of treatment compared with placebo in the LEADER trial.¹⁰

In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6),²⁰ the mean body weight in the semaglutide group, compared with the placebo group, was 2.9 kg lower in the group receiving a lower dose and 4.3 kg lower in the group receiving a higher dose of the drug.

In a 24-week trial in 182 patients with type 2 diabetes inadequately controlled on metformin, dapagliflozin produced a statistically significant weight reduction of 2.08 kg (95% confidence interval 2.84–1.31; P < .0001) compared with placebo.²¹

Lifestyle changes aimed at weight management should be emphasized and discussed at every visit.

HYPOGLYCEMIA RISK

Hypoglycemia is a major consideration when tailoring hemoglobin A_1c targets. In the Action to Control Cardiovascular Risk (ACCORD) trial,²² severe, symptomatic hypoglycemia increased the risk of death in both the intensive and conventional treatment groups. In VADT, the occurrence of a recent severe hypoglycemic event was the strongest independent predictor of death within 90 days. Further analysis showed that even though serious hypoglycemia occurred more often in the intensive therapy group, it was associated with progression of coronary artery calcification in the standard therapy group.²³ Hence, it is imperative that tight glycemic control not be achieved at the cost of severe or recurrent hypoglycemia.

In terms of hypoglycemia, metformin is an excellent medication. The American Diabetes Association²⁴ recommends metformin as the first-line therapy for newly diagnosed diabetes. Long-term follow-up data from UKPDS showed that metformin decreased mortality and the incidence of myocardial infarction and lowered treatment costs as well as the overall risk of hypoglycemia.²⁵ When prescribed, it should be titrated to the highest dose.

The FDA²⁶ has changed the prescribing information for metformin in patients with renal impairment. Metformin should not be started if the eGFR is less than 45 mL/min/1.73 m², but it can be continued if the patient is already receiving it and the eGFR is between 30 and 45. Previously, creatinine levels were used to define renal impairment and suitability for metformin. This change has increased the number of patients who can benefit from this medication.

In patients who have a contraindication to metformin, DPP-4 inhibitors can be considered, as they carry a low risk of hypoglycemia as well. Sulfonylureas should be used with caution in these patients, especially if their oral intake is variable. When sulfonylureas were compared to the DPP-4 inhibitor sitagliptin as an add-on to metformin, the rate of hypoglycemia was 32% in the sulfonylurea group vs 5% in the sitagliptin group.²⁷

Of the sulfonylureas, glipizide and glimepiride are better than glyburide because of a comparatively lower risk of hypoglycemia and a higher selectivity for binding the K_ATP channel on the pancreatic beta cell.²⁸

Meglitinides can be a good option for patients who skip meals, but they are more expensive than other generic oral hypoglycemic agents and require multiple daily dosing.

GLP-1 analogues also have a low risk of hypoglycemia but are only available in injectable formulations. Patients must be willing and able to perform the injections themselves.²⁹

 

 

LOOSER TARGETS FOR OLDER PATIENTS

In 2010, among US residents age 65 and older, 10.9 million (about 27%) had diabetes,³⁰ and this number is projected to increase to 26.7 million by 2050.³¹ This population is prone to hypoglycemia when treated with insulin and sulfonylureas. An injury sustained by a fall induced by hypoglycemia can be life-altering. In addition, no randomized clinical trials show the effect of tight glycemic control on complications in older patients with diabetes because patients older than 80 are often excluded.

A reasonable goal suggested by the European Diabetes Working Party for Older People 2011³² and reiterated by the American Geriatrics Society in 2013³³ is a hemoglobin A_1c between 7% and 7.5% for relatively healthy older patients and 7.5% to 8% or 8.5% in frail elderly patients with diabetes.

Consider prescribing medications that carry a low risk of hypoglycemia, can be dose-adjusted for kidney function, and do not rely on manual dexterity for administration (ie, do not require patients to give themselves injections). These include metformin and DPP-4 inhibitors.

DRUG COMBINATIONS

Polypharmacy is a concern for all patients with diabetes, especially since it increases the risk of drug interactions and adverse effects, increases out-of-pocket costs, and decreases the likelihood that patients will remain adherent to their treatment regimen. The use of combination medications can reduce the number of pills or injections required, as well as copayments.

Due to concern for multiple drug-drug interactions (and also due to the progressive nature of diabetes), many people with type 2 diabetes are given insulin in lieu of pills to lower their blood glucose. In addition to premixed insulin combinations (such as combinations of neutral protamine Hagedorn and regular insulin or combinations of insulin analogues), long-acting basal insulins can now be prescribed with a GLP-1 drug in fixed-dose combinations such as insulin glargine plus lixisenatide and insulin degludec plus liraglutide.

COST CONSIDERATIONS

It is important to discuss medication cost with patients, because many newer diabetic drugs are expensive and add to the financial burden of patients already paying for multiple medications, such as antihypertensives and statins.

Metformin and sulfonylureas are less expensive alternatives for patients who cannot afford GLP-1 analogues or SGLT2 inhibitors. Even within the same drug class, the formulary-preferred drug may be cheaper than the nonformulary alternative. Thus, it is helpful to research formulary alternatives before discussing treatment regimens with patients.

When scientists discovered the band of hemoglobin A_1c during electrophoresis in the 1950s and 1960s and discerned it was elevated in patients with diabetes, little did they know the important role it would play in the diagnosis and treatment of diabetes in the decades to come.^1–3 Despite some caveats, a hemoglobin A_1c level of 6.5% or higher is diagnostic of diabetes across most populations, and hemoglobin A_1c goals ranging from 6.5% to 7.5% have been set for different subsets of patients depending on comorbidities, complications, risk of hypoglycemia, life expectancy, disease duration, patient preferences, and available resources.⁴

With a growing number of medications for diabetes—insulin in its various formulations and 11 other classes—hemoglobin A_1c targets can now be tailored to fit individual patient profiles. Although helping patients attain their glycemic goals is paramount, other factors should be considered when prescribing or changing a drug treatment regimen, such as cardiovascular risk reduction, weight control, avoidance of hypoglycemia, and minimizing out-of-pocket drug costs (Table 1).

CARDIOVASCULAR BENEFIT

Patients with type 2 diabetes have a 2 to 3 times higher risk of clinical atherosclerotic disease, according to 20 years of surveillance data from the Framingham cohort.⁵

Mixed results with intensive treatment

Reducing cardiovascular risk remains an important goal in diabetes management, but unfortunately, data from the long-term clinical trials aimed at reducing macrovascular risk with intensive glycemic management have been conflicting.

The United Kingdom Prospective Diabetes Study (UKPDS),⁶ which enrolled more than 4,000 patients with newly diagnosed type 2 diabetes, did not initially show a statistically significant difference in the incidence of myocardial infarction with intensive control vs conventional control, although intensive treatment did reduce the incidence of microvascular disease. However, 10 years after the trial ended, the incidence was 15% lower in the intensive-treatment group than in the conventional-treatment group, and the difference was statistically significant.⁷

A 10-year follow-up analysis of the Veterans Affairs Diabetes Trial (VADT)⁸ showed that patients who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1,000 person-years than those assigned to standard therapy, but no improvement in median overall survival. The hemoglobin A_1c levels achieved during the trial were 6.9% and 8.4%, respectively.

In 2008, the US Food and Drug Administration (FDA)⁹ mandated that all new applications for diabetes drugs must include cardiovascular outcome studies. Therefore, we now have data on the cardiovascular benefits of two antihyperglycemic drug classes—incretins and sodium-glucose cotransporter 2 (SGLT2) inhibitors, making them attractive medications to target both cardiac and glucose concerns.

Incretins

The incretin drugs comprise 2 classes, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors.

Liraglutide. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial¹⁰ compared liraglutide (a GLP-1 receptor agonist) and placebo in 9,000 patients with diabetes who either had or were at high risk of cardiovascular disease. Patients in the liraglutide group had a lower risk of the primary composite end point of death from cardiovascular causes or the first episode of nonfatal (including silent) myocardial infarction or nonfatal stroke, and a lower risk of cardiovascular death, all-cause mortality, and microvascular events than those in the placebo group. The number of patients who would need to be treated to prevent 1 event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause.⁹

Lixisenatide. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial¹¹ studied the effect of the once-daily GLP-1 receptor agonist lixisenatide on cardiovascular outcomes in 6,000 patients with type 2 diabetes with a recent coronary event. In contrast to LEADER, ELIXA did not show a cardiovascular benefit over placebo.

Exenatide. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL)¹² assessed another GLP-1 extended-release drug, exenatide, in 14,000 patients, 73% of whom had established cardiovascular disease. In those patients, the drug had a modest benefit in terms of first occurrence of any component of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-component major adverse cardiac event [MACE] outcome) in a time-to-event analysis, but the results were not statistically significant. However, the drug did significantly reduce all-cause mortality.

Semaglutide, another GLP-1 receptor agonist recently approved by the FDA, also showed benefit in patients who had cardiovascular disease or were at high risk, with significant reduction in the primary composite end point of death from cardiovascular causes or the first occurrence of nonfatal myocardial infarction (including silent) or nonfatal stroke.¹³

Dulaglutide, a newer GLP-1 drug, was associated with significantly reduced major adverse cardiovascular events (a composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in about 9,900 patients with diabetes, with a median follow-up of more than 5 years. Only 31% of the patients in the trial had established cardiovascular disease.¹⁴

Comment. GLP-1 drugs as a class are a good option for patients with diabetes who require weight loss, and liraglutide is now FDA-approved for reduction of cardiovascular events in patients with type 2 diabetes with established cardiovascular disease. However, other factors should be considered when prescribing these drugs: they have adverse gastrointestinal effects, the cardiovascular benefit was not a class effect, they are relatively expensive, and they must be injected. Also, they should not be prescribed concurrently with a DPP-4 inhibitor because they target the same pathway.

 

 

SGLT2 inhibitors

The other class of diabetes drugs that have shown cardiovascular benefit are the SGLT2 inhibitors.

Empagliflozin. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG)¹⁵ compared the efficacy of empagliflozin vs placebo in 7,000 patients with diabetes and cardiovascular disease and showed relative risk reductions of 38% in death from cardiovascular death, 31% in sudden death, and 35% in heart failure hospitalizations. Empagliflozin also showed benefit in terms of progression of kidney disease and occurrence of clinically relevant renal events in this population.¹⁶

Canagliflozin also has cardiovascular outcome data and showed significant benefit when compared with placebo in the primary outcome of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, but no significant effects on cardiovascular death or all-cause mortality.¹⁷ Data from this trial also suggested a nonsignificant benefit of canagliflozin in decreasing progression of albuminuria and in the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes.

The above data led to an additional indication from the FDA for empagliflozin—and recently, canagliflozin—to prevent cardiovascular death in patients with diabetes with established disease, but other factors should be considered when prescribing them. Patients taking canagliflozin showed a significantly increased risk of amputation. SGLT2 inhibitors as a class also increase the risk of genital infections in men and women; this is an important consideration since patients with diabetes complain of vaginal fungal and urinary tract infections even without the use of these drugs. A higher incidence of fractures with canagliflozin should also be considered when using these medications in elderly and osteoporosis-prone patients at high risk of falling.

Dapagliflozin, the third drug in this class, was associated with a lower rate of hospitalization for heart failure in about 17,160 patients—including 10,186 without atherosclerotic cardiovascular disease—who were followed for a median of 4.2 years.¹⁸ It did not show benefit for the primary safety outcome, a composite of major adverse cardiovascular events defined as cardiovascular death, myocardial infarction, or ischemic stroke.

WEIGHT MANAGEMENT

Weight loss can help overweight patients reach their hemoglobin A_1c target.

Metformin should be continued as other drugs are added because it does not induce weight gain and may help with weight loss of up to 2 kg as shown in the Diabetes Prevention Program Outcomes Study.¹⁹

GLP-1 receptor agonists and SGLT2 inhibitors help with weight loss and are good additions to a basal insulin regimen to minimize weight gain.

Liraglutide was associated with a mean weight loss of 2.3 kg over 36 months of treatment compared with placebo in the LEADER trial.¹⁰

In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6),²⁰ the mean body weight in the semaglutide group, compared with the placebo group, was 2.9 kg lower in the group receiving a lower dose and 4.3 kg lower in the group receiving a higher dose of the drug.

In a 24-week trial in 182 patients with type 2 diabetes inadequately controlled on metformin, dapagliflozin produced a statistically significant weight reduction of 2.08 kg (95% confidence interval 2.84–1.31; P < .0001) compared with placebo.²¹

Lifestyle changes aimed at weight management should be emphasized and discussed at every visit.

HYPOGLYCEMIA RISK

Hypoglycemia is a major consideration when tailoring hemoglobin A_1c targets. In the Action to Control Cardiovascular Risk (ACCORD) trial,²² severe, symptomatic hypoglycemia increased the risk of death in both the intensive and conventional treatment groups. In VADT, the occurrence of a recent severe hypoglycemic event was the strongest independent predictor of death within 90 days. Further analysis showed that even though serious hypoglycemia occurred more often in the intensive therapy group, it was associated with progression of coronary artery calcification in the standard therapy group.²³ Hence, it is imperative that tight glycemic control not be achieved at the cost of severe or recurrent hypoglycemia.

In terms of hypoglycemia, metformin is an excellent medication. The American Diabetes Association²⁴ recommends metformin as the first-line therapy for newly diagnosed diabetes. Long-term follow-up data from UKPDS showed that metformin decreased mortality and the incidence of myocardial infarction and lowered treatment costs as well as the overall risk of hypoglycemia.²⁵ When prescribed, it should be titrated to the highest dose.

The FDA²⁶ has changed the prescribing information for metformin in patients with renal impairment. Metformin should not be started if the eGFR is less than 45 mL/min/1.73 m², but it can be continued if the patient is already receiving it and the eGFR is between 30 and 45. Previously, creatinine levels were used to define renal impairment and suitability for metformin. This change has increased the number of patients who can benefit from this medication.

In patients who have a contraindication to metformin, DPP-4 inhibitors can be considered, as they carry a low risk of hypoglycemia as well. Sulfonylureas should be used with caution in these patients, especially if their oral intake is variable. When sulfonylureas were compared to the DPP-4 inhibitor sitagliptin as an add-on to metformin, the rate of hypoglycemia was 32% in the sulfonylurea group vs 5% in the sitagliptin group.²⁷

Of the sulfonylureas, glipizide and glimepiride are better than glyburide because of a comparatively lower risk of hypoglycemia and a higher selectivity for binding the K_ATP channel on the pancreatic beta cell.²⁸

Meglitinides can be a good option for patients who skip meals, but they are more expensive than other generic oral hypoglycemic agents and require multiple daily dosing.

GLP-1 analogues also have a low risk of hypoglycemia but are only available in injectable formulations. Patients must be willing and able to perform the injections themselves.²⁹

 

 

LOOSER TARGETS FOR OLDER PATIENTS

In 2010, among US residents age 65 and older, 10.9 million (about 27%) had diabetes,³⁰ and this number is projected to increase to 26.7 million by 2050.³¹ This population is prone to hypoglycemia when treated with insulin and sulfonylureas. An injury sustained by a fall induced by hypoglycemia can be life-altering. In addition, no randomized clinical trials show the effect of tight glycemic control on complications in older patients with diabetes because patients older than 80 are often excluded.

A reasonable goal suggested by the European Diabetes Working Party for Older People 2011³² and reiterated by the American Geriatrics Society in 2013³³ is a hemoglobin A_1c between 7% and 7.5% for relatively healthy older patients and 7.5% to 8% or 8.5% in frail elderly patients with diabetes.

Consider prescribing medications that carry a low risk of hypoglycemia, can be dose-adjusted for kidney function, and do not rely on manual dexterity for administration (ie, do not require patients to give themselves injections). These include metformin and DPP-4 inhibitors.

DRUG COMBINATIONS

Polypharmacy is a concern for all patients with diabetes, especially since it increases the risk of drug interactions and adverse effects, increases out-of-pocket costs, and decreases the likelihood that patients will remain adherent to their treatment regimen. The use of combination medications can reduce the number of pills or injections required, as well as copayments.

Due to concern for multiple drug-drug interactions (and also due to the progressive nature of diabetes), many people with type 2 diabetes are given insulin in lieu of pills to lower their blood glucose. In addition to premixed insulin combinations (such as combinations of neutral protamine Hagedorn and regular insulin or combinations of insulin analogues), long-acting basal insulins can now be prescribed with a GLP-1 drug in fixed-dose combinations such as insulin glargine plus lixisenatide and insulin degludec plus liraglutide.

COST CONSIDERATIONS

It is important to discuss medication cost with patients, because many newer diabetic drugs are expensive and add to the financial burden of patients already paying for multiple medications, such as antihypertensives and statins.

Metformin and sulfonylureas are less expensive alternatives for patients who cannot afford GLP-1 analogues or SGLT2 inhibitors. Even within the same drug class, the formulary-preferred drug may be cheaper than the nonformulary alternative. Thus, it is helpful to research formulary alternatives before discussing treatment regimens with patients.

PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.

Mitchel L. Zoler/MDedge News

“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.

The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.

Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.

The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.

The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.

“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.

DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.

The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.

The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.

“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.

“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.

[email protected]

PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.

Mitchel L. Zoler/MDedge News

“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.

The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.

Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.

The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.

The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.

“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.

DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.

The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.

The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.

“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.

“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.

[email protected]

PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.

Mitchel L. Zoler/MDedge News

“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.

The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.

Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.

The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.

The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.

“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.

DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.

The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.

The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.

“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.

“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.

[email protected]

Weight-loss surgery in people with type 2 diabetes and obesity is associated with significant reductions in major adverse cardiovascular events, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.

The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.

At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).

The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA_1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.

Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).

In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.

In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m² or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.

The surgery was also associated with significantly greater reductions in HbA_1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.

The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.

In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.

“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.

“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.

The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.

“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.

The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.

SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.

Weight-loss surgery in people with type 2 diabetes and obesity is associated with significant reductions in major adverse cardiovascular events, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.

The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.

At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).

The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA_1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.

Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).

In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.

In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m² or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.

The surgery was also associated with significantly greater reductions in HbA_1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.

The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.

In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.

“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.

“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.

The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.

“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.

The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.

SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.

Weight-loss surgery in people with type 2 diabetes and obesity is associated with significant reductions in major adverse cardiovascular events, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.

The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.

At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).

The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA_1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.

Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).

In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.

In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m² or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.

The surgery was also associated with significantly greater reductions in HbA_1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.

The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.

In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.

“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.

“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.

The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.

“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.

The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.

SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.

PARIS – Patients with stable coronary artery disease and type 2 diabetes saw fewer ischemic cardiovascular events when they received dual antiplatelet therapy with ticagrelor plus aspirin, though they also had more major bleeding events than patients receiving placebo plus aspirin.

The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.

Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).

“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.

Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.

Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.

Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.

Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.

Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.

koakes@mdedgecom

Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)

PARIS – Patients with stable coronary artery disease and type 2 diabetes saw fewer ischemic cardiovascular events when they received dual antiplatelet therapy with ticagrelor plus aspirin, though they also had more major bleeding events than patients receiving placebo plus aspirin.

The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.

Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).

“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.

Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.

Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.

Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.

Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.

Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.

koakes@mdedgecom

Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)

PARIS – Patients with stable coronary artery disease and type 2 diabetes saw fewer ischemic cardiovascular events when they received dual antiplatelet therapy with ticagrelor plus aspirin, though they also had more major bleeding events than patients receiving placebo plus aspirin.

The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.

Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).

“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.

Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.

Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.

Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.

Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.

Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.

koakes@mdedgecom

Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)

Colorectal cancer (CRC) survivor rates are improving, which means people are living long enough after the cancer to have other chronic conditions. CRC is the third most commonly diagnosed cancer among users of the US Department of Veterans Affairs (VA) health care system, according to VA researchers, and there is a high prevalence of cardiovascular disease (CVD). The researchers also say emerging evidence suggests that survivors of CRC may be more likely to develop diabetes mellitus (DM) in the 5 years following their cancer diagnosis. But they add that there is a paucity of research about control of CVD-related chronic conditions among survivors of CRC.

In a retrospective study, the researchers compared 9,758 nonmetastatic patients with CRC with 29,066 people who had not had cancer. At baseline, 69% of the survivors of CRC and the matched controls were diagnosed with hypertension, 52% with hyperlipidemia, and 37% with DM.

But somewhat contrary to expectations, the researchers found no significant differences between the 2 groups for DM in the year following the baseline assessment. The researchers point to the VA’s “strong history” of DM risk reduction research and 2 national programs targeting DM, although they do not know whether the people in their study participated in those.

The survivors of CRC also had half the odds of being diagnosed with hyperlipidemia. However, they did have 57% higher odds of being diagnosed with hypertension.

Although the researchers acknowledge that hypertension is a transient adverse effect of certain chemotherapy regimens, they found only 7 survivors of CRC and 11 controls were treated with bevacizumab during their first year postanchor date.

The relationship between nonmetastatic CRC and CVD risk-related chronic conditions is complex, the researchers say. But they share risk factors, including obesity, physical inactivity, and diet.

The researchers call behavioral change interventions that improve survivors of CRC physical activity, dietary habits, and body mass index a “promising beginning” but call for other similar interventions, particularly those targeting blood pressure management and adherence to antihypertensive medications (which was significantly lower among the survivors).

While the magnitude of the effect regarding hypertension seems relatively small, the researchers say, they believe it is still an important difference when considered from a population health perspective—and one that should be addressed. The researchers also note that nonmetastatic survivors of CRC and controls had very similar rates of primary care visits in the 3 years postanchor date and as a result similar opportunities to receive a hypertension diagnosis.

Colorectal cancer (CRC) survivor rates are improving, which means people are living long enough after the cancer to have other chronic conditions. CRC is the third most commonly diagnosed cancer among users of the US Department of Veterans Affairs (VA) health care system, according to VA researchers, and there is a high prevalence of cardiovascular disease (CVD). The researchers also say emerging evidence suggests that survivors of CRC may be more likely to develop diabetes mellitus (DM) in the 5 years following their cancer diagnosis. But they add that there is a paucity of research about control of CVD-related chronic conditions among survivors of CRC.

In a retrospective study, the researchers compared 9,758 nonmetastatic patients with CRC with 29,066 people who had not had cancer. At baseline, 69% of the survivors of CRC and the matched controls were diagnosed with hypertension, 52% with hyperlipidemia, and 37% with DM.

But somewhat contrary to expectations, the researchers found no significant differences between the 2 groups for DM in the year following the baseline assessment. The researchers point to the VA’s “strong history” of DM risk reduction research and 2 national programs targeting DM, although they do not know whether the people in their study participated in those.

The survivors of CRC also had half the odds of being diagnosed with hyperlipidemia. However, they did have 57% higher odds of being diagnosed with hypertension.

Although the researchers acknowledge that hypertension is a transient adverse effect of certain chemotherapy regimens, they found only 7 survivors of CRC and 11 controls were treated with bevacizumab during their first year postanchor date.

The relationship between nonmetastatic CRC and CVD risk-related chronic conditions is complex, the researchers say. But they share risk factors, including obesity, physical inactivity, and diet.

The researchers call behavioral change interventions that improve survivors of CRC physical activity, dietary habits, and body mass index a “promising beginning” but call for other similar interventions, particularly those targeting blood pressure management and adherence to antihypertensive medications (which was significantly lower among the survivors).

While the magnitude of the effect regarding hypertension seems relatively small, the researchers say, they believe it is still an important difference when considered from a population health perspective—and one that should be addressed. The researchers also note that nonmetastatic survivors of CRC and controls had very similar rates of primary care visits in the 3 years postanchor date and as a result similar opportunities to receive a hypertension diagnosis.

Colorectal cancer (CRC) survivor rates are improving, which means people are living long enough after the cancer to have other chronic conditions. CRC is the third most commonly diagnosed cancer among users of the US Department of Veterans Affairs (VA) health care system, according to VA researchers, and there is a high prevalence of cardiovascular disease (CVD). The researchers also say emerging evidence suggests that survivors of CRC may be more likely to develop diabetes mellitus (DM) in the 5 years following their cancer diagnosis. But they add that there is a paucity of research about control of CVD-related chronic conditions among survivors of CRC.

In a retrospective study, the researchers compared 9,758 nonmetastatic patients with CRC with 29,066 people who had not had cancer. At baseline, 69% of the survivors of CRC and the matched controls were diagnosed with hypertension, 52% with hyperlipidemia, and 37% with DM.

But somewhat contrary to expectations, the researchers found no significant differences between the 2 groups for DM in the year following the baseline assessment. The researchers point to the VA’s “strong history” of DM risk reduction research and 2 national programs targeting DM, although they do not know whether the people in their study participated in those.

The survivors of CRC also had half the odds of being diagnosed with hyperlipidemia. However, they did have 57% higher odds of being diagnosed with hypertension.

Although the researchers acknowledge that hypertension is a transient adverse effect of certain chemotherapy regimens, they found only 7 survivors of CRC and 11 controls were treated with bevacizumab during their first year postanchor date.

The relationship between nonmetastatic CRC and CVD risk-related chronic conditions is complex, the researchers say. But they share risk factors, including obesity, physical inactivity, and diet.

The researchers call behavioral change interventions that improve survivors of CRC physical activity, dietary habits, and body mass index a “promising beginning” but call for other similar interventions, particularly those targeting blood pressure management and adherence to antihypertensive medications (which was significantly lower among the survivors).

While the magnitude of the effect regarding hypertension seems relatively small, the researchers say, they believe it is still an important difference when considered from a population health perspective—and one that should be addressed. The researchers also note that nonmetastatic survivors of CRC and controls had very similar rates of primary care visits in the 3 years postanchor date and as a result similar opportunities to receive a hypertension diagnosis.