Type 2 Diabetes ICYMI

According to the American Diabetes Association (ADA), about 29 million Americans have diabetes mellitus (DM). Uncontrolled DM causes various microvascular and macrovascular complications and leads to significant mortality. In 2011, DM was the seventh leading cause of death.¹ The ADA recommends setting a hemoglobin A_1c (HbA_1c) goal of < 7% to prevent microvascular and macrovascular complications.¹

The treatment cost of DM continues to rise and accounts for about $245 billion annually.¹ Given its effectiveness, low cost, and low adverse-event (AE) profile, metformin has been the cornerstone of therapy in DM over the past 20 years. The ADA recommends metformin as first-line therapy in type 2 DM (T2DM). In 2014, 14.4 million Americans were dispensed a metformin-containing product.² Metformin exerts its effect mainly by decreasing hepatic glucose production and increasing insulin sensitivity. Study results suggest gluconeogenesis may be decreased up to 75% in these patients.³ Metformin is effective in reducing the level of HbA_1c by an average of 1.5%.³

Background

Metformin-induced lactic acidosis is a rare concern in patients with renal impairment (0.03 case/1,000 patient-years).⁴ Much of this concern stems from the high incidence of lactic acidosis associated with the medication phenformin, which was approved in the 1950s but taken off the market because of its high incidence of lactic acidosis in patients with a serum creatinine (SCr) level > 1.4 mg/dL.

Although phenformin and metformin are both biguanide class medications, they vastly differ. Increased phenformin levels in the blood are correlated with decreased glucose oxidation and increased lactate production. Conversely, metformin may enhance glucose oxidation, and there seems to be no correlation between metformin levels with lactate levels. Lactic acidosis occurred 10 to 20 times more often with phenformin than it does with metformin.⁵ In studies in which patients with an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m² continued to use metformin, lactic acidosis was rare, even in the presence of comorbid conditions that may promote lactic acidosis, such as chronic obstructive pulmonary disease, congestive heart failure, and liver disease.⁶ In 2012, the National Kidney Foundation (NKF) suggested an eGFR cutoff be considered when prescribing metformin.⁷

When the present study was initiated, metformin was contraindicated in patients with renal dysfunction (SCr levels ≥ 1.5 mg/dL in males≥ 1.4 mg/dL in females).⁵ The estimated incidence of renal dysfunction in patients with T2DM is 12%. Under this labeling, metformin use is prohibited in at least 2.5 million people. Study results have shown that, when package insert guidelines were disregarded and metformin was given against renal recommendations, the rate of AEs was not increased, and patients benefited clinically.⁸ Data suggest that the rate of lactic acidosis may be increased in patients with advanced kidney disease.⁸

In April 2016, the FDA started requiring that manufacturers update their labeling to indicate metformin may be used safely in cases of mild-to-moderate renal impairment. The FDA also changed a recommendation: now, before starting metformin, health care professionals should obtain the patient’s eGFR, which provides a more accurate determination of kidney function by taking into account age, sex, and race. Metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m² and is not recommended to be initiated in patients with an eGFR of 30 to 45 mL/min/1.73 m². The suggestion for patients already using metformin is to obtain eGFR at least annually. In addition, when eGFR drops to between 30 and 45 mL/min/1.73 m², the risks and benefits of continuing metformin should be weighed on a patient-specific basis.^2,4

Methods

The authors retrospectively reviewed the charts of 199 randomly selected patients at Huntington VAMC in West Virginia who had metformin discontinued because of elevated SCr (defined as ≥ 1.5 mg/dL) between September 1, 2009 and September 1, 2014. Clinician notes written at time of discontinuation were assessed for other reasons for discontinuation, and patients thus identified were excluded. Change in glycemic control was assessed by comparing first HbA1c level 60 to 365 days after discontinuation of metformin with the most recent HbA1c level before discontinuation. Other data analyzed included age, time to next recorded SCr level, reinitiation of metformin (yes or no), and change in diabetic medication regimen. Class of medication initiated was recorded but not dose or insulin type. Subgroup analysis was performed on patients initiated on insulin after discontinuation of metformin. Evaluations were made of most recent HbA_1c level at time of discontinuation of metformin, first HbA_1c level after discontinuation, and HbA_1c level 1 year after discontinuation in patients on insulin.

The primary endpoint of the study was change in HbA_1c after discontinuation of metformin. This was studied to justify the value of metformin in T2DM and to evaluate whether patients could remain on metformin with mild-to-moderate renal impairment without AEs. Secondary endpoints were time to next recorded SCr level after discontinuation of metformin, reinitiation of metformin (yes or no), when next recorded SCr level was < 1.5 mg/dL, change in medication regimen after discontinuation of metformin, and incidence of lactic acidosis. Study inclusion criteria were male sex, age between 18 and 89 years, discontinuation of metformin because of elevated SCr, and documented repeat HbA_1c level 60 to 365 days after discontinuation of metformin. Exclusion criteria were insulin therapy at time of discontinuation of metformin and type 1 DM diagnosis. A 2-sided t test was used to compare change in HbA_1c level.

Results

Of the 199 patients who had metformin discontinued because of elevated SCr (> 1.5 mg/dL), 106 were excluded for reasons listed in Figure 1; the other 93 met the study inclusion criteria and had their cases analyzed for change in glycemic control after discontinuation of metformin.

The mean age was 68.2 years and mean weight was 97.36 kg for the included patients. Four were African American, and 89 were white. At time of discontinuation of metformin, mean SCr level was 1.65 mg/dL, and mean eGFR was 43.25 mL/min/1.73 m² (Table). Mean (SD) HbA_1c level was 7.2% (1.1%) before discontinuation of metformin and 7.7% (1.5%) after discontinuation (P < .05) (Figure 2). Subgroup analysis of patients initiated on insulin after discontinuation of metformin (n = 47) revealed mean (SD) HbA_1c levels of 7.5% (1.1%) before discontinuation and 8.3% (1.3%) after discontinuation (P < .05). One year or more after discontinuation of metformin in patients in whom insulin was initiated, mean HbA_1c level decreased to the prediscontinuation (baseline) level of 7.5% (P = .91).

Discussion

Overall, a decline in glycemic control was found in patients who had metformin discontinued. This anticipated decline prompted clinicians to replace metformin with other oral medications as well as insulin. Despite DM medication regimen changes, mean HbA_1c level increased significantly after discontinuation of metformin. The initial decline in glycemic control after starting insulin could be attributable either to clinician preference in insulin initiation—starting at lower doses to avoid hypoglycemia—or to a delay in initiating insulin, as opposed to initiating insulin at time of discontinuation of metformin. Subgroup analysis of the large number of patients who started on insulin after discontinuation of metformin (51%) revealed the same HbA_1c levels before and 1 year after discontinuation. This finding is clinically relevant because many patients showed a decline in glycemic control for a year, despite initiation of insulin therapy.

In 43 (46%) of the 93 patients studied, SCr level improved to < 1.5 mg/dL after discontinuation of metformin. Of the patients in the subgroup started on insulin, 20 had improved renal function. This finding suggests that many of the patients who were initiated on insulin showed an improvement in renal function and potentially could have had metformin reinitiated. If these patients had continued or restarted metformin, insulin therapy may have been avoided or delayed. Overall, many opportunities to resume metformin were missed; only 9 of the 43 patients with improved SCr levels (< 1.5 mg/dL) on recheck were restarted on metformin. Many clinicians seemed hesitant to restart metformin even after kidney function improved. In addition, mean time to next recorded SCr level after discontinuation of metformin was 95.7 days. If SCr levels are more closely monitored after discontinuation of metformin, metformin possibly could be restarted sooner, leading to improved glycemic control and prevention of both microvascular and macrovascular complications.

In its 2012 update, the NKF suggested that it may be reasonable to consider using an eGFR cutoff when prescribing metformin. Clearance of metformin is reduced by 75% when eGFR is under 60 mL/min/1.73m² but declines no further until eGFR is < 30 mL/min/1.73 m².⁷ A systematic review of 65 articles found that, overall, levels of metformin remained in the therapeutic range, and lactate concentrations did not increase significantly in mild-to-moderate renal impairment (eGFR, 30-60 mL/min/1.73 m²).⁸ This finding corresponds to the updated 2016 FDA recommendations regarding use of metformin in mild-to-moderate renal impairment.

In the present study, patients who had metformin discontinued earlier, under strict package labeling, may have been able to continue metformin with use of eGFR under the revised labeling. Thirty-seven patients had an eGFR > 45 mL/min/1.73 m² at the time of discontinuation of metformin, 49 had an eGFR between 45 and 30 mL/min/1.73 m², and 7 had an eGFR < 30 mL/min/1.73 m². Only 7 (8%) of the 93 patients would have had a contraindication to continuing metformin on the basis of current FDA recommendations. Forty-nine patients (53%) could have continued metformin if the benefit outweighed the risk, and 37 (39%) could have continued metformin given an eGFR > 45 mL/min/1.73 m². The earlier labeling required initial discontinuation of metformin in these patients, but new FDA recommendations would allow more of them with mild-to-moderate renal impairment to benefit from treatment with metformin.

Limitations

This study had a few limitations. Its design was retrospective, and its narrow demographics may not permit generalizability to other patient populations. In addition, the study evaluated initiation of new medications at time of discontinuation of metformin but not dosage adjustments of current medications. Insulin type and dosage were not evaluated—only whether insulin was initiated. Further, follow-up time was limited; change in long-term glycemic control requires more study. Another limitation was that adherence could not be assessed.

Conclusion

After discontinuation of metformin, there was a statistically significant increase in HbA_1c level. Insulin was initiated in 51% of patients after discontinuation of metformin. Subgroup analysis of the patients who started insulin after discontinuation of metformin revealed the same HbA_1c levels before and 1 year after discontinuation with a loss of glycemic control throughout the year. Of the 47 patients who were initiated on insulin, 20 had their SCr level decrease to < 1.5 mg/dL and could have been restarted on metformin. This finding indicates that many patients may have been able to delay time to insulin initiation and maintain the same glycemic control if metformin could have been continued. With more study, long-term change in glycemic control after discontinuation of metformin can be determined. In many patients, metformin is needed for adequate glycemic control. The revised FDA labeling allows many patients with mild-to-moderate kidney disease to benefit from treatment with metformin.

Click here to read the digital edition.

According to the American Diabetes Association (ADA), about 29 million Americans have diabetes mellitus (DM). Uncontrolled DM causes various microvascular and macrovascular complications and leads to significant mortality. In 2011, DM was the seventh leading cause of death.¹ The ADA recommends setting a hemoglobin A_1c (HbA_1c) goal of < 7% to prevent microvascular and macrovascular complications.¹

The treatment cost of DM continues to rise and accounts for about $245 billion annually.¹ Given its effectiveness, low cost, and low adverse-event (AE) profile, metformin has been the cornerstone of therapy in DM over the past 20 years. The ADA recommends metformin as first-line therapy in type 2 DM (T2DM). In 2014, 14.4 million Americans were dispensed a metformin-containing product.² Metformin exerts its effect mainly by decreasing hepatic glucose production and increasing insulin sensitivity. Study results suggest gluconeogenesis may be decreased up to 75% in these patients.³ Metformin is effective in reducing the level of HbA_1c by an average of 1.5%.³

Background

Metformin-induced lactic acidosis is a rare concern in patients with renal impairment (0.03 case/1,000 patient-years).⁴ Much of this concern stems from the high incidence of lactic acidosis associated with the medication phenformin, which was approved in the 1950s but taken off the market because of its high incidence of lactic acidosis in patients with a serum creatinine (SCr) level > 1.4 mg/dL.

Although phenformin and metformin are both biguanide class medications, they vastly differ. Increased phenformin levels in the blood are correlated with decreased glucose oxidation and increased lactate production. Conversely, metformin may enhance glucose oxidation, and there seems to be no correlation between metformin levels with lactate levels. Lactic acidosis occurred 10 to 20 times more often with phenformin than it does with metformin.⁵ In studies in which patients with an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m² continued to use metformin, lactic acidosis was rare, even in the presence of comorbid conditions that may promote lactic acidosis, such as chronic obstructive pulmonary disease, congestive heart failure, and liver disease.⁶ In 2012, the National Kidney Foundation (NKF) suggested an eGFR cutoff be considered when prescribing metformin.⁷

When the present study was initiated, metformin was contraindicated in patients with renal dysfunction (SCr levels ≥ 1.5 mg/dL in males≥ 1.4 mg/dL in females).⁵ The estimated incidence of renal dysfunction in patients with T2DM is 12%. Under this labeling, metformin use is prohibited in at least 2.5 million people. Study results have shown that, when package insert guidelines were disregarded and metformin was given against renal recommendations, the rate of AEs was not increased, and patients benefited clinically.⁸ Data suggest that the rate of lactic acidosis may be increased in patients with advanced kidney disease.⁸

In April 2016, the FDA started requiring that manufacturers update their labeling to indicate metformin may be used safely in cases of mild-to-moderate renal impairment. The FDA also changed a recommendation: now, before starting metformin, health care professionals should obtain the patient’s eGFR, which provides a more accurate determination of kidney function by taking into account age, sex, and race. Metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m² and is not recommended to be initiated in patients with an eGFR of 30 to 45 mL/min/1.73 m². The suggestion for patients already using metformin is to obtain eGFR at least annually. In addition, when eGFR drops to between 30 and 45 mL/min/1.73 m², the risks and benefits of continuing metformin should be weighed on a patient-specific basis.^2,4

Methods

The authors retrospectively reviewed the charts of 199 randomly selected patients at Huntington VAMC in West Virginia who had metformin discontinued because of elevated SCr (defined as ≥ 1.5 mg/dL) between September 1, 2009 and September 1, 2014. Clinician notes written at time of discontinuation were assessed for other reasons for discontinuation, and patients thus identified were excluded. Change in glycemic control was assessed by comparing first HbA1c level 60 to 365 days after discontinuation of metformin with the most recent HbA1c level before discontinuation. Other data analyzed included age, time to next recorded SCr level, reinitiation of metformin (yes or no), and change in diabetic medication regimen. Class of medication initiated was recorded but not dose or insulin type. Subgroup analysis was performed on patients initiated on insulin after discontinuation of metformin. Evaluations were made of most recent HbA_1c level at time of discontinuation of metformin, first HbA_1c level after discontinuation, and HbA_1c level 1 year after discontinuation in patients on insulin.

The primary endpoint of the study was change in HbA_1c after discontinuation of metformin. This was studied to justify the value of metformin in T2DM and to evaluate whether patients could remain on metformin with mild-to-moderate renal impairment without AEs. Secondary endpoints were time to next recorded SCr level after discontinuation of metformin, reinitiation of metformin (yes or no), when next recorded SCr level was < 1.5 mg/dL, change in medication regimen after discontinuation of metformin, and incidence of lactic acidosis. Study inclusion criteria were male sex, age between 18 and 89 years, discontinuation of metformin because of elevated SCr, and documented repeat HbA_1c level 60 to 365 days after discontinuation of metformin. Exclusion criteria were insulin therapy at time of discontinuation of metformin and type 1 DM diagnosis. A 2-sided t test was used to compare change in HbA_1c level.

Results

Of the 199 patients who had metformin discontinued because of elevated SCr (> 1.5 mg/dL), 106 were excluded for reasons listed in Figure 1; the other 93 met the study inclusion criteria and had their cases analyzed for change in glycemic control after discontinuation of metformin.

The mean age was 68.2 years and mean weight was 97.36 kg for the included patients. Four were African American, and 89 were white. At time of discontinuation of metformin, mean SCr level was 1.65 mg/dL, and mean eGFR was 43.25 mL/min/1.73 m² (Table). Mean (SD) HbA_1c level was 7.2% (1.1%) before discontinuation of metformin and 7.7% (1.5%) after discontinuation (P < .05) (Figure 2). Subgroup analysis of patients initiated on insulin after discontinuation of metformin (n = 47) revealed mean (SD) HbA_1c levels of 7.5% (1.1%) before discontinuation and 8.3% (1.3%) after discontinuation (P < .05). One year or more after discontinuation of metformin in patients in whom insulin was initiated, mean HbA_1c level decreased to the prediscontinuation (baseline) level of 7.5% (P = .91).

Discussion

Overall, a decline in glycemic control was found in patients who had metformin discontinued. This anticipated decline prompted clinicians to replace metformin with other oral medications as well as insulin. Despite DM medication regimen changes, mean HbA_1c level increased significantly after discontinuation of metformin. The initial decline in glycemic control after starting insulin could be attributable either to clinician preference in insulin initiation—starting at lower doses to avoid hypoglycemia—or to a delay in initiating insulin, as opposed to initiating insulin at time of discontinuation of metformin. Subgroup analysis of the large number of patients who started on insulin after discontinuation of metformin (51%) revealed the same HbA_1c levels before and 1 year after discontinuation. This finding is clinically relevant because many patients showed a decline in glycemic control for a year, despite initiation of insulin therapy.

In 43 (46%) of the 93 patients studied, SCr level improved to < 1.5 mg/dL after discontinuation of metformin. Of the patients in the subgroup started on insulin, 20 had improved renal function. This finding suggests that many of the patients who were initiated on insulin showed an improvement in renal function and potentially could have had metformin reinitiated. If these patients had continued or restarted metformin, insulin therapy may have been avoided or delayed. Overall, many opportunities to resume metformin were missed; only 9 of the 43 patients with improved SCr levels (< 1.5 mg/dL) on recheck were restarted on metformin. Many clinicians seemed hesitant to restart metformin even after kidney function improved. In addition, mean time to next recorded SCr level after discontinuation of metformin was 95.7 days. If SCr levels are more closely monitored after discontinuation of metformin, metformin possibly could be restarted sooner, leading to improved glycemic control and prevention of both microvascular and macrovascular complications.

In its 2012 update, the NKF suggested that it may be reasonable to consider using an eGFR cutoff when prescribing metformin. Clearance of metformin is reduced by 75% when eGFR is under 60 mL/min/1.73m² but declines no further until eGFR is < 30 mL/min/1.73 m².⁷ A systematic review of 65 articles found that, overall, levels of metformin remained in the therapeutic range, and lactate concentrations did not increase significantly in mild-to-moderate renal impairment (eGFR, 30-60 mL/min/1.73 m²).⁸ This finding corresponds to the updated 2016 FDA recommendations regarding use of metformin in mild-to-moderate renal impairment.

In the present study, patients who had metformin discontinued earlier, under strict package labeling, may have been able to continue metformin with use of eGFR under the revised labeling. Thirty-seven patients had an eGFR > 45 mL/min/1.73 m² at the time of discontinuation of metformin, 49 had an eGFR between 45 and 30 mL/min/1.73 m², and 7 had an eGFR < 30 mL/min/1.73 m². Only 7 (8%) of the 93 patients would have had a contraindication to continuing metformin on the basis of current FDA recommendations. Forty-nine patients (53%) could have continued metformin if the benefit outweighed the risk, and 37 (39%) could have continued metformin given an eGFR > 45 mL/min/1.73 m². The earlier labeling required initial discontinuation of metformin in these patients, but new FDA recommendations would allow more of them with mild-to-moderate renal impairment to benefit from treatment with metformin.

Limitations

This study had a few limitations. Its design was retrospective, and its narrow demographics may not permit generalizability to other patient populations. In addition, the study evaluated initiation of new medications at time of discontinuation of metformin but not dosage adjustments of current medications. Insulin type and dosage were not evaluated—only whether insulin was initiated. Further, follow-up time was limited; change in long-term glycemic control requires more study. Another limitation was that adherence could not be assessed.

Conclusion

After discontinuation of metformin, there was a statistically significant increase in HbA_1c level. Insulin was initiated in 51% of patients after discontinuation of metformin. Subgroup analysis of the patients who started insulin after discontinuation of metformin revealed the same HbA_1c levels before and 1 year after discontinuation with a loss of glycemic control throughout the year. Of the 47 patients who were initiated on insulin, 20 had their SCr level decrease to < 1.5 mg/dL and could have been restarted on metformin. This finding indicates that many patients may have been able to delay time to insulin initiation and maintain the same glycemic control if metformin could have been continued. With more study, long-term change in glycemic control after discontinuation of metformin can be determined. In many patients, metformin is needed for adequate glycemic control. The revised FDA labeling allows many patients with mild-to-moderate kidney disease to benefit from treatment with metformin.

Click here to read the digital edition.

According to the American Diabetes Association (ADA), about 29 million Americans have diabetes mellitus (DM). Uncontrolled DM causes various microvascular and macrovascular complications and leads to significant mortality. In 2011, DM was the seventh leading cause of death.¹ The ADA recommends setting a hemoglobin A_1c (HbA_1c) goal of < 7% to prevent microvascular and macrovascular complications.¹

The treatment cost of DM continues to rise and accounts for about $245 billion annually.¹ Given its effectiveness, low cost, and low adverse-event (AE) profile, metformin has been the cornerstone of therapy in DM over the past 20 years. The ADA recommends metformin as first-line therapy in type 2 DM (T2DM). In 2014, 14.4 million Americans were dispensed a metformin-containing product.² Metformin exerts its effect mainly by decreasing hepatic glucose production and increasing insulin sensitivity. Study results suggest gluconeogenesis may be decreased up to 75% in these patients.³ Metformin is effective in reducing the level of HbA_1c by an average of 1.5%.³

Background

Metformin-induced lactic acidosis is a rare concern in patients with renal impairment (0.03 case/1,000 patient-years).⁴ Much of this concern stems from the high incidence of lactic acidosis associated with the medication phenformin, which was approved in the 1950s but taken off the market because of its high incidence of lactic acidosis in patients with a serum creatinine (SCr) level > 1.4 mg/dL.

Although phenformin and metformin are both biguanide class medications, they vastly differ. Increased phenformin levels in the blood are correlated with decreased glucose oxidation and increased lactate production. Conversely, metformin may enhance glucose oxidation, and there seems to be no correlation between metformin levels with lactate levels. Lactic acidosis occurred 10 to 20 times more often with phenformin than it does with metformin.⁵ In studies in which patients with an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m² continued to use metformin, lactic acidosis was rare, even in the presence of comorbid conditions that may promote lactic acidosis, such as chronic obstructive pulmonary disease, congestive heart failure, and liver disease.⁶ In 2012, the National Kidney Foundation (NKF) suggested an eGFR cutoff be considered when prescribing metformin.⁷

When the present study was initiated, metformin was contraindicated in patients with renal dysfunction (SCr levels ≥ 1.5 mg/dL in males≥ 1.4 mg/dL in females).⁵ The estimated incidence of renal dysfunction in patients with T2DM is 12%. Under this labeling, metformin use is prohibited in at least 2.5 million people. Study results have shown that, when package insert guidelines were disregarded and metformin was given against renal recommendations, the rate of AEs was not increased, and patients benefited clinically.⁸ Data suggest that the rate of lactic acidosis may be increased in patients with advanced kidney disease.⁸

In April 2016, the FDA started requiring that manufacturers update their labeling to indicate metformin may be used safely in cases of mild-to-moderate renal impairment. The FDA also changed a recommendation: now, before starting metformin, health care professionals should obtain the patient’s eGFR, which provides a more accurate determination of kidney function by taking into account age, sex, and race. Metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m² and is not recommended to be initiated in patients with an eGFR of 30 to 45 mL/min/1.73 m². The suggestion for patients already using metformin is to obtain eGFR at least annually. In addition, when eGFR drops to between 30 and 45 mL/min/1.73 m², the risks and benefits of continuing metformin should be weighed on a patient-specific basis.^2,4

Methods

The authors retrospectively reviewed the charts of 199 randomly selected patients at Huntington VAMC in West Virginia who had metformin discontinued because of elevated SCr (defined as ≥ 1.5 mg/dL) between September 1, 2009 and September 1, 2014. Clinician notes written at time of discontinuation were assessed for other reasons for discontinuation, and patients thus identified were excluded. Change in glycemic control was assessed by comparing first HbA1c level 60 to 365 days after discontinuation of metformin with the most recent HbA1c level before discontinuation. Other data analyzed included age, time to next recorded SCr level, reinitiation of metformin (yes or no), and change in diabetic medication regimen. Class of medication initiated was recorded but not dose or insulin type. Subgroup analysis was performed on patients initiated on insulin after discontinuation of metformin. Evaluations were made of most recent HbA_1c level at time of discontinuation of metformin, first HbA_1c level after discontinuation, and HbA_1c level 1 year after discontinuation in patients on insulin.

The primary endpoint of the study was change in HbA_1c after discontinuation of metformin. This was studied to justify the value of metformin in T2DM and to evaluate whether patients could remain on metformin with mild-to-moderate renal impairment without AEs. Secondary endpoints were time to next recorded SCr level after discontinuation of metformin, reinitiation of metformin (yes or no), when next recorded SCr level was < 1.5 mg/dL, change in medication regimen after discontinuation of metformin, and incidence of lactic acidosis. Study inclusion criteria were male sex, age between 18 and 89 years, discontinuation of metformin because of elevated SCr, and documented repeat HbA_1c level 60 to 365 days after discontinuation of metformin. Exclusion criteria were insulin therapy at time of discontinuation of metformin and type 1 DM diagnosis. A 2-sided t test was used to compare change in HbA_1c level.

Results

Of the 199 patients who had metformin discontinued because of elevated SCr (> 1.5 mg/dL), 106 were excluded for reasons listed in Figure 1; the other 93 met the study inclusion criteria and had their cases analyzed for change in glycemic control after discontinuation of metformin.

The mean age was 68.2 years and mean weight was 97.36 kg for the included patients. Four were African American, and 89 were white. At time of discontinuation of metformin, mean SCr level was 1.65 mg/dL, and mean eGFR was 43.25 mL/min/1.73 m² (Table). Mean (SD) HbA_1c level was 7.2% (1.1%) before discontinuation of metformin and 7.7% (1.5%) after discontinuation (P < .05) (Figure 2). Subgroup analysis of patients initiated on insulin after discontinuation of metformin (n = 47) revealed mean (SD) HbA_1c levels of 7.5% (1.1%) before discontinuation and 8.3% (1.3%) after discontinuation (P < .05). One year or more after discontinuation of metformin in patients in whom insulin was initiated, mean HbA_1c level decreased to the prediscontinuation (baseline) level of 7.5% (P = .91).

Discussion

Overall, a decline in glycemic control was found in patients who had metformin discontinued. This anticipated decline prompted clinicians to replace metformin with other oral medications as well as insulin. Despite DM medication regimen changes, mean HbA_1c level increased significantly after discontinuation of metformin. The initial decline in glycemic control after starting insulin could be attributable either to clinician preference in insulin initiation—starting at lower doses to avoid hypoglycemia—or to a delay in initiating insulin, as opposed to initiating insulin at time of discontinuation of metformin. Subgroup analysis of the large number of patients who started on insulin after discontinuation of metformin (51%) revealed the same HbA_1c levels before and 1 year after discontinuation. This finding is clinically relevant because many patients showed a decline in glycemic control for a year, despite initiation of insulin therapy.

In 43 (46%) of the 93 patients studied, SCr level improved to < 1.5 mg/dL after discontinuation of metformin. Of the patients in the subgroup started on insulin, 20 had improved renal function. This finding suggests that many of the patients who were initiated on insulin showed an improvement in renal function and potentially could have had metformin reinitiated. If these patients had continued or restarted metformin, insulin therapy may have been avoided or delayed. Overall, many opportunities to resume metformin were missed; only 9 of the 43 patients with improved SCr levels (< 1.5 mg/dL) on recheck were restarted on metformin. Many clinicians seemed hesitant to restart metformin even after kidney function improved. In addition, mean time to next recorded SCr level after discontinuation of metformin was 95.7 days. If SCr levels are more closely monitored after discontinuation of metformin, metformin possibly could be restarted sooner, leading to improved glycemic control and prevention of both microvascular and macrovascular complications.

In its 2012 update, the NKF suggested that it may be reasonable to consider using an eGFR cutoff when prescribing metformin. Clearance of metformin is reduced by 75% when eGFR is under 60 mL/min/1.73m² but declines no further until eGFR is < 30 mL/min/1.73 m².⁷ A systematic review of 65 articles found that, overall, levels of metformin remained in the therapeutic range, and lactate concentrations did not increase significantly in mild-to-moderate renal impairment (eGFR, 30-60 mL/min/1.73 m²).⁸ This finding corresponds to the updated 2016 FDA recommendations regarding use of metformin in mild-to-moderate renal impairment.

In the present study, patients who had metformin discontinued earlier, under strict package labeling, may have been able to continue metformin with use of eGFR under the revised labeling. Thirty-seven patients had an eGFR > 45 mL/min/1.73 m² at the time of discontinuation of metformin, 49 had an eGFR between 45 and 30 mL/min/1.73 m², and 7 had an eGFR < 30 mL/min/1.73 m². Only 7 (8%) of the 93 patients would have had a contraindication to continuing metformin on the basis of current FDA recommendations. Forty-nine patients (53%) could have continued metformin if the benefit outweighed the risk, and 37 (39%) could have continued metformin given an eGFR > 45 mL/min/1.73 m². The earlier labeling required initial discontinuation of metformin in these patients, but new FDA recommendations would allow more of them with mild-to-moderate renal impairment to benefit from treatment with metformin.

Limitations

This study had a few limitations. Its design was retrospective, and its narrow demographics may not permit generalizability to other patient populations. In addition, the study evaluated initiation of new medications at time of discontinuation of metformin but not dosage adjustments of current medications. Insulin type and dosage were not evaluated—only whether insulin was initiated. Further, follow-up time was limited; change in long-term glycemic control requires more study. Another limitation was that adherence could not be assessed.

Conclusion

After discontinuation of metformin, there was a statistically significant increase in HbA_1c level. Insulin was initiated in 51% of patients after discontinuation of metformin. Subgroup analysis of the patients who started insulin after discontinuation of metformin revealed the same HbA_1c levels before and 1 year after discontinuation with a loss of glycemic control throughout the year. Of the 47 patients who were initiated on insulin, 20 had their SCr level decrease to < 1.5 mg/dL and could have been restarted on metformin. This finding indicates that many patients may have been able to delay time to insulin initiation and maintain the same glycemic control if metformin could have been continued. With more study, long-term change in glycemic control after discontinuation of metformin can be determined. In many patients, metformin is needed for adequate glycemic control. The revised FDA labeling allows many patients with mild-to-moderate kidney disease to benefit from treatment with metformin.

Click here to read the digital edition.

For a long time, 500 U/mL (U-500) insulin was the only concentrated insulin available on the market. With many diabetes mellitus (DM) patients requiring larger doses, additional 200 U/mL (U-200) and 300 U/mL (U-300) concentrations became available. As clinical guidelines lack specific recommendations for optimal use of U-200 and U-300 insulins, clinical discretion is warranted in identifying patients for whom use of these insulins is appropriate. U-500 insulin is recommended in cases that require ≥ 200 U/d or > 2 U/kg/d. Given the ongoing DM and obesity epidemics, increased use of concentrated insulins is likely. Clinicians must stay well informed about the characteristics and benefits of concentrated insulins to remain confident recommending, prescribing, and adjusting these medications.

U-200 Insulin Lispro

Pharmacokinetics/Pharmacodynamics

The amino acid structure of U-200 insulin lispro is different from that of endogenous insulin. In U-200 lispro, lysine replaces a proline at position B28, and proline replaces a lysine at position B29.

In a euglycemic clamp study of patients without DM, a 20-U dose of U-200 lispro and a single 20-U dose of U-100 lispro were found to have similar mean area under the glucose infusion rate curves, mean area under the serum insulin concentration-time curves from time 0 to infinity, mean peak serum insulin levels, and time to maximum glucose-lowering effects.¹ For both U-200 lispro and U-100 lispro, time to maximum effect was 1 hour.²

Even numbers are marked on the dial of the pen. Odd numbers are not marked, but longer lines appear in their place. U-200 lispro should not be mixed with any other insulin, whereas U-100 lispro can be mixed with neutral protamine Hagedorn insulin.

Safety/Efficacy

There has been 1 bioequivalence study of euglycemic patients without type 2 DM (T2DM) but no studies of the safety or efficacy of U-200 lispro in patients with DM.^3,4 U-100 lispro converts 1:1 to U-200 lispro (eg, 60 U of U-100 lispro converts to 60 U of U-200 lispro).¹ The volume of U-200 lispro would be smaller than that of U-100 lispro.

Economic Analysis

There are no published U-200 lispro economic analyses.

Dosing

U-200 lispro should be converted from other bolus insulins in a 1:1 ratio.¹

Recommendations

Definitive recommendations await efficacy trials comparing use of U-200 lispro and other bolus insulins in patients with DM. Currently, U-200 lispro may be considered for patients with DM who require high doses of bolus insulin and who may benefit from smaller volumes of lispro.

U-200 Insulin Degludec

Pharmacokinetics/Pharmacodynamics

The basal insulin degludec (Tresiba) is available in U-100 and U-200 concentrations in a pen. After subcutaneous injection, degludec forms gradually dissociating multihexamer chains, which account for its flat and stable PK/PD profile. U-100 degludec and U-200 degludec have similar duration of action (≥ 42 hours) and time to steady state (2-3 days).^5,6 A patient who misses a regularly scheduled dose should allow at least 8 hours between injections. Taking degludec at variable times does not decrease efficacy as long as this 8-hour minimum interval is observed.⁷

Safety/Efficacy

During its development, degludec was evaluated in more than 5,000 patients across 11 therapeutic trials.⁸ The key studies that led to the approval of degludec used insulin glargine as a comparator. In a 52-week study of 1,030 insulin-naïve patients with T2DM, degludec was noninferior to glargine in hemoglobin A_1c (HbA_1c) reduction (1.06% vs 1.19%). Overall hypoglycemia rates were similar, though there were fewer nocturnal hypoglycemia episodes with degludec than with glargine (0.25 vs 0.39 per patient-year of exposure; P = .38).⁹

The BEGIN Basal-Bolus trial series evaluated use of degludec combined with bolus insulin aspart in insulin-experienced patients with T2DM (n = 992) and type 1 DM (T1DM) (n = 629) over 52 weeks.^10,11 Both trials found noninferiority in A_1c reduction: 1.1% (degludec) and 1.18% (glargine) in patients with T2DM and 0.4% (degludec) and 0.39% (glargine) in those with T1DM.^10,11 Significantly fewer episodes of overall hypoglycemia (11.09 vs 13.63 per patient-year) and nocturnal hypoglycemia (1.39 vs 1.84 per patient-year) were found with degludec in patients with T2DM.⁵ Overall hypoglycemia rates were similar, though there was a 25% lower rate of nocturnal hypoglycemia with degludec in patients with T1DM.¹¹

A meta-analysis of 7 phase 3a trials that compared degludec with glargine revealed significantly lower rates of overall, nocturnal, and severe hypoglycemia with degludec in insulin-naïve patients.¹² The analysis confirmed findings of significantly lower rates of overall and nocturnal hypoglycemia with degludec in the overall T2DM population and significantly lower rates of nocturnal hypoglycemia in the T1DM population.¹²

In the DEVOTE trial, which included 7,637 T2DM patients at high risk for a cardiovascular event, degludec and glargine were compared on the composite primary outcome of death with a cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke. After a median of 1.99 years, the primary outcome occurred in 8.5% of degludec patients and 9.3% of glargine patients (hazard ratio, 0.91; 95% confidence interval, 0.78-1.06; P < .001 for noninferiority). Mean HbA_1c level was 7.5 in both groups; severe hypoglycemia occurred more often in the glargine group (odds ratio, 0.73; P < .001 for superiority).¹³ Findings from the randomized, crossover SWITCH 1 and SWITCH 2 trials confirmed lower rates of symptomatic hypoglycemia with degludec compared with glargine in patients with T1DM and T2DM, respectively.^14,15 No statistically significant differences in weight gain were observed in the clinical trials comparing degludec and glargine.

Economic Analysis

Weatherall and colleagues used a budget impact model to evaluate the costs of degludec and glargine for commercially insured patients with DM in the U.S.¹⁶ Three treatment groups were analyzed: basal/bolus combination in T1DM and T2DM, and basal/oral combination in T2DM. Although degludec cost more, overall cost was reduced in T1DM because of reduced insulin usage and fewer hypoglycemic episodes in T2DM with basal/oral combination therapy. The authors acknowledged the many assumptions needed and the potential oversimplification of their model.¹⁶ In other countries, economic analyses had similar findings.^17-19

Dosing

Degludec converts 1:1 to other basal insulins. Recommended starting doses for U-200 degludec are 10 U once daily for insulin-naïve adults with T2DM and one-third to one-half the total weight-based daily insulin dose for insulin-naïve adults with T1DM.⁴

Recommendations

For some patients, lower PD variability may make degludec a desirable alternative. As degludec retains its efficacy with variable dosing times, it may be ideal for patients who have difficulty with a once-daily dosing schedule. It is important to inform patients that the degludec pen allows for 2-U increments. Given the lower frequency of nocturnal hypoglycemic events with degludec compared with glargine, degludec is an appropriate basal insulin option for patients with nocturnal hypoglycemia. In addition, U-200 degludec may be considered for DM patients who require high doses of basal insulin and who may benefit from smaller volumes of degludec.

U-300 Isulin Glargine

Pharmacokinetics/Pharmacodynamics

U-300 glargine is a concentrated basal insulin. There are notable differences between its U-100 and U-300 concentrations. For U-300 glargine dosed at 0.4 U/kg, duration of action is 24 hours; for U-300 glargine dosed at 0.6 U/kg or higher, longer duration is expected.²⁰ Steady state is reached after 5 days.²¹ The U-300 glargine pen contains 1.5 mL, less than the 3 mL in the U-100 pen. U-300 glargine typically is administered in 1 injection once daily if the dose is < 80 U; 2 injections are required if the dose is > 80 U.

Safety/Efficacy

In the EDITION trials, which compared U-300 and U-100 glargine in patients with T1DM and T2DM, the primary endpoint was 6-month HbA_1c reduction.^22-24 Comparable HbA_1c reductions were found in all of the studies. In EDITION 1, in which 2,474 patients with T2DM were taking concomitant bolus insulin with or without metformin, 11% more U-300 glargine than U-100 glargine was needed to achieve similar results.²² In EDITION 4, in which bolus insulin was used in combination in 546 patients with T1DM, 17.5% more U-300 glargine than U-100 glargine was needed to achieve similar glycemic goals.²⁵

Economic Analysis

Compared with other insulins, U-300 glargine has limited published data and economic analyses. Using a cost-utility model to compare U-300 with U-100 glargine in Spanish patients with T2DM, and reporting results in euros per quality-adjusted life years, Monero and colleagues concluded that the hypoglycemia reduction and possible time-of-dose flexibility found with U-300 glargine may contribute to its cost-effectiveness.²⁶

Dosing

U-300 glargine should be converted in a 1:1 ratio from U-100 glargine or detemir. The U-300 glargine dose should be reduced by 20% when switching from NPH insulin.²¹

Recommendations

A meta-analysis of the EDITION trials 1 to 3 revealed a lower incidence of daytime and nocturnal hypoglycemia with use of U-300 glargine over U-100 glargine and a beneficial shorter hold time after injection of U-300 glargine (5 seconds) compared with U-100 glargine (10 seconds).²⁷ There was statistically lower weight gain with U-300 glargine compared with U-100 glargine however weight gain was < 1 kg in both groups.²⁷ These characteristics of U-300 glargine may prove advantageous for individual patients.

U-500 Insulin

Pharmacokinetics/Pharmacodynamics

U-500 insulin (Humulin R) has been available in a vial since 1997, but other formulations have been used therapeutically since 1952.²⁸ The U-500 KwikPen device, recently added to the market, has improved the vial and syringe dosing. The new U-500 BD (Becton, Dickinson, Franklin Lakes, NJ) syringes allow doses up to 250 U, and the U-500 KwikPens provide up to 300 U per injection.²⁹ When it was first introduced, U-500 insulin had no dedicated delivery device and dose conversion was required to deliver the appropriate dose using an allergy or TB syringe. As a consequence, confusion often resulted between prescribers, pharmacists and patients.^30,31 U-500 insulin acts as basal and bolus insulins do. Onset of action is ~15 minutes, time to peak is 4 to 8 hours, and duration of action is ≤ 21 hours.³² As its onset of action is similar to that of U-100, U-500 should be injected 30 minutes before meals.

A single-site, randomized, double-blind, crossover euglycemic clamp study that compared equivalent doses of U-500 and U-100 in healthy obese patients found the formulations had similar overall exposures and effects—the only differences were that U-500 had an extended time to peak and a prolonged post-peak effect. The longer post-peak effect contributes to longer duration of action and allows for fewer daily injections.³³

Safety/Efficacy

In the Humulin R U-500 Initiation trial, both of these algorithms improved glycemic control and were associated with a low incidence of severe hypoglycemia. In addition, the associated weight gains were similar. Last, the rate of nonsevere hypoglycemia was slightly lower for the 3-times-daily than for the 2-times-daily regimen.³⁴ A real-world outcome analysis of U-500 initiation confirmed the benefits of switching from U-100 to U-500. A clinically significant improvement in glycemic control was found in all the study participants. Dose and frequency of administration, however, were not reported.³⁵

According to a secondary analysis in the Humulin R U-500 Initiation trial, baseline U-100 total daily dose did not yield a difference in efficacy or safety between the 2-times-a-day and 3-times-a-day arms—allowing use of a simpler 2-times-a-day schedule without regard to baseline total daily dose.^28,36 The 2-times-a-day regimen is preferred in clinical practice given that the 2 regimens are equivalent in safety and efficacy and that the 2-times-a-day regimen is simpler, allows for easier titrations, improves patient perceptions of the effect of insulin on daily life function and psychological health, lowers daily injection burden, and maximizes adherence.³⁷

Economic Analysis

A retrospective database analysis revealed lower overall cost and lower pharmacy cost associated with U-500 in comparison with high-dose U-100, as well as reduced hypoglycemia-specific costs or resource utilization, even though U-500 was associated with a slightly higher incidence of hypoglycemia.²⁸ However, the fact that hypoglycemia was reported with a billing code (ICD-9) implies the hypoglycemic event was severe enough to require medical attention. Given these findings, 2-times-a-day U-500 seems more cost-effective than high-dose U-100.

Dosing

The U-500 Humulin R package insert recommends converting a dose to U-500 on the basis of most recent HbA_1c level. U-500 can be dosed 2 times daily (60%, 40%) or 3 times daily (40%, 30%, 30%). If HbA_1c is > 8%, then the starting total daily dose (TDD) of U-500 is 100% of the U-100 TDD. If HbA_1c is ≤ 8%, then the starting TDD of U-500 is 80% of the final U-100 TDD (20% reduction). Dose adjustments may range from 5% to 10% depending on subsequent blood glucose readings.³²

Recommendations

U-500 is a safe and effective monotherapy alternative for patients who require high doses of U-100. Initial conversion from U-100 is based on HbA_1c level. The total daily dose of U-500 is then divided by 2 (60%, 40%) or 3 (40%, 30%, 30%). The 2-times-a-day regimen enhances adherence and thus may be preferred.

Discussion

It has been suggested that large volumes or depots of insulin approaching 100 units impedes absorption and are more painful compared with smaller volume injections.³⁷ For patients with DM who require higher doses of insulin, concentrated insulins offer the advantage of smaller volumes. Also smaller volumes are a substantial benefit in addressing the growing epidemic of DM and the progressive nature of insulin resistance. Furthermore, concentrated insulins are available in pens. Compared with syringes and vials, pens are associated with a lower risk of dosing errors. The major advantages to the use of concentrated insulins include patient acceptability and the potential for decreased volumes and frequency of injections.

Potential disadvantages also exist for the use of concentrated insulins. Depending on insurance coverage, concentrated insulins may be more expensive than U-100 insulin options. Additionally, thorough counseling and education are of paramount importance when concentrated insulins are initiated or switched in patients with DM. The dosing errors that occur with concentrated insulins could increase the risk of hypoglycemia. Pharmacists should provide detailed counseling to DM patients initiating or switching concentrated insulins. It is important to implement or revise institution and clinic safe practices for concentrated insulins to avoid errors in prescribing, distributing, administering, and monitoring these medications.

Conclusion

Concentrated insulins provide expanded treatment options for patients with DM. Clinicians must stay well informed about concentrated insulin characteristics and dosing strategies to optimize DM treatment. As more evidence becomes available, standardized recommendations can be developed to guide clinicians in the appropriate use of concentrated insulins.

Click here to read the digital edition.

For a long time, 500 U/mL (U-500) insulin was the only concentrated insulin available on the market. With many diabetes mellitus (DM) patients requiring larger doses, additional 200 U/mL (U-200) and 300 U/mL (U-300) concentrations became available. As clinical guidelines lack specific recommendations for optimal use of U-200 and U-300 insulins, clinical discretion is warranted in identifying patients for whom use of these insulins is appropriate. U-500 insulin is recommended in cases that require ≥ 200 U/d or > 2 U/kg/d. Given the ongoing DM and obesity epidemics, increased use of concentrated insulins is likely. Clinicians must stay well informed about the characteristics and benefits of concentrated insulins to remain confident recommending, prescribing, and adjusting these medications.

U-200 Insulin Lispro

Pharmacokinetics/Pharmacodynamics

The amino acid structure of U-200 insulin lispro is different from that of endogenous insulin. In U-200 lispro, lysine replaces a proline at position B28, and proline replaces a lysine at position B29.

In a euglycemic clamp study of patients without DM, a 20-U dose of U-200 lispro and a single 20-U dose of U-100 lispro were found to have similar mean area under the glucose infusion rate curves, mean area under the serum insulin concentration-time curves from time 0 to infinity, mean peak serum insulin levels, and time to maximum glucose-lowering effects.¹ For both U-200 lispro and U-100 lispro, time to maximum effect was 1 hour.²

Even numbers are marked on the dial of the pen. Odd numbers are not marked, but longer lines appear in their place. U-200 lispro should not be mixed with any other insulin, whereas U-100 lispro can be mixed with neutral protamine Hagedorn insulin.

Safety/Efficacy

There has been 1 bioequivalence study of euglycemic patients without type 2 DM (T2DM) but no studies of the safety or efficacy of U-200 lispro in patients with DM.^3,4 U-100 lispro converts 1:1 to U-200 lispro (eg, 60 U of U-100 lispro converts to 60 U of U-200 lispro).¹ The volume of U-200 lispro would be smaller than that of U-100 lispro.

Economic Analysis

There are no published U-200 lispro economic analyses.

Dosing

U-200 lispro should be converted from other bolus insulins in a 1:1 ratio.¹

Recommendations

Definitive recommendations await efficacy trials comparing use of U-200 lispro and other bolus insulins in patients with DM. Currently, U-200 lispro may be considered for patients with DM who require high doses of bolus insulin and who may benefit from smaller volumes of lispro.

U-200 Insulin Degludec

Pharmacokinetics/Pharmacodynamics

The basal insulin degludec (Tresiba) is available in U-100 and U-200 concentrations in a pen. After subcutaneous injection, degludec forms gradually dissociating multihexamer chains, which account for its flat and stable PK/PD profile. U-100 degludec and U-200 degludec have similar duration of action (≥ 42 hours) and time to steady state (2-3 days).^5,6 A patient who misses a regularly scheduled dose should allow at least 8 hours between injections. Taking degludec at variable times does not decrease efficacy as long as this 8-hour minimum interval is observed.⁷

Safety/Efficacy

During its development, degludec was evaluated in more than 5,000 patients across 11 therapeutic trials.⁸ The key studies that led to the approval of degludec used insulin glargine as a comparator. In a 52-week study of 1,030 insulin-naïve patients with T2DM, degludec was noninferior to glargine in hemoglobin A_1c (HbA_1c) reduction (1.06% vs 1.19%). Overall hypoglycemia rates were similar, though there were fewer nocturnal hypoglycemia episodes with degludec than with glargine (0.25 vs 0.39 per patient-year of exposure; P = .38).⁹

The BEGIN Basal-Bolus trial series evaluated use of degludec combined with bolus insulin aspart in insulin-experienced patients with T2DM (n = 992) and type 1 DM (T1DM) (n = 629) over 52 weeks.^10,11 Both trials found noninferiority in A_1c reduction: 1.1% (degludec) and 1.18% (glargine) in patients with T2DM and 0.4% (degludec) and 0.39% (glargine) in those with T1DM.^10,11 Significantly fewer episodes of overall hypoglycemia (11.09 vs 13.63 per patient-year) and nocturnal hypoglycemia (1.39 vs 1.84 per patient-year) were found with degludec in patients with T2DM.⁵ Overall hypoglycemia rates were similar, though there was a 25% lower rate of nocturnal hypoglycemia with degludec in patients with T1DM.¹¹

A meta-analysis of 7 phase 3a trials that compared degludec with glargine revealed significantly lower rates of overall, nocturnal, and severe hypoglycemia with degludec in insulin-naïve patients.¹² The analysis confirmed findings of significantly lower rates of overall and nocturnal hypoglycemia with degludec in the overall T2DM population and significantly lower rates of nocturnal hypoglycemia in the T1DM population.¹²

In the DEVOTE trial, which included 7,637 T2DM patients at high risk for a cardiovascular event, degludec and glargine were compared on the composite primary outcome of death with a cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke. After a median of 1.99 years, the primary outcome occurred in 8.5% of degludec patients and 9.3% of glargine patients (hazard ratio, 0.91; 95% confidence interval, 0.78-1.06; P < .001 for noninferiority). Mean HbA_1c level was 7.5 in both groups; severe hypoglycemia occurred more often in the glargine group (odds ratio, 0.73; P < .001 for superiority).¹³ Findings from the randomized, crossover SWITCH 1 and SWITCH 2 trials confirmed lower rates of symptomatic hypoglycemia with degludec compared with glargine in patients with T1DM and T2DM, respectively.^14,15 No statistically significant differences in weight gain were observed in the clinical trials comparing degludec and glargine.

Economic Analysis

Weatherall and colleagues used a budget impact model to evaluate the costs of degludec and glargine for commercially insured patients with DM in the U.S.¹⁶ Three treatment groups were analyzed: basal/bolus combination in T1DM and T2DM, and basal/oral combination in T2DM. Although degludec cost more, overall cost was reduced in T1DM because of reduced insulin usage and fewer hypoglycemic episodes in T2DM with basal/oral combination therapy. The authors acknowledged the many assumptions needed and the potential oversimplification of their model.¹⁶ In other countries, economic analyses had similar findings.^17-19

Dosing

Degludec converts 1:1 to other basal insulins. Recommended starting doses for U-200 degludec are 10 U once daily for insulin-naïve adults with T2DM and one-third to one-half the total weight-based daily insulin dose for insulin-naïve adults with T1DM.⁴

Recommendations

For some patients, lower PD variability may make degludec a desirable alternative. As degludec retains its efficacy with variable dosing times, it may be ideal for patients who have difficulty with a once-daily dosing schedule. It is important to inform patients that the degludec pen allows for 2-U increments. Given the lower frequency of nocturnal hypoglycemic events with degludec compared with glargine, degludec is an appropriate basal insulin option for patients with nocturnal hypoglycemia. In addition, U-200 degludec may be considered for DM patients who require high doses of basal insulin and who may benefit from smaller volumes of degludec.

U-300 Isulin Glargine

Pharmacokinetics/Pharmacodynamics

U-300 glargine is a concentrated basal insulin. There are notable differences between its U-100 and U-300 concentrations. For U-300 glargine dosed at 0.4 U/kg, duration of action is 24 hours; for U-300 glargine dosed at 0.6 U/kg or higher, longer duration is expected.²⁰ Steady state is reached after 5 days.²¹ The U-300 glargine pen contains 1.5 mL, less than the 3 mL in the U-100 pen. U-300 glargine typically is administered in 1 injection once daily if the dose is < 80 U; 2 injections are required if the dose is > 80 U.

Safety/Efficacy

In the EDITION trials, which compared U-300 and U-100 glargine in patients with T1DM and T2DM, the primary endpoint was 6-month HbA_1c reduction.^22-24 Comparable HbA_1c reductions were found in all of the studies. In EDITION 1, in which 2,474 patients with T2DM were taking concomitant bolus insulin with or without metformin, 11% more U-300 glargine than U-100 glargine was needed to achieve similar results.²² In EDITION 4, in which bolus insulin was used in combination in 546 patients with T1DM, 17.5% more U-300 glargine than U-100 glargine was needed to achieve similar glycemic goals.²⁵

Economic Analysis

Compared with other insulins, U-300 glargine has limited published data and economic analyses. Using a cost-utility model to compare U-300 with U-100 glargine in Spanish patients with T2DM, and reporting results in euros per quality-adjusted life years, Monero and colleagues concluded that the hypoglycemia reduction and possible time-of-dose flexibility found with U-300 glargine may contribute to its cost-effectiveness.²⁶

Dosing

U-300 glargine should be converted in a 1:1 ratio from U-100 glargine or detemir. The U-300 glargine dose should be reduced by 20% when switching from NPH insulin.²¹

Recommendations

A meta-analysis of the EDITION trials 1 to 3 revealed a lower incidence of daytime and nocturnal hypoglycemia with use of U-300 glargine over U-100 glargine and a beneficial shorter hold time after injection of U-300 glargine (5 seconds) compared with U-100 glargine (10 seconds).²⁷ There was statistically lower weight gain with U-300 glargine compared with U-100 glargine however weight gain was < 1 kg in both groups.²⁷ These characteristics of U-300 glargine may prove advantageous for individual patients.

U-500 Insulin

Pharmacokinetics/Pharmacodynamics

U-500 insulin (Humulin R) has been available in a vial since 1997, but other formulations have been used therapeutically since 1952.²⁸ The U-500 KwikPen device, recently added to the market, has improved the vial and syringe dosing. The new U-500 BD (Becton, Dickinson, Franklin Lakes, NJ) syringes allow doses up to 250 U, and the U-500 KwikPens provide up to 300 U per injection.²⁹ When it was first introduced, U-500 insulin had no dedicated delivery device and dose conversion was required to deliver the appropriate dose using an allergy or TB syringe. As a consequence, confusion often resulted between prescribers, pharmacists and patients.^30,31 U-500 insulin acts as basal and bolus insulins do. Onset of action is ~15 minutes, time to peak is 4 to 8 hours, and duration of action is ≤ 21 hours.³² As its onset of action is similar to that of U-100, U-500 should be injected 30 minutes before meals.

A single-site, randomized, double-blind, crossover euglycemic clamp study that compared equivalent doses of U-500 and U-100 in healthy obese patients found the formulations had similar overall exposures and effects—the only differences were that U-500 had an extended time to peak and a prolonged post-peak effect. The longer post-peak effect contributes to longer duration of action and allows for fewer daily injections.³³

Safety/Efficacy

In the Humulin R U-500 Initiation trial, both of these algorithms improved glycemic control and were associated with a low incidence of severe hypoglycemia. In addition, the associated weight gains were similar. Last, the rate of nonsevere hypoglycemia was slightly lower for the 3-times-daily than for the 2-times-daily regimen.³⁴ A real-world outcome analysis of U-500 initiation confirmed the benefits of switching from U-100 to U-500. A clinically significant improvement in glycemic control was found in all the study participants. Dose and frequency of administration, however, were not reported.³⁵

According to a secondary analysis in the Humulin R U-500 Initiation trial, baseline U-100 total daily dose did not yield a difference in efficacy or safety between the 2-times-a-day and 3-times-a-day arms—allowing use of a simpler 2-times-a-day schedule without regard to baseline total daily dose.^28,36 The 2-times-a-day regimen is preferred in clinical practice given that the 2 regimens are equivalent in safety and efficacy and that the 2-times-a-day regimen is simpler, allows for easier titrations, improves patient perceptions of the effect of insulin on daily life function and psychological health, lowers daily injection burden, and maximizes adherence.³⁷

Economic Analysis

A retrospective database analysis revealed lower overall cost and lower pharmacy cost associated with U-500 in comparison with high-dose U-100, as well as reduced hypoglycemia-specific costs or resource utilization, even though U-500 was associated with a slightly higher incidence of hypoglycemia.²⁸ However, the fact that hypoglycemia was reported with a billing code (ICD-9) implies the hypoglycemic event was severe enough to require medical attention. Given these findings, 2-times-a-day U-500 seems more cost-effective than high-dose U-100.

Dosing

The U-500 Humulin R package insert recommends converting a dose to U-500 on the basis of most recent HbA_1c level. U-500 can be dosed 2 times daily (60%, 40%) or 3 times daily (40%, 30%, 30%). If HbA_1c is > 8%, then the starting total daily dose (TDD) of U-500 is 100% of the U-100 TDD. If HbA_1c is ≤ 8%, then the starting TDD of U-500 is 80% of the final U-100 TDD (20% reduction). Dose adjustments may range from 5% to 10% depending on subsequent blood glucose readings.³²

Recommendations

U-500 is a safe and effective monotherapy alternative for patients who require high doses of U-100. Initial conversion from U-100 is based on HbA_1c level. The total daily dose of U-500 is then divided by 2 (60%, 40%) or 3 (40%, 30%, 30%). The 2-times-a-day regimen enhances adherence and thus may be preferred.

Discussion

It has been suggested that large volumes or depots of insulin approaching 100 units impedes absorption and are more painful compared with smaller volume injections.³⁷ For patients with DM who require higher doses of insulin, concentrated insulins offer the advantage of smaller volumes. Also smaller volumes are a substantial benefit in addressing the growing epidemic of DM and the progressive nature of insulin resistance. Furthermore, concentrated insulins are available in pens. Compared with syringes and vials, pens are associated with a lower risk of dosing errors. The major advantages to the use of concentrated insulins include patient acceptability and the potential for decreased volumes and frequency of injections.

Potential disadvantages also exist for the use of concentrated insulins. Depending on insurance coverage, concentrated insulins may be more expensive than U-100 insulin options. Additionally, thorough counseling and education are of paramount importance when concentrated insulins are initiated or switched in patients with DM. The dosing errors that occur with concentrated insulins could increase the risk of hypoglycemia. Pharmacists should provide detailed counseling to DM patients initiating or switching concentrated insulins. It is important to implement or revise institution and clinic safe practices for concentrated insulins to avoid errors in prescribing, distributing, administering, and monitoring these medications.

Conclusion

Concentrated insulins provide expanded treatment options for patients with DM. Clinicians must stay well informed about concentrated insulin characteristics and dosing strategies to optimize DM treatment. As more evidence becomes available, standardized recommendations can be developed to guide clinicians in the appropriate use of concentrated insulins.

Click here to read the digital edition.

For a long time, 500 U/mL (U-500) insulin was the only concentrated insulin available on the market. With many diabetes mellitus (DM) patients requiring larger doses, additional 200 U/mL (U-200) and 300 U/mL (U-300) concentrations became available. As clinical guidelines lack specific recommendations for optimal use of U-200 and U-300 insulins, clinical discretion is warranted in identifying patients for whom use of these insulins is appropriate. U-500 insulin is recommended in cases that require ≥ 200 U/d or > 2 U/kg/d. Given the ongoing DM and obesity epidemics, increased use of concentrated insulins is likely. Clinicians must stay well informed about the characteristics and benefits of concentrated insulins to remain confident recommending, prescribing, and adjusting these medications.

U-200 Insulin Lispro

Pharmacokinetics/Pharmacodynamics

The amino acid structure of U-200 insulin lispro is different from that of endogenous insulin. In U-200 lispro, lysine replaces a proline at position B28, and proline replaces a lysine at position B29.

In a euglycemic clamp study of patients without DM, a 20-U dose of U-200 lispro and a single 20-U dose of U-100 lispro were found to have similar mean area under the glucose infusion rate curves, mean area under the serum insulin concentration-time curves from time 0 to infinity, mean peak serum insulin levels, and time to maximum glucose-lowering effects.¹ For both U-200 lispro and U-100 lispro, time to maximum effect was 1 hour.²

Even numbers are marked on the dial of the pen. Odd numbers are not marked, but longer lines appear in their place. U-200 lispro should not be mixed with any other insulin, whereas U-100 lispro can be mixed with neutral protamine Hagedorn insulin.

Safety/Efficacy

There has been 1 bioequivalence study of euglycemic patients without type 2 DM (T2DM) but no studies of the safety or efficacy of U-200 lispro in patients with DM.^3,4 U-100 lispro converts 1:1 to U-200 lispro (eg, 60 U of U-100 lispro converts to 60 U of U-200 lispro).¹ The volume of U-200 lispro would be smaller than that of U-100 lispro.

Economic Analysis

There are no published U-200 lispro economic analyses.

Dosing

U-200 lispro should be converted from other bolus insulins in a 1:1 ratio.¹

Recommendations

Definitive recommendations await efficacy trials comparing use of U-200 lispro and other bolus insulins in patients with DM. Currently, U-200 lispro may be considered for patients with DM who require high doses of bolus insulin and who may benefit from smaller volumes of lispro.

U-200 Insulin Degludec

Pharmacokinetics/Pharmacodynamics

The basal insulin degludec (Tresiba) is available in U-100 and U-200 concentrations in a pen. After subcutaneous injection, degludec forms gradually dissociating multihexamer chains, which account for its flat and stable PK/PD profile. U-100 degludec and U-200 degludec have similar duration of action (≥ 42 hours) and time to steady state (2-3 days).^5,6 A patient who misses a regularly scheduled dose should allow at least 8 hours between injections. Taking degludec at variable times does not decrease efficacy as long as this 8-hour minimum interval is observed.⁷

Safety/Efficacy

During its development, degludec was evaluated in more than 5,000 patients across 11 therapeutic trials.⁸ The key studies that led to the approval of degludec used insulin glargine as a comparator. In a 52-week study of 1,030 insulin-naïve patients with T2DM, degludec was noninferior to glargine in hemoglobin A_1c (HbA_1c) reduction (1.06% vs 1.19%). Overall hypoglycemia rates were similar, though there were fewer nocturnal hypoglycemia episodes with degludec than with glargine (0.25 vs 0.39 per patient-year of exposure; P = .38).⁹

The BEGIN Basal-Bolus trial series evaluated use of degludec combined with bolus insulin aspart in insulin-experienced patients with T2DM (n = 992) and type 1 DM (T1DM) (n = 629) over 52 weeks.^10,11 Both trials found noninferiority in A_1c reduction: 1.1% (degludec) and 1.18% (glargine) in patients with T2DM and 0.4% (degludec) and 0.39% (glargine) in those with T1DM.^10,11 Significantly fewer episodes of overall hypoglycemia (11.09 vs 13.63 per patient-year) and nocturnal hypoglycemia (1.39 vs 1.84 per patient-year) were found with degludec in patients with T2DM.⁵ Overall hypoglycemia rates were similar, though there was a 25% lower rate of nocturnal hypoglycemia with degludec in patients with T1DM.¹¹

A meta-analysis of 7 phase 3a trials that compared degludec with glargine revealed significantly lower rates of overall, nocturnal, and severe hypoglycemia with degludec in insulin-naïve patients.¹² The analysis confirmed findings of significantly lower rates of overall and nocturnal hypoglycemia with degludec in the overall T2DM population and significantly lower rates of nocturnal hypoglycemia in the T1DM population.¹²

In the DEVOTE trial, which included 7,637 T2DM patients at high risk for a cardiovascular event, degludec and glargine were compared on the composite primary outcome of death with a cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke. After a median of 1.99 years, the primary outcome occurred in 8.5% of degludec patients and 9.3% of glargine patients (hazard ratio, 0.91; 95% confidence interval, 0.78-1.06; P < .001 for noninferiority). Mean HbA_1c level was 7.5 in both groups; severe hypoglycemia occurred more often in the glargine group (odds ratio, 0.73; P < .001 for superiority).¹³ Findings from the randomized, crossover SWITCH 1 and SWITCH 2 trials confirmed lower rates of symptomatic hypoglycemia with degludec compared with glargine in patients with T1DM and T2DM, respectively.^14,15 No statistically significant differences in weight gain were observed in the clinical trials comparing degludec and glargine.

Economic Analysis

Weatherall and colleagues used a budget impact model to evaluate the costs of degludec and glargine for commercially insured patients with DM in the U.S.¹⁶ Three treatment groups were analyzed: basal/bolus combination in T1DM and T2DM, and basal/oral combination in T2DM. Although degludec cost more, overall cost was reduced in T1DM because of reduced insulin usage and fewer hypoglycemic episodes in T2DM with basal/oral combination therapy. The authors acknowledged the many assumptions needed and the potential oversimplification of their model.¹⁶ In other countries, economic analyses had similar findings.^17-19

Dosing

Degludec converts 1:1 to other basal insulins. Recommended starting doses for U-200 degludec are 10 U once daily for insulin-naïve adults with T2DM and one-third to one-half the total weight-based daily insulin dose for insulin-naïve adults with T1DM.⁴

Recommendations

For some patients, lower PD variability may make degludec a desirable alternative. As degludec retains its efficacy with variable dosing times, it may be ideal for patients who have difficulty with a once-daily dosing schedule. It is important to inform patients that the degludec pen allows for 2-U increments. Given the lower frequency of nocturnal hypoglycemic events with degludec compared with glargine, degludec is an appropriate basal insulin option for patients with nocturnal hypoglycemia. In addition, U-200 degludec may be considered for DM patients who require high doses of basal insulin and who may benefit from smaller volumes of degludec.

U-300 Isulin Glargine

Pharmacokinetics/Pharmacodynamics

U-300 glargine is a concentrated basal insulin. There are notable differences between its U-100 and U-300 concentrations. For U-300 glargine dosed at 0.4 U/kg, duration of action is 24 hours; for U-300 glargine dosed at 0.6 U/kg or higher, longer duration is expected.²⁰ Steady state is reached after 5 days.²¹ The U-300 glargine pen contains 1.5 mL, less than the 3 mL in the U-100 pen. U-300 glargine typically is administered in 1 injection once daily if the dose is < 80 U; 2 injections are required if the dose is > 80 U.

Safety/Efficacy

In the EDITION trials, which compared U-300 and U-100 glargine in patients with T1DM and T2DM, the primary endpoint was 6-month HbA_1c reduction.^22-24 Comparable HbA_1c reductions were found in all of the studies. In EDITION 1, in which 2,474 patients with T2DM were taking concomitant bolus insulin with or without metformin, 11% more U-300 glargine than U-100 glargine was needed to achieve similar results.²² In EDITION 4, in which bolus insulin was used in combination in 546 patients with T1DM, 17.5% more U-300 glargine than U-100 glargine was needed to achieve similar glycemic goals.²⁵

Economic Analysis

Compared with other insulins, U-300 glargine has limited published data and economic analyses. Using a cost-utility model to compare U-300 with U-100 glargine in Spanish patients with T2DM, and reporting results in euros per quality-adjusted life years, Monero and colleagues concluded that the hypoglycemia reduction and possible time-of-dose flexibility found with U-300 glargine may contribute to its cost-effectiveness.²⁶

Dosing

U-300 glargine should be converted in a 1:1 ratio from U-100 glargine or detemir. The U-300 glargine dose should be reduced by 20% when switching from NPH insulin.²¹

Recommendations

A meta-analysis of the EDITION trials 1 to 3 revealed a lower incidence of daytime and nocturnal hypoglycemia with use of U-300 glargine over U-100 glargine and a beneficial shorter hold time after injection of U-300 glargine (5 seconds) compared with U-100 glargine (10 seconds).²⁷ There was statistically lower weight gain with U-300 glargine compared with U-100 glargine however weight gain was < 1 kg in both groups.²⁷ These characteristics of U-300 glargine may prove advantageous for individual patients.

U-500 Insulin

Pharmacokinetics/Pharmacodynamics

U-500 insulin (Humulin R) has been available in a vial since 1997, but other formulations have been used therapeutically since 1952.²⁸ The U-500 KwikPen device, recently added to the market, has improved the vial and syringe dosing. The new U-500 BD (Becton, Dickinson, Franklin Lakes, NJ) syringes allow doses up to 250 U, and the U-500 KwikPens provide up to 300 U per injection.²⁹ When it was first introduced, U-500 insulin had no dedicated delivery device and dose conversion was required to deliver the appropriate dose using an allergy or TB syringe. As a consequence, confusion often resulted between prescribers, pharmacists and patients.^30,31 U-500 insulin acts as basal and bolus insulins do. Onset of action is ~15 minutes, time to peak is 4 to 8 hours, and duration of action is ≤ 21 hours.³² As its onset of action is similar to that of U-100, U-500 should be injected 30 minutes before meals.

A single-site, randomized, double-blind, crossover euglycemic clamp study that compared equivalent doses of U-500 and U-100 in healthy obese patients found the formulations had similar overall exposures and effects—the only differences were that U-500 had an extended time to peak and a prolonged post-peak effect. The longer post-peak effect contributes to longer duration of action and allows for fewer daily injections.³³

Safety/Efficacy

In the Humulin R U-500 Initiation trial, both of these algorithms improved glycemic control and were associated with a low incidence of severe hypoglycemia. In addition, the associated weight gains were similar. Last, the rate of nonsevere hypoglycemia was slightly lower for the 3-times-daily than for the 2-times-daily regimen.³⁴ A real-world outcome analysis of U-500 initiation confirmed the benefits of switching from U-100 to U-500. A clinically significant improvement in glycemic control was found in all the study participants. Dose and frequency of administration, however, were not reported.³⁵

According to a secondary analysis in the Humulin R U-500 Initiation trial, baseline U-100 total daily dose did not yield a difference in efficacy or safety between the 2-times-a-day and 3-times-a-day arms—allowing use of a simpler 2-times-a-day schedule without regard to baseline total daily dose.^28,36 The 2-times-a-day regimen is preferred in clinical practice given that the 2 regimens are equivalent in safety and efficacy and that the 2-times-a-day regimen is simpler, allows for easier titrations, improves patient perceptions of the effect of insulin on daily life function and psychological health, lowers daily injection burden, and maximizes adherence.³⁷

Economic Analysis

A retrospective database analysis revealed lower overall cost and lower pharmacy cost associated with U-500 in comparison with high-dose U-100, as well as reduced hypoglycemia-specific costs or resource utilization, even though U-500 was associated with a slightly higher incidence of hypoglycemia.²⁸ However, the fact that hypoglycemia was reported with a billing code (ICD-9) implies the hypoglycemic event was severe enough to require medical attention. Given these findings, 2-times-a-day U-500 seems more cost-effective than high-dose U-100.

Dosing

The U-500 Humulin R package insert recommends converting a dose to U-500 on the basis of most recent HbA_1c level. U-500 can be dosed 2 times daily (60%, 40%) or 3 times daily (40%, 30%, 30%). If HbA_1c is > 8%, then the starting total daily dose (TDD) of U-500 is 100% of the U-100 TDD. If HbA_1c is ≤ 8%, then the starting TDD of U-500 is 80% of the final U-100 TDD (20% reduction). Dose adjustments may range from 5% to 10% depending on subsequent blood glucose readings.³²

Recommendations

U-500 is a safe and effective monotherapy alternative for patients who require high doses of U-100. Initial conversion from U-100 is based on HbA_1c level. The total daily dose of U-500 is then divided by 2 (60%, 40%) or 3 (40%, 30%, 30%). The 2-times-a-day regimen enhances adherence and thus may be preferred.

Discussion

It has been suggested that large volumes or depots of insulin approaching 100 units impedes absorption and are more painful compared with smaller volume injections.³⁷ For patients with DM who require higher doses of insulin, concentrated insulins offer the advantage of smaller volumes. Also smaller volumes are a substantial benefit in addressing the growing epidemic of DM and the progressive nature of insulin resistance. Furthermore, concentrated insulins are available in pens. Compared with syringes and vials, pens are associated with a lower risk of dosing errors. The major advantages to the use of concentrated insulins include patient acceptability and the potential for decreased volumes and frequency of injections.

Potential disadvantages also exist for the use of concentrated insulins. Depending on insurance coverage, concentrated insulins may be more expensive than U-100 insulin options. Additionally, thorough counseling and education are of paramount importance when concentrated insulins are initiated or switched in patients with DM. The dosing errors that occur with concentrated insulins could increase the risk of hypoglycemia. Pharmacists should provide detailed counseling to DM patients initiating or switching concentrated insulins. It is important to implement or revise institution and clinic safe practices for concentrated insulins to avoid errors in prescribing, distributing, administering, and monitoring these medications.

Conclusion

Concentrated insulins provide expanded treatment options for patients with DM. Clinicians must stay well informed about concentrated insulin characteristics and dosing strategies to optimize DM treatment. As more evidence becomes available, standardized recommendations can be developed to guide clinicians in the appropriate use of concentrated insulins.

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Supplement to The Journal of Family Practice

Financial support provided by Sanofi US, Inc.

Vol. 67, No. 10  |  OCTOBER 2018

This video roundtable was peer reviewed by The Journal of Family Practice.

CLICK HERE TO VIEW THE VIDEOS

Abstract

Data suggest that in patients with type 2 diabetes, there has been little or no improvement in glycated hemoglobin (A1C) and other glycemic parameters over recent decades. In this digital roundtable discussion, the speakers address challenges faced every day in clinical practice, and provide practical advice regarding how primary care clinicians can overcome clinical inertia. The speakers particularly focus on how to manage patients who are treated with basal insulin, yet are unable to achieve good glycemic control. The discussion is broken down into 3 main parts.

First, the speakers discuss reasons why clinicians don’t move forward with therapy. These reasons may include not recognizing the importance of treatment intensification, clinicians' concerns about hypoglycemia in their patients, and delays in initiating injectable therapy.

Second, the speakers discuss when clinicians should move forward with therapy. American Diabetes Association (ADA) guidelines state that patients who do not meet A1C goals on current medication should intensify therapy with­in 3 months. Importantly, patients intensifying oral antidia­betic drugs therapy with basal insulin who do not achieve A1C goals of <7% within 12 months have been shown to have a very low conditional probability to do so thereafter, highlighting the importance of timely intensification.

Finally, the speakers discuss options for therapeutic inten­sification, and their respective benefits and risks. These options include glucagon-like peptide-1 receptor agonists (GLP-1 RAs), fixed-ratio combinations of basal insulin and GLP-1 RA, bas­al/bolus insulin, and continued basal insulin titration. Fur­ther, the speakers discuss the role of patient counseling and how clinicians can be supported in patient management.

CLICK HERE TO VIEW THE VIDEOS

About the panel

Disclosures

Acknowledgements

The authors wish to acknowledge the comments and review provided by Miss Davida Kruger. This review was funded by Sanofi US, Inc. The authors received writing/editorial support in the preparation of this material provided by Michael Van der Veer, PhD, of Excerpta Medica, funded by Sanofi US, Inc.

CLICK HERE TO VIEW THE VIDEOS

Supplement to The Journal of Family Practice

Financial support provided by Sanofi US, Inc.

Vol. 67, No. 10  |  OCTOBER 2018

This video roundtable was peer reviewed by The Journal of Family Practice.

CLICK HERE TO VIEW THE VIDEOS

Abstract

Data suggest that in patients with type 2 diabetes, there has been little or no improvement in glycated hemoglobin (A1C) and other glycemic parameters over recent decades. In this digital roundtable discussion, the speakers address challenges faced every day in clinical practice, and provide practical advice regarding how primary care clinicians can overcome clinical inertia. The speakers particularly focus on how to manage patients who are treated with basal insulin, yet are unable to achieve good glycemic control. The discussion is broken down into 3 main parts.

First, the speakers discuss reasons why clinicians don’t move forward with therapy. These reasons may include not recognizing the importance of treatment intensification, clinicians' concerns about hypoglycemia in their patients, and delays in initiating injectable therapy.

Second, the speakers discuss when clinicians should move forward with therapy. American Diabetes Association (ADA) guidelines state that patients who do not meet A1C goals on current medication should intensify therapy with­in 3 months. Importantly, patients intensifying oral antidia­betic drugs therapy with basal insulin who do not achieve A1C goals of <7% within 12 months have been shown to have a very low conditional probability to do so thereafter, highlighting the importance of timely intensification.

Finally, the speakers discuss options for therapeutic inten­sification, and their respective benefits and risks. These options include glucagon-like peptide-1 receptor agonists (GLP-1 RAs), fixed-ratio combinations of basal insulin and GLP-1 RA, bas­al/bolus insulin, and continued basal insulin titration. Fur­ther, the speakers discuss the role of patient counseling and how clinicians can be supported in patient management.

CLICK HERE TO VIEW THE VIDEOS

About the panel

Disclosures

Acknowledgements

The authors wish to acknowledge the comments and review provided by Miss Davida Kruger. This review was funded by Sanofi US, Inc. The authors received writing/editorial support in the preparation of this material provided by Michael Van der Veer, PhD, of Excerpta Medica, funded by Sanofi US, Inc.

CLICK HERE TO VIEW THE VIDEOS

Supplement to The Journal of Family Practice

Financial support provided by Sanofi US, Inc.

Vol. 67, No. 10  |  OCTOBER 2018

This video roundtable was peer reviewed by The Journal of Family Practice.

CLICK HERE TO VIEW THE VIDEOS

Abstract

Data suggest that in patients with type 2 diabetes, there has been little or no improvement in glycated hemoglobin (A1C) and other glycemic parameters over recent decades. In this digital roundtable discussion, the speakers address challenges faced every day in clinical practice, and provide practical advice regarding how primary care clinicians can overcome clinical inertia. The speakers particularly focus on how to manage patients who are treated with basal insulin, yet are unable to achieve good glycemic control. The discussion is broken down into 3 main parts.

First, the speakers discuss reasons why clinicians don’t move forward with therapy. These reasons may include not recognizing the importance of treatment intensification, clinicians' concerns about hypoglycemia in their patients, and delays in initiating injectable therapy.

Second, the speakers discuss when clinicians should move forward with therapy. American Diabetes Association (ADA) guidelines state that patients who do not meet A1C goals on current medication should intensify therapy with­in 3 months. Importantly, patients intensifying oral antidia­betic drugs therapy with basal insulin who do not achieve A1C goals of <7% within 12 months have been shown to have a very low conditional probability to do so thereafter, highlighting the importance of timely intensification.

Finally, the speakers discuss options for therapeutic inten­sification, and their respective benefits and risks. These options include glucagon-like peptide-1 receptor agonists (GLP-1 RAs), fixed-ratio combinations of basal insulin and GLP-1 RA, bas­al/bolus insulin, and continued basal insulin titration. Fur­ther, the speakers discuss the role of patient counseling and how clinicians can be supported in patient management.

CLICK HERE TO VIEW THE VIDEOS

About the panel

Disclosures

Acknowledgements

The authors wish to acknowledge the comments and review provided by Miss Davida Kruger. This review was funded by Sanofi US, Inc. The authors received writing/editorial support in the preparation of this material provided by Michael Van der Veer, PhD, of Excerpta Medica, funded by Sanofi US, Inc.

CLICK HERE TO VIEW THE VIDEOS

Diabetes mellitus (DM) is considered one of the most psychologically and behaviorally demanding chronic medical conditions. Patients with DM and serious mental illness (SMI), including schizophrenia, schizoaffective disorder, major depressive disorder (MDD), and bipolar disorder, are more likely to have poor adherence to medications as well as poor adherence to diet and lifestyle recommendations, which can lead to poor glycemic control, decreased quality of life, and increased health care expenses.^1-4 Up to 27% of patients with DM have a depression diagnosis, and up to 60% of patients with DM experience depressive symptoms.⁵ Additionally, 1 in 4 patients with schizophrenia have a DM diagnosis.⁶ Serious mental illness can compromise DM self-management and glycemic control, which increases the risk of DM-related complications.⁷

These factors combine to make DM self-management essential for optimal glycemic control and prevention of DM-related complications. The American Diabetes Association recommends coordinated management of DM and SMI to achieve DM treatment targets.⁸ Interventions involving collaborative care teams have assisted in managing patients with concurrent SMI and DM. Collaborative interventions have reduced all-cause mortality, increased the number of patients reaching hemoglobin A_1c (HbA_1c) targets, increased overall improvement in HbA_1c, increased rates of depression remission, and increased medication adherence.^9-12

Background

Collaborative interventions have improved glycemic control in patients with concurrent SMI and DM. A study by Desai and colleagues examined the relationship between psychiatric disorders and the quality of DM care in a national sample of veterans.⁷ Data were collected using chart-abstracted quality data from administrative database records for a sample of veterans with DM who had at least 3 outpatient visits in the previous year (n = 38,020). About 25% of the sample had a diagnosed psychiatric disorder, 91.5% of veterans completed an HbA_1c test, and most veterans with a psychiatric disorder completed the 5 quality indicators for DM care (foot inspection, HbA_1c determination, pedal pulses examination, foot sensory examination, and retina examination). Veterans with psychiatric disorders did not have a poorer quality of care for secondary prevention of DM compared with that of other veterans.⁷

In the PROSPECT study (Prevention of Suicide in Primary Care Elderly: Collaborative Trial), a primary care-based depression management program assessed a collaborative intervention to improve care in patients with depression and DM.⁹ Fifteen depression care managers, including trained social workers, registered nurses (RNs), and psychologists, collaborated with primary care physicians (PCPs) to assist in recognizing depression, offer guideline-based treatment recommendations, and provide algorithm-based care, monitoring, and follow-up. After a median follow-up of 52 months, patients with depression and DM in the intervention group were less likely to die during the 5-year follow-up period compared with those in usual care (adjusted hazard ratio, 0.49 [95% confidence interval (CI), 0.24-0.98]). The study authors concluded that integrated depression care management significantly reduced all-cause mortality in patients with depression and DM.⁹

A single-blind, randomized, controlled trial conducted by Katon and colleagues examined patients with poorly controlled DM, coronary artery disease (CAD), or both, and concurrent depression in 14 primary care clinics (n = 214).¹⁰ The intervention consisted of nurse care managers who were trained RNs with experience in DM education and supervised by PCPs, providing guideline-based, collaborative care over 12 months to improve glycemic control, blood pressure (BP), and lipid control. The nurse care managers followed up with patients every 2 to3 weeks at office visits, and the intervention was compared with usual care by a physician. At 12 months, patients in the intervention group had significant improvement in HbA_1c, low-density lipoprotein cholesterol, systolic BP, and depression compared with that of those under usual care. At 12 months, the HbA_1c in the patients in the intervention group was significantly improved with an overall percentage change of 0.81 compared with 0.23 in the usual care group (estimated between-group difference, -0.56 [95% CI, -0.85 to -0.27]). The study authors concluded that integrated management and proactive follow-up of medical and psychological illnesses improved both medical outcomes and depression in patients with DM, CAD, or both.¹⁰

Another study by Bogner and colleagues investigated an integrated care intervention for patients with depression and DM to improve adherence to antidepressant and antidiabetic medications, glycemic control, and depression remission.¹¹ Two trained research coordinators (a bachelor’s level and a master’s level) administered all intervention activities. The integrated care managers collaborated with physicians, offering education and guideline-based treatment recommendations to patients to monitor medication adherence and clinical status. The intervention supplemented regular primary care follow-up visits and was compared with usual care. At 12 weeks, patients in the integrated care group were more likely to achieve an HbA_1c < 7% (60.9% vs 35.7%; P < .001) and remission of depression (58.7% vs 30.7%; P < .001) compared with those in usual care. There also was a significant improvement in adherence to DM and antidepressant medications in the intervention group compared with those in usual care during the study period.¹¹

A systematic review and meta-analysis by Huang and colleagues assessed randomized controlled trials of collaborative care for diabetic patients with depression.¹² Trials that reported depression treatment response, depression remission, HbA_1c values, and adherence to antidepressant and/or hypoglycemic medications were included. A total of 8 trials randomized 2,238 patients with concurrent depression and DM and compared collaborative care with usual care. Collaborative care was associated with a significant increase in depression treatment response, reduction in HbA_1c, and significant improvement in adherence rates for antidepressant and hypoglycemic medications compared with that of usual care. A reduction in HbA_1c favored the collaborative care group; however, this reduction was not significant (mean difference, -0.13 [95% CI, -0.46 to 0.19]; P = .08 for heterogeneity; I² = 51%). The study authors concluded that a collaborative care model significantly improved depression outcomes and adherence to medications in patients with concurrent DM and depression and recommended continued collaborative care for this population.¹²

Methods

The current study examines a novel service involving the collaboration of a registered nurse-certified DM educator (RN CDE) and clinical pharmacy specialist (PharmD) to improve access to care and maximize DM outcomes. The Louis Stokes Cleveland VAMC defines the PharmD scope of practice. One of the pharmacist’s clinical obligations includes serving as a preceptor for the RN CDE, a collaboration that has not been investigated in previous studies. A primary care provider (PCP) refers veterans to the RN CDE/PharmD clinic, with HbA_1c ≥ 8%. 

The RN CDE/PharmD clinic tends to receive referrals for the most challenging veterans who may have very elevated HbA_1c readings, complex multidrug regimens, or basal/bolus insulin regimens. The RN CDE sees veterans in individual appointments and takes manual BP readings, checks point-of-care glucose/HbA_1c readings, downloads home glucometer results into the electronic medical record (EMR), and provides education on DM management specific to the veteran’s individual needs. Because there is no established treatment algorithm for the RN CDE to follow, all medication changes are determined by a preceptor in real time. 

When the RN CDE clinic was established, the RN CDE presented veterans to their PCP who determined the veteran’s plan of care. However, this plan was frustrating for the RN CDE because the PCP was not always readily available, causing delays in the workflow of the RN CDE clinic. Since the PharmD has a scope of practice and is more frequently available to discuss veteran cases, RN CDE/PharmD collaboration was initiated. Based on information gathered during the appointment, medication additions, titrations, and changes are precepted with the PharmD. Veterans can be seen in clinic every 2 to 4 weeks, allowing for continued medication adjustments if warranted until their HbA_1c target is achieved. Veterans are discharged to their PCP once their HbA_1c is at target. 

Within the primary care clinic, this service was compared with usual care by a PCP and was associated with a clinically significant reduction in HbA_1c by 2.5% compared with usual care after 1 year (P < .001).¹³ The same study population was investigated to determine whether there was a difference in glycemic control between veterans with SMI compared with veterans without SMI (non-SMI) to provide insight and better support for veterans with SMI and their DM care.

A retrospective review of the veterans referred to the RN CDE/PharmD clinic from January 1, 2011 to December 31, 2014 was performed with institutional review board approval. Veterans were identified using a pharmacy-generated list searching for clinic note titles from the Computerized Patient Record System (CPRS).

The primary objective of this study was to determine the percentage change in mean HbA_1c in veterans with SMI compared with that of veterans without SMI after referral to the RN CDE/PharmD clinic. The following secondary objectives also were investigated: the difference in the percentage of veterans with glycemic relapse after the intervention in veterans with SMI compared with that of veterans without SMI, and the difference in time to glycemic relapse between veterans with SMI compared with that of veterans without SMI. Serious mental illness was defined as schizophrenia, schizoaffective disorder, bipolar disorder, and MDD and identified in CPRS using ICD-9 and ICD-10 codes, medicine progress notes, and psychiatry progress notes. Glycemic relapse was defined as > 1% increase in HbA_1c from the lowest HbA_1c within 1 year of being followed by the RN CDE/PharmD clinic (nadir).

Veterans were included in the study if they were aged ≥ 18 years, referred to the RN CDE/PharmD clinic from January 1, 2011 to December 31, 2014, had at least 2 clinic visits, an HbA_1c > 8% at the date of the first clinic visit, and at least 1 HbA_1c test at baseline and 1 HbA_1c test at least 2 months after referral to the clinic. Veterans were excluded from the study if they met the following criteria: diagnosed with SMI during the study period, followed by the RN CDE or PharmD in other primary care clinics prior to referral, followed by the PharmD clinic within 365 days after the initial RN CDE/PharmD clinic visit, referred to or followed by endocrinology, or veterans enrolled in a VA DM research trial. Veterans continued to be enrolled until target enrollment was met.

Medical records were reviewed to capture the following information: demographics (age and gender), type of SMI, date diagnosed with SMI, number of mental health-related visits, antidepressant and antipsychotic use, HbA_1c prior to referral to the RN CDE/PharmD clinic (initial HbA_1c) and date, HbA_1c nadir and date, and highest postnadir HbA_1c (glycemic relapse) and date, number of clinic visits, time followed by the clinic, and reason for glycemic relapse.

A total sample size of 100 veterans was needed to determine a medium effect size of 0.25 for between-group treatment effect on veterans with SMI compared with that of veterans without SMI, using a 2-group by 2 time-point repeated measures analysis of variance (ANOVA) with a power of 80% and alpha of 0.05. Of the 100 veterans, 50 veterans in each group were necessary to meet power. The percentage change in mean HbA_1c from the initial time point to nadir was analyzed using a 2-time point by 2-group repeated measures ANOVA analysis. The secondary objectives were analyzed using descriptive statistics, a repeated measures ANOVA test to determine the percentage change in mean HbA_1c from nadir to relapse, and an independent samples Student t test to analyze time to glycemic relapse.

Results

Discussion

Collaborative interventions have improved glycemic control in patients with concurrent SMI and DM. Although there was not a significant difference in mean HbA_1c from the initial HbA_1c to the nadir HbA_1c between study groups, this study provided valuable insight for the RN CDE/PharmD clinic. The mean HbA_1c decreased over time in both study groups, demonstrating that the collaborative intervention was effective in improving glycemic control in veterans with SMI and veterans without SMI. The mean HbA_1c decrease in the SMI group was slightly higher compared with that of the non-SMI group, but the difference was not significant. The decrease in mean HbA_1c also demonstrated that the RN CDE/PharmD interventions were effective in each group. Contrary to this study’s hypothesis that veterans with SMI would have worse glycemic control compared with that of veterans without SMI, this study demonstrated that there was no difference in glycemic control between groups.

Veterans in the SMI group had a significantly greater percentage increase in mean HbA_1c postnadir, indicating that their glycemic control worsened postnadir compared with that of the non-SMI group. If veterans with SMI relapsed, they tended to relapse to a greater extent compared with veterans without SMI, as indicated by a larger percentage increase in mean HbA_1c. Time to relapse was shorter in veterans with SMI compared with that of veterans without SMI, but the difference was not significant. Using the information gathered, if veterans with SMI relapsed, they tended to relapse sooner and with a greater percentage increase in HbA_1c compared with that of veterans without SMI.

Limitations

As a retrospective study, data collection was limited to the information found in the veteran’s EMR: Data collected were dependent on accurate and comprehensive documentation in the veteran’s problem list and progress notes. Additionally, the time between HbA_1c tests was not analyzed when determining the differences in mean HbA_1c. These data may be helpful in identifying reasons for glycemic relapse. Glycemic relapse depended on the number of HbA_1c tests that the veteran completed. Time to glycemic relapse may occur sooner in veterans who completed more frequent HbA_1c testing.

Conclusion

There was a significant decrease in mean HbA_1c for the entire group over time. In comparing the percentage change in mean HbA_1c between groups, there was not a significant difference in the decrease in mean HbA_1c from initial to nadir HbA_1c in veterans with SMI compared with that of veterans without SMI. However, veterans with SMI had a significantly larger increase in HbA_1c postnadir compared with that of veterans without SMI, indicating that support would likely be needed after the veteran achieves his or her HbA_1c target. Strategies such as extending the follow-up time in the RN CDE/PharmD clinic, expanding collaborative services with behavioral medicine and psychiatry, additional shared medical appointments or support groups for veterans with DM and SMI, and health literacy assessments may need to be adapted to assist in maintaining glycemic control in veterans with concurrent SMI and DM.

Click here to read the digital edition.
 

Diabetes mellitus (DM) is considered one of the most psychologically and behaviorally demanding chronic medical conditions. Patients with DM and serious mental illness (SMI), including schizophrenia, schizoaffective disorder, major depressive disorder (MDD), and bipolar disorder, are more likely to have poor adherence to medications as well as poor adherence to diet and lifestyle recommendations, which can lead to poor glycemic control, decreased quality of life, and increased health care expenses.^1-4 Up to 27% of patients with DM have a depression diagnosis, and up to 60% of patients with DM experience depressive symptoms.⁵ Additionally, 1 in 4 patients with schizophrenia have a DM diagnosis.⁶ Serious mental illness can compromise DM self-management and glycemic control, which increases the risk of DM-related complications.⁷

These factors combine to make DM self-management essential for optimal glycemic control and prevention of DM-related complications. The American Diabetes Association recommends coordinated management of DM and SMI to achieve DM treatment targets.⁸ Interventions involving collaborative care teams have assisted in managing patients with concurrent SMI and DM. Collaborative interventions have reduced all-cause mortality, increased the number of patients reaching hemoglobin A_1c (HbA_1c) targets, increased overall improvement in HbA_1c, increased rates of depression remission, and increased medication adherence.^9-12

Background

Collaborative interventions have improved glycemic control in patients with concurrent SMI and DM. A study by Desai and colleagues examined the relationship between psychiatric disorders and the quality of DM care in a national sample of veterans.⁷ Data were collected using chart-abstracted quality data from administrative database records for a sample of veterans with DM who had at least 3 outpatient visits in the previous year (n = 38,020). About 25% of the sample had a diagnosed psychiatric disorder, 91.5% of veterans completed an HbA_1c test, and most veterans with a psychiatric disorder completed the 5 quality indicators for DM care (foot inspection, HbA_1c determination, pedal pulses examination, foot sensory examination, and retina examination). Veterans with psychiatric disorders did not have a poorer quality of care for secondary prevention of DM compared with that of other veterans.⁷

In the PROSPECT study (Prevention of Suicide in Primary Care Elderly: Collaborative Trial), a primary care-based depression management program assessed a collaborative intervention to improve care in patients with depression and DM.⁹ Fifteen depression care managers, including trained social workers, registered nurses (RNs), and psychologists, collaborated with primary care physicians (PCPs) to assist in recognizing depression, offer guideline-based treatment recommendations, and provide algorithm-based care, monitoring, and follow-up. After a median follow-up of 52 months, patients with depression and DM in the intervention group were less likely to die during the 5-year follow-up period compared with those in usual care (adjusted hazard ratio, 0.49 [95% confidence interval (CI), 0.24-0.98]). The study authors concluded that integrated depression care management significantly reduced all-cause mortality in patients with depression and DM.⁹

A single-blind, randomized, controlled trial conducted by Katon and colleagues examined patients with poorly controlled DM, coronary artery disease (CAD), or both, and concurrent depression in 14 primary care clinics (n = 214).¹⁰ The intervention consisted of nurse care managers who were trained RNs with experience in DM education and supervised by PCPs, providing guideline-based, collaborative care over 12 months to improve glycemic control, blood pressure (BP), and lipid control. The nurse care managers followed up with patients every 2 to3 weeks at office visits, and the intervention was compared with usual care by a physician. At 12 months, patients in the intervention group had significant improvement in HbA_1c, low-density lipoprotein cholesterol, systolic BP, and depression compared with that of those under usual care. At 12 months, the HbA_1c in the patients in the intervention group was significantly improved with an overall percentage change of 0.81 compared with 0.23 in the usual care group (estimated between-group difference, -0.56 [95% CI, -0.85 to -0.27]). The study authors concluded that integrated management and proactive follow-up of medical and psychological illnesses improved both medical outcomes and depression in patients with DM, CAD, or both.¹⁰

Another study by Bogner and colleagues investigated an integrated care intervention for patients with depression and DM to improve adherence to antidepressant and antidiabetic medications, glycemic control, and depression remission.¹¹ Two trained research coordinators (a bachelor’s level and a master’s level) administered all intervention activities. The integrated care managers collaborated with physicians, offering education and guideline-based treatment recommendations to patients to monitor medication adherence and clinical status. The intervention supplemented regular primary care follow-up visits and was compared with usual care. At 12 weeks, patients in the integrated care group were more likely to achieve an HbA_1c < 7% (60.9% vs 35.7%; P < .001) and remission of depression (58.7% vs 30.7%; P < .001) compared with those in usual care. There also was a significant improvement in adherence to DM and antidepressant medications in the intervention group compared with those in usual care during the study period.¹¹

A systematic review and meta-analysis by Huang and colleagues assessed randomized controlled trials of collaborative care for diabetic patients with depression.¹² Trials that reported depression treatment response, depression remission, HbA_1c values, and adherence to antidepressant and/or hypoglycemic medications were included. A total of 8 trials randomized 2,238 patients with concurrent depression and DM and compared collaborative care with usual care. Collaborative care was associated with a significant increase in depression treatment response, reduction in HbA_1c, and significant improvement in adherence rates for antidepressant and hypoglycemic medications compared with that of usual care. A reduction in HbA_1c favored the collaborative care group; however, this reduction was not significant (mean difference, -0.13 [95% CI, -0.46 to 0.19]; P = .08 for heterogeneity; I² = 51%). The study authors concluded that a collaborative care model significantly improved depression outcomes and adherence to medications in patients with concurrent DM and depression and recommended continued collaborative care for this population.¹²

Methods

The current study examines a novel service involving the collaboration of a registered nurse-certified DM educator (RN CDE) and clinical pharmacy specialist (PharmD) to improve access to care and maximize DM outcomes. The Louis Stokes Cleveland VAMC defines the PharmD scope of practice. One of the pharmacist’s clinical obligations includes serving as a preceptor for the RN CDE, a collaboration that has not been investigated in previous studies. A primary care provider (PCP) refers veterans to the RN CDE/PharmD clinic, with HbA_1c ≥ 8%. 

The RN CDE/PharmD clinic tends to receive referrals for the most challenging veterans who may have very elevated HbA_1c readings, complex multidrug regimens, or basal/bolus insulin regimens. The RN CDE sees veterans in individual appointments and takes manual BP readings, checks point-of-care glucose/HbA_1c readings, downloads home glucometer results into the electronic medical record (EMR), and provides education on DM management specific to the veteran’s individual needs. Because there is no established treatment algorithm for the RN CDE to follow, all medication changes are determined by a preceptor in real time. 

When the RN CDE clinic was established, the RN CDE presented veterans to their PCP who determined the veteran’s plan of care. However, this plan was frustrating for the RN CDE because the PCP was not always readily available, causing delays in the workflow of the RN CDE clinic. Since the PharmD has a scope of practice and is more frequently available to discuss veteran cases, RN CDE/PharmD collaboration was initiated. Based on information gathered during the appointment, medication additions, titrations, and changes are precepted with the PharmD. Veterans can be seen in clinic every 2 to 4 weeks, allowing for continued medication adjustments if warranted until their HbA_1c target is achieved. Veterans are discharged to their PCP once their HbA_1c is at target. 

Within the primary care clinic, this service was compared with usual care by a PCP and was associated with a clinically significant reduction in HbA_1c by 2.5% compared with usual care after 1 year (P < .001).¹³ The same study population was investigated to determine whether there was a difference in glycemic control between veterans with SMI compared with veterans without SMI (non-SMI) to provide insight and better support for veterans with SMI and their DM care.

A retrospective review of the veterans referred to the RN CDE/PharmD clinic from January 1, 2011 to December 31, 2014 was performed with institutional review board approval. Veterans were identified using a pharmacy-generated list searching for clinic note titles from the Computerized Patient Record System (CPRS).

The primary objective of this study was to determine the percentage change in mean HbA_1c in veterans with SMI compared with that of veterans without SMI after referral to the RN CDE/PharmD clinic. The following secondary objectives also were investigated: the difference in the percentage of veterans with glycemic relapse after the intervention in veterans with SMI compared with that of veterans without SMI, and the difference in time to glycemic relapse between veterans with SMI compared with that of veterans without SMI. Serious mental illness was defined as schizophrenia, schizoaffective disorder, bipolar disorder, and MDD and identified in CPRS using ICD-9 and ICD-10 codes, medicine progress notes, and psychiatry progress notes. Glycemic relapse was defined as > 1% increase in HbA_1c from the lowest HbA_1c within 1 year of being followed by the RN CDE/PharmD clinic (nadir).

Veterans were included in the study if they were aged ≥ 18 years, referred to the RN CDE/PharmD clinic from January 1, 2011 to December 31, 2014, had at least 2 clinic visits, an HbA_1c > 8% at the date of the first clinic visit, and at least 1 HbA_1c test at baseline and 1 HbA_1c test at least 2 months after referral to the clinic. Veterans were excluded from the study if they met the following criteria: diagnosed with SMI during the study period, followed by the RN CDE or PharmD in other primary care clinics prior to referral, followed by the PharmD clinic within 365 days after the initial RN CDE/PharmD clinic visit, referred to or followed by endocrinology, or veterans enrolled in a VA DM research trial. Veterans continued to be enrolled until target enrollment was met.

Medical records were reviewed to capture the following information: demographics (age and gender), type of SMI, date diagnosed with SMI, number of mental health-related visits, antidepressant and antipsychotic use, HbA_1c prior to referral to the RN CDE/PharmD clinic (initial HbA_1c) and date, HbA_1c nadir and date, and highest postnadir HbA_1c (glycemic relapse) and date, number of clinic visits, time followed by the clinic, and reason for glycemic relapse.

A total sample size of 100 veterans was needed to determine a medium effect size of 0.25 for between-group treatment effect on veterans with SMI compared with that of veterans without SMI, using a 2-group by 2 time-point repeated measures analysis of variance (ANOVA) with a power of 80% and alpha of 0.05. Of the 100 veterans, 50 veterans in each group were necessary to meet power. The percentage change in mean HbA_1c from the initial time point to nadir was analyzed using a 2-time point by 2-group repeated measures ANOVA analysis. The secondary objectives were analyzed using descriptive statistics, a repeated measures ANOVA test to determine the percentage change in mean HbA_1c from nadir to relapse, and an independent samples Student t test to analyze time to glycemic relapse.

Results

Discussion

Collaborative interventions have improved glycemic control in patients with concurrent SMI and DM. Although there was not a significant difference in mean HbA_1c from the initial HbA_1c to the nadir HbA_1c between study groups, this study provided valuable insight for the RN CDE/PharmD clinic. The mean HbA_1c decreased over time in both study groups, demonstrating that the collaborative intervention was effective in improving glycemic control in veterans with SMI and veterans without SMI. The mean HbA_1c decrease in the SMI group was slightly higher compared with that of the non-SMI group, but the difference was not significant. The decrease in mean HbA_1c also demonstrated that the RN CDE/PharmD interventions were effective in each group. Contrary to this study’s hypothesis that veterans with SMI would have worse glycemic control compared with that of veterans without SMI, this study demonstrated that there was no difference in glycemic control between groups.

Veterans in the SMI group had a significantly greater percentage increase in mean HbA_1c postnadir, indicating that their glycemic control worsened postnadir compared with that of the non-SMI group. If veterans with SMI relapsed, they tended to relapse to a greater extent compared with veterans without SMI, as indicated by a larger percentage increase in mean HbA_1c. Time to relapse was shorter in veterans with SMI compared with that of veterans without SMI, but the difference was not significant. Using the information gathered, if veterans with SMI relapsed, they tended to relapse sooner and with a greater percentage increase in HbA_1c compared with that of veterans without SMI.

Limitations

As a retrospective study, data collection was limited to the information found in the veteran’s EMR: Data collected were dependent on accurate and comprehensive documentation in the veteran’s problem list and progress notes. Additionally, the time between HbA_1c tests was not analyzed when determining the differences in mean HbA_1c. These data may be helpful in identifying reasons for glycemic relapse. Glycemic relapse depended on the number of HbA_1c tests that the veteran completed. Time to glycemic relapse may occur sooner in veterans who completed more frequent HbA_1c testing.

Conclusion

There was a significant decrease in mean HbA_1c for the entire group over time. In comparing the percentage change in mean HbA_1c between groups, there was not a significant difference in the decrease in mean HbA_1c from initial to nadir HbA_1c in veterans with SMI compared with that of veterans without SMI. However, veterans with SMI had a significantly larger increase in HbA_1c postnadir compared with that of veterans without SMI, indicating that support would likely be needed after the veteran achieves his or her HbA_1c target. Strategies such as extending the follow-up time in the RN CDE/PharmD clinic, expanding collaborative services with behavioral medicine and psychiatry, additional shared medical appointments or support groups for veterans with DM and SMI, and health literacy assessments may need to be adapted to assist in maintaining glycemic control in veterans with concurrent SMI and DM.

Click here to read the digital edition.
 

Diabetes mellitus (DM) is considered one of the most psychologically and behaviorally demanding chronic medical conditions. Patients with DM and serious mental illness (SMI), including schizophrenia, schizoaffective disorder, major depressive disorder (MDD), and bipolar disorder, are more likely to have poor adherence to medications as well as poor adherence to diet and lifestyle recommendations, which can lead to poor glycemic control, decreased quality of life, and increased health care expenses.^1-4 Up to 27% of patients with DM have a depression diagnosis, and up to 60% of patients with DM experience depressive symptoms.⁵ Additionally, 1 in 4 patients with schizophrenia have a DM diagnosis.⁶ Serious mental illness can compromise DM self-management and glycemic control, which increases the risk of DM-related complications.⁷

These factors combine to make DM self-management essential for optimal glycemic control and prevention of DM-related complications. The American Diabetes Association recommends coordinated management of DM and SMI to achieve DM treatment targets.⁸ Interventions involving collaborative care teams have assisted in managing patients with concurrent SMI and DM. Collaborative interventions have reduced all-cause mortality, increased the number of patients reaching hemoglobin A_1c (HbA_1c) targets, increased overall improvement in HbA_1c, increased rates of depression remission, and increased medication adherence.^9-12

Background

Collaborative interventions have improved glycemic control in patients with concurrent SMI and DM. A study by Desai and colleagues examined the relationship between psychiatric disorders and the quality of DM care in a national sample of veterans.⁷ Data were collected using chart-abstracted quality data from administrative database records for a sample of veterans with DM who had at least 3 outpatient visits in the previous year (n = 38,020). About 25% of the sample had a diagnosed psychiatric disorder, 91.5% of veterans completed an HbA_1c test, and most veterans with a psychiatric disorder completed the 5 quality indicators for DM care (foot inspection, HbA_1c determination, pedal pulses examination, foot sensory examination, and retina examination). Veterans with psychiatric disorders did not have a poorer quality of care for secondary prevention of DM compared with that of other veterans.⁷

In the PROSPECT study (Prevention of Suicide in Primary Care Elderly: Collaborative Trial), a primary care-based depression management program assessed a collaborative intervention to improve care in patients with depression and DM.⁹ Fifteen depression care managers, including trained social workers, registered nurses (RNs), and psychologists, collaborated with primary care physicians (PCPs) to assist in recognizing depression, offer guideline-based treatment recommendations, and provide algorithm-based care, monitoring, and follow-up. After a median follow-up of 52 months, patients with depression and DM in the intervention group were less likely to die during the 5-year follow-up period compared with those in usual care (adjusted hazard ratio, 0.49 [95% confidence interval (CI), 0.24-0.98]). The study authors concluded that integrated depression care management significantly reduced all-cause mortality in patients with depression and DM.⁹

A single-blind, randomized, controlled trial conducted by Katon and colleagues examined patients with poorly controlled DM, coronary artery disease (CAD), or both, and concurrent depression in 14 primary care clinics (n = 214).¹⁰ The intervention consisted of nurse care managers who were trained RNs with experience in DM education and supervised by PCPs, providing guideline-based, collaborative care over 12 months to improve glycemic control, blood pressure (BP), and lipid control. The nurse care managers followed up with patients every 2 to3 weeks at office visits, and the intervention was compared with usual care by a physician. At 12 months, patients in the intervention group had significant improvement in HbA_1c, low-density lipoprotein cholesterol, systolic BP, and depression compared with that of those under usual care. At 12 months, the HbA_1c in the patients in the intervention group was significantly improved with an overall percentage change of 0.81 compared with 0.23 in the usual care group (estimated between-group difference, -0.56 [95% CI, -0.85 to -0.27]). The study authors concluded that integrated management and proactive follow-up of medical and psychological illnesses improved both medical outcomes and depression in patients with DM, CAD, or both.¹⁰

Another study by Bogner and colleagues investigated an integrated care intervention for patients with depression and DM to improve adherence to antidepressant and antidiabetic medications, glycemic control, and depression remission.¹¹ Two trained research coordinators (a bachelor’s level and a master’s level) administered all intervention activities. The integrated care managers collaborated with physicians, offering education and guideline-based treatment recommendations to patients to monitor medication adherence and clinical status. The intervention supplemented regular primary care follow-up visits and was compared with usual care. At 12 weeks, patients in the integrated care group were more likely to achieve an HbA_1c < 7% (60.9% vs 35.7%; P < .001) and remission of depression (58.7% vs 30.7%; P < .001) compared with those in usual care. There also was a significant improvement in adherence to DM and antidepressant medications in the intervention group compared with those in usual care during the study period.¹¹

A systematic review and meta-analysis by Huang and colleagues assessed randomized controlled trials of collaborative care for diabetic patients with depression.¹² Trials that reported depression treatment response, depression remission, HbA_1c values, and adherence to antidepressant and/or hypoglycemic medications were included. A total of 8 trials randomized 2,238 patients with concurrent depression and DM and compared collaborative care with usual care. Collaborative care was associated with a significant increase in depression treatment response, reduction in HbA_1c, and significant improvement in adherence rates for antidepressant and hypoglycemic medications compared with that of usual care. A reduction in HbA_1c favored the collaborative care group; however, this reduction was not significant (mean difference, -0.13 [95% CI, -0.46 to 0.19]; P = .08 for heterogeneity; I² = 51%). The study authors concluded that a collaborative care model significantly improved depression outcomes and adherence to medications in patients with concurrent DM and depression and recommended continued collaborative care for this population.¹²

Methods

The current study examines a novel service involving the collaboration of a registered nurse-certified DM educator (RN CDE) and clinical pharmacy specialist (PharmD) to improve access to care and maximize DM outcomes. The Louis Stokes Cleveland VAMC defines the PharmD scope of practice. One of the pharmacist’s clinical obligations includes serving as a preceptor for the RN CDE, a collaboration that has not been investigated in previous studies. A primary care provider (PCP) refers veterans to the RN CDE/PharmD clinic, with HbA_1c ≥ 8%. 

The RN CDE/PharmD clinic tends to receive referrals for the most challenging veterans who may have very elevated HbA_1c readings, complex multidrug regimens, or basal/bolus insulin regimens. The RN CDE sees veterans in individual appointments and takes manual BP readings, checks point-of-care glucose/HbA_1c readings, downloads home glucometer results into the electronic medical record (EMR), and provides education on DM management specific to the veteran’s individual needs. Because there is no established treatment algorithm for the RN CDE to follow, all medication changes are determined by a preceptor in real time. 

When the RN CDE clinic was established, the RN CDE presented veterans to their PCP who determined the veteran’s plan of care. However, this plan was frustrating for the RN CDE because the PCP was not always readily available, causing delays in the workflow of the RN CDE clinic. Since the PharmD has a scope of practice and is more frequently available to discuss veteran cases, RN CDE/PharmD collaboration was initiated. Based on information gathered during the appointment, medication additions, titrations, and changes are precepted with the PharmD. Veterans can be seen in clinic every 2 to 4 weeks, allowing for continued medication adjustments if warranted until their HbA_1c target is achieved. Veterans are discharged to their PCP once their HbA_1c is at target. 

Within the primary care clinic, this service was compared with usual care by a PCP and was associated with a clinically significant reduction in HbA_1c by 2.5% compared with usual care after 1 year (P < .001).¹³ The same study population was investigated to determine whether there was a difference in glycemic control between veterans with SMI compared with veterans without SMI (non-SMI) to provide insight and better support for veterans with SMI and their DM care.

A retrospective review of the veterans referred to the RN CDE/PharmD clinic from January 1, 2011 to December 31, 2014 was performed with institutional review board approval. Veterans were identified using a pharmacy-generated list searching for clinic note titles from the Computerized Patient Record System (CPRS).

The primary objective of this study was to determine the percentage change in mean HbA_1c in veterans with SMI compared with that of veterans without SMI after referral to the RN CDE/PharmD clinic. The following secondary objectives also were investigated: the difference in the percentage of veterans with glycemic relapse after the intervention in veterans with SMI compared with that of veterans without SMI, and the difference in time to glycemic relapse between veterans with SMI compared with that of veterans without SMI. Serious mental illness was defined as schizophrenia, schizoaffective disorder, bipolar disorder, and MDD and identified in CPRS using ICD-9 and ICD-10 codes, medicine progress notes, and psychiatry progress notes. Glycemic relapse was defined as > 1% increase in HbA_1c from the lowest HbA_1c within 1 year of being followed by the RN CDE/PharmD clinic (nadir).

Veterans were included in the study if they were aged ≥ 18 years, referred to the RN CDE/PharmD clinic from January 1, 2011 to December 31, 2014, had at least 2 clinic visits, an HbA_1c > 8% at the date of the first clinic visit, and at least 1 HbA_1c test at baseline and 1 HbA_1c test at least 2 months after referral to the clinic. Veterans were excluded from the study if they met the following criteria: diagnosed with SMI during the study period, followed by the RN CDE or PharmD in other primary care clinics prior to referral, followed by the PharmD clinic within 365 days after the initial RN CDE/PharmD clinic visit, referred to or followed by endocrinology, or veterans enrolled in a VA DM research trial. Veterans continued to be enrolled until target enrollment was met.

Medical records were reviewed to capture the following information: demographics (age and gender), type of SMI, date diagnosed with SMI, number of mental health-related visits, antidepressant and antipsychotic use, HbA_1c prior to referral to the RN CDE/PharmD clinic (initial HbA_1c) and date, HbA_1c nadir and date, and highest postnadir HbA_1c (glycemic relapse) and date, number of clinic visits, time followed by the clinic, and reason for glycemic relapse.

A total sample size of 100 veterans was needed to determine a medium effect size of 0.25 for between-group treatment effect on veterans with SMI compared with that of veterans without SMI, using a 2-group by 2 time-point repeated measures analysis of variance (ANOVA) with a power of 80% and alpha of 0.05. Of the 100 veterans, 50 veterans in each group were necessary to meet power. The percentage change in mean HbA_1c from the initial time point to nadir was analyzed using a 2-time point by 2-group repeated measures ANOVA analysis. The secondary objectives were analyzed using descriptive statistics, a repeated measures ANOVA test to determine the percentage change in mean HbA_1c from nadir to relapse, and an independent samples Student t test to analyze time to glycemic relapse.

Results

Discussion

Collaborative interventions have improved glycemic control in patients with concurrent SMI and DM. Although there was not a significant difference in mean HbA_1c from the initial HbA_1c to the nadir HbA_1c between study groups, this study provided valuable insight for the RN CDE/PharmD clinic. The mean HbA_1c decreased over time in both study groups, demonstrating that the collaborative intervention was effective in improving glycemic control in veterans with SMI and veterans without SMI. The mean HbA_1c decrease in the SMI group was slightly higher compared with that of the non-SMI group, but the difference was not significant. The decrease in mean HbA_1c also demonstrated that the RN CDE/PharmD interventions were effective in each group. Contrary to this study’s hypothesis that veterans with SMI would have worse glycemic control compared with that of veterans without SMI, this study demonstrated that there was no difference in glycemic control between groups.

Veterans in the SMI group had a significantly greater percentage increase in mean HbA_1c postnadir, indicating that their glycemic control worsened postnadir compared with that of the non-SMI group. If veterans with SMI relapsed, they tended to relapse to a greater extent compared with veterans without SMI, as indicated by a larger percentage increase in mean HbA_1c. Time to relapse was shorter in veterans with SMI compared with that of veterans without SMI, but the difference was not significant. Using the information gathered, if veterans with SMI relapsed, they tended to relapse sooner and with a greater percentage increase in HbA_1c compared with that of veterans without SMI.

Limitations

As a retrospective study, data collection was limited to the information found in the veteran’s EMR: Data collected were dependent on accurate and comprehensive documentation in the veteran’s problem list and progress notes. Additionally, the time between HbA_1c tests was not analyzed when determining the differences in mean HbA_1c. These data may be helpful in identifying reasons for glycemic relapse. Glycemic relapse depended on the number of HbA_1c tests that the veteran completed. Time to glycemic relapse may occur sooner in veterans who completed more frequent HbA_1c testing.

Conclusion

There was a significant decrease in mean HbA_1c for the entire group over time. In comparing the percentage change in mean HbA_1c between groups, there was not a significant difference in the decrease in mean HbA_1c from initial to nadir HbA_1c in veterans with SMI compared with that of veterans without SMI. However, veterans with SMI had a significantly larger increase in HbA_1c postnadir compared with that of veterans without SMI, indicating that support would likely be needed after the veteran achieves his or her HbA_1c target. Strategies such as extending the follow-up time in the RN CDE/PharmD clinic, expanding collaborative services with behavioral medicine and psychiatry, additional shared medical appointments or support groups for veterans with DM and SMI, and health literacy assessments may need to be adapted to assist in maintaining glycemic control in veterans with concurrent SMI and DM.

Click here to read the digital edition.
 

Individuals with type 2 diabetes mellitus (T2DM) spend between 5 and 10 years with elevated hemoglobin A_1c (HbA_1c) before initiation of insulin.¹ Once the basal insulin is initiated, the patient can go years with only adjustment of the basal insulin, resulting in over-basalization. In general, the total daily dose (TDD) of insulin should be composed of about 50% basal “background” insulin and 50% bolus “meal” insulin. When the fasting glucose readings are on target but HbA_1c is still above the mutually set goal range, postprandial readings need to be evaluated.

This article focuses on initiating and titrating bolus insulin in nonpregnant patients with T2DM. Before initiation of bolus insulin, it is important for the patient to be actively engaged with a diabetes educator for diabetes self-management education and support (DSME/S), including the understanding of the correct use of insulin, carbohydrate counting, and increasing physical activities. Ensuring the correct technique of insulin administration and self-monitoring of blood glucose (SMBG) is critical. A knowledge deficit of carbohydrate information can lead to uncontrolled blood glucose (BG). The authors have encountered numerous times when patients were drinking sugary beverages or consuming large amounts of “healthy” food without realizing the carbohydrate content. Therefore, treatment in concert with a registered dietitian and certified diabetes educator is highly recommended.

Initiation of Bolus Insulin

There are 3 options of postprandial coverage with bolus insulin when a patient is taking basal insulin: basal plus, basal-bolus, or premix insulin. A possible fourth option for postprandial coverage is to add glucagon-like peptide-1 receptor agonist (GLP-1 RA), an injectable noninsulin antihyperglycemic agent, which has shown noninferior efficacy to adding bolus insulin and a favorable effect on weight with less risk of hypoglycemia.^2-5 Although it can be expensive, combining GLP-1 RA to basal insulin results in lowering HbA_1c of 0.66 up to 1.74% (or lowering mmol/mol of 7 up to 19) from the baseline.⁶ However, adding bolus insulin may be the only option to avoid glucotoxicity and prevent further diabetes complications when the HbA_1c level is well above the goal range. It is usually recommended to discontinue sulfonylurea when bolus insulin is added due to the β-cell exhaustion with advancing natural history of diabetes.^7,8

Method 1: Basal Plus

The health care provider (HCP) needs to consider whether the patient is over-basalized when the HbA_lc and postprandial BG readings are still not at goal despite careful titration of basal insulin dose to > 0.5 U/kg/d.⁹ This is the time to discuss with the patient the coverage of mealtime glucose excursions. In the basal plus regimen, the prescribing provider may add 1 bolus insulin injection for the meal with the highest amount of carbohydrates or add 2 bolus injections for the most and second most meals with carbohydrates. Multiple types of bolus insulin are available in the current U.S. market (Table 1).

There are 2 ways to add bolus insulin: fixed and flexible. In the fixed regimen, the patient will take the same amount of bolus insulin regardless of premeal BG readings and carbohydrate content of the food. The authors recommend adding bolus insulin of about 4 to 6 units once or twice a day with meals, depending on the number of meals a day, carbohydrate content of the meal, current and desired degree of diabetes control, and physical activities. Another way to calculate a bolus insulin dose is to start at 0.1 U/kg if adding to the basal insulin.¹⁰ Flexible regimen allows various bolus doses based on premeal BG, carbohydrate intake, and activities. Information on this regimen, will be discussed more later.

Patient Cases

Tables 2 and 3 describe 2 patient cases. For example, patient 1 weighs 80 kg. If the prescribing HCP and patient decide to add only 1 bolus to the largest carbohydrate meal at dinnertime, then the patient may take 8 units (80 kg × 0.1 U/kg/meal = 8 units for meal). The patient’s current insulin dose, medical comorbidities, current diabetes control status, living situations, and overall cognition also should be considered.

Imagine patient 1 is taking 14 units daily of a long-acting insulin (LAI). If the patient is taking a fairly low dose of LAI, has multiple comorbidities, recent BG log/HgA_lc, and lives alone but demonstrates good cognition to follow instructions, the prescriber may consider adding the bolus insulin of 4 units for dinner; thus, the bolus dose is about one-third of total basal insulin dose. However, if the patient is on 40 units of LAI and has symptoms of hyperglycemia, 6 to 8 units for the dinner is reasonable. An important point to convey to this patient is to make sure there is carbohydrate consistency. The patient’s premeal BG was 137 mg/dL (7.6 mmol/L) on Monday, but it rose significantly to 313 mg/dL (17.4 mmol/L) after dinner. On Wednesday, the patient’s premeal BG prior to dinner was 150 mg/dL (8.3 mmol/L); it rose to 202 mg/dL (11.2 mmol/L) after dinner, which is high but not as high as on Monday.

Multiple factors may affect this variability; for example, on Monday the patient may have consumed more than the usual amount of carbohydrates for dinner, forgot to take oral medication for dinner, or missed his/her usual after-dinner walk. Or simply, the patient may have eaten a lot less than the usual amount of carbohydrates, walked the neighborhood, or vacuumed the entire house after dinner on Wednesday. Thus, it is imperative to carefully assess the patient’s lifestyle and recommend carbohydrate consistency at each meal.

Method 2: Basal-Bolus

When basal plus is insufficient to get the HbA_1c and BG readings to goal, taking bolus insulin for all main meals containing carbohydrates must be considered. This is often called basal-bolus, multiple daily injections, or intensive insulin therapy.

In order to understand the concept of basal-bolus, HCPs should consider normal physiology. The pancreas releases a constant amount of insulin, aka background insulin, to cover glucose produced by the liver to the cells between meals. In addition, a burst of insulin, aka bolus insulin, to meet the blood glucose elevation from food to maintain homeostasis. In patients with T2DM, the relative amount produced by the pancreas is insufficient to meet the demand due to pancreatic exhaustion or insulin resistance. This necessitates the need to replace background and bolus insulin.⁷

The ideal final total bolus insulin amount (the sum of all meal bolus doses) should be about half the basal dosing. Calculation of starting bolus dosing can be done as in the basal plus regimen, either 4 to 6 units per meal or 0.1 U/kg/d.¹⁰ Alternatively, if the patient is on 60 units of long-acting analog and BGs are well above goal range, the prescriber could consider about 20 units of bolus dose (60 U divided by 3 meals) if the patient eats 3 routine meals a day with at least 30 g of carbohydrates, and physical activity levels are fairly consistent. If the patient eats the most carbohydrates at lunchtime, consider more bolus at lunch (ie, 18 U of bolus for breakfast and dinner and 24 U of bolus for lunch coverage). 
Patients need to separate the time between the bolus doses, usually a minimum of 4 hours apart, to avoid insulin stacking, which is a common reason for hypoglycemia. Insulin stacking occurs when additional quick or rapid insulin is injected when the previous insulin is still in the body or when there is insulin on board.^8,11 Typically, bolus analogs stay in the body for about 4 to 6 hours, thus necessitating separation of the doses at least 4 hours apart. Patients sometimes inject more bolus insulin after high postprandial readings, which can result in insulin stacking. In some cases, the patient may misunderstand and take mealtime insulin at a scheduled time instead of at the time of the meal.

Injecting bolus insulin for every snack must be avoided to prevent a vicious cycle: Postprandial hyperglycemia –> extra bolus insulin, resulting in insulin stacking –> hypoglycemia –> overtreatment with food –> hyperglycemia –> extra bolus insulin, resulting in insulin stacking –> and so on. Whenever there are readings in the hypoglycemic and hyperglycemic range, address hypoglycemia first because hyperglycemia often is due to overtreatment of hypoglycemia.

Method 3: Premix or Split-Mix (Patient-Mix) Insulin

Postprandial BG excursions can be minimized by changing basal insulin to premix or split-mix (patient-mix) insulin that has a mixture of mealtime and intermediate action insulin (Table 4).^12-16 The use of premixed insulin is a viable option due to its ease of use and for those who have restrictions based on the complexity of the basal-bolus regimen.⁷ If a patient has routine meals and prefers not to carry around insulin for lunch, the schedule of premix insulin taken at breakfast and dinner is ideal.

Some caveats for safe prescribing should be understood. A recent summary of premixed insulin regimens noted that they seem to have a similar efficacy and safety profile compared with regimens that include basal insulin with or without mealtime insulin; however, cost and patient adherence are improved.¹⁷ It is important to monitor insulin-naïve patients for hypoglycemia and reduced efficacy when used twice daily compared with basal plus 3-times daily prandial insulin in patients needing insulin intensification.¹⁷

A randomized trial noted that hypoglycemia rates were twice as high with premixed insulin compared with basal-bolus insulin.¹⁸ This study also noted that the premixed insulin group experienced the highest dropout rate, partly due to hypoglycemia. A regimen of basal insulin with the option to add a single prandial insulin injection at the main meal was as effective in reducing HbA_1c with less hypoglycemia. The premixed insulin is convenient but does not allow a separate correction of either mealtime or intermediate-acting insulin doses. If the premixed dose needs to be adjusted due to fasting hyperglycemia > 180 mg/dL(10.0 mmol/L), the TDD can be increased by 10%.²

In contrast, a split-mix (patient-mix) insulin regimen allows for the ability to vary the amount/ratio of combinations and adjustment of bolus and intermediate insulin doses. The disadvantages of split-mix insulin include the inconvenience of manually mixing of insulin and the potential for dosing errors. The patient needs to be taught additional steps on how to mix both insulins. Ensure the correct mixing order to maintain insulin potency; regular first, then neutral protamine Hagedorn (NPH). An HCP should remember the RN acronym if the patient is combining regular insulin and NPH. If there is doubt about the patient’s insulin injection technique, HCPs should ask the patient to demonstrate how to correctly pull up a dose of normal saline and inject it during a clinic visit. The only basal insulin that can be physically mixed with quick or rapid insulin is NPH. It should never be mixed with long-acting analogs. The patient should not even use the same syringe to draw up bolus analog insulin and inject it and then use the same syringe to draw up long-acting analog insulin.

One caveat to a fixed regimen (same amount of insulin dose) is that providers often expect that the patient will eat a consistent amount of carbohydrates at each meal and premeal glucose readings are fairly stable. Oftentimes, this is not true. If a patient took a bolus dose of 8 units of rapid-acting insulin and ate a 6 oz steak, 3 oz baked potato, steamed broccoli at a dinner; and no bread, the after dinner BG might register 145 mg/dL (8.1 mmol/L). Then, the next day for dinner, if he or she took the same amount of 8 units of rapid-acting insulin and ate 1 cup of spaghetti, ½ cup of spaghetti meat sauce, and 2 slices of garlic bread, the after dinner reading might be 322 mg/dL (17.9 mmol/L). The patient’s BG was higher on the second day because of the higher carbohydrate content of the meal. If the rapid-acting insulin was increased to 12 units of bolus based on the high carbohydrate meal and the patient ate a lower carbohydrate meal, hypoglycemia could ensue. Thus, it is important to work with the patient regarding the consumption of a consistent amount of carbohydrates and refer to a registered dietitian for carbohydrate consistency.

For the flexible regimen, the prescriber may consider using an insulin to carbohydrate (IC) ratio and sensitivity factor (SF), also called sliding scale or correction factor. The IC ratio represents how much insulin is needed to cover consumed carbohydrates. For instance, if the patient uses IC ratio of 1:15, 1 unit of bolus insulin will cover 15 g of carbohydrates. If the patient eats a meal with 60 g of carbohydrates and is using IC ratio of 1:15, the patient will inject 4 units of bolus insulin. Sensitivity factor represents how much BG will be lowered in mg/dL by taking 1 unit of bolus insulin. For example, if the patient uses SF of 1:50, 1 unit of bolus insulin will lower BG by 50 mg/dL (2.8 mmol/L). When the desired (target) BG reading is 100 mg/dL (5.6 mmol/L) and the patient’s current BG is 200 mg/dL (11.1 mmol/L), the patient will divide 100 mg/dL (5.6 mmol/L) by 50 (derived from SF of 1:50). The net result is 2 units of bolus insulin are needed to lower BG by 100 mg/dL (5.6 mmol/L). If the premeal BG is 200 mg/dL (11.1 mmol/L) and 60 g of carbohydrates are eaten, then the patient will need a total of 6 units (4 U for carbohydrate and 2 U for high BG) bolus before the meal. For additional information, readers are encouraged to read the articles by Petznick and by Joslin Diabetes Center for IC and SF.^19,20

Bolus Insulin Titration

When the difference in BG readings before and 2 hours after a meal, called the Δ value, is > 50 mg/dL (2.8 mmol/L), the bolus insulin may need to be adjusted after ensuring the patient is ingesting consistent carbohydrates and performs the usual amount of activities around mealtime. For example, if the premeal reading was 130 mg/dL (7.2 mmol/L) but the 2-hour postprandial reading is > 180 mg/dL (10.0 mmol/L), the prescriber can increase the mealtime insulin by 1 unit if the mealtime insulin is < 10 units, by 2 units if < 20 units, or by 10% of the mealtime insulin dose. If the premeal BG is < 80 mg/dL (4.4 mmol/L) and the drop in BG is > Δ value of 50 mg/dL (2.8 mmol/L), the prescriber can decrease the mealtime insulin using the same calculation. Monitoring BG and titration recommendations are shown in Table 5. When adjusting the bolus insulin dose, it is best to make adjustments gradually rather than making several changes at once.

The 15/15 rule needs to be followed in cases involving hypoglycemia.²¹ When the BG is ≤ 70 mg/dL (3.9 mmol/L) and the patient is conscious and able to eat or drink, it is recommended they eat 15 g (30 g if BG is below 50) of carbohydrates then repeat BG check every 15 minutes until the BG is in the target range.^22,23 If the patient is unconscious, providers should administer glucagon (if available), place the patient in a lateral position to avoid aspiration, and call 911. If hyperkalemia is an issue in chronic kidney disease, patients should consume apple juice rather than orange juice due to its lower potassium content. If the patient is taking α glucosidase inhibitors (AGI) like acarbose or miglitol, only pure glucose like glucose tablets needs to be given to treat hypoglycemia instead of regular soda or candy, as the AGI will slow absorption of other types of carbohydrates.^24,25 After the severe hypoglycemic episode, it is imperative to assess for the cause and explore ways to prevent subsequent hypoglycemia. Providers also should advise the patient to wear medical emergency identification. 

Conclusion

Click here to read the digital edition.

Individuals with type 2 diabetes mellitus (T2DM) spend between 5 and 10 years with elevated hemoglobin A_1c (HbA_1c) before initiation of insulin.¹ Once the basal insulin is initiated, the patient can go years with only adjustment of the basal insulin, resulting in over-basalization. In general, the total daily dose (TDD) of insulin should be composed of about 50% basal “background” insulin and 50% bolus “meal” insulin. When the fasting glucose readings are on target but HbA_1c is still above the mutually set goal range, postprandial readings need to be evaluated.

This article focuses on initiating and titrating bolus insulin in nonpregnant patients with T2DM. Before initiation of bolus insulin, it is important for the patient to be actively engaged with a diabetes educator for diabetes self-management education and support (DSME/S), including the understanding of the correct use of insulin, carbohydrate counting, and increasing physical activities. Ensuring the correct technique of insulin administration and self-monitoring of blood glucose (SMBG) is critical. A knowledge deficit of carbohydrate information can lead to uncontrolled blood glucose (BG). The authors have encountered numerous times when patients were drinking sugary beverages or consuming large amounts of “healthy” food without realizing the carbohydrate content. Therefore, treatment in concert with a registered dietitian and certified diabetes educator is highly recommended.

Initiation of Bolus Insulin

There are 3 options of postprandial coverage with bolus insulin when a patient is taking basal insulin: basal plus, basal-bolus, or premix insulin. A possible fourth option for postprandial coverage is to add glucagon-like peptide-1 receptor agonist (GLP-1 RA), an injectable noninsulin antihyperglycemic agent, which has shown noninferior efficacy to adding bolus insulin and a favorable effect on weight with less risk of hypoglycemia.^2-5 Although it can be expensive, combining GLP-1 RA to basal insulin results in lowering HbA_1c of 0.66 up to 1.74% (or lowering mmol/mol of 7 up to 19) from the baseline.⁶ However, adding bolus insulin may be the only option to avoid glucotoxicity and prevent further diabetes complications when the HbA_1c level is well above the goal range. It is usually recommended to discontinue sulfonylurea when bolus insulin is added due to the β-cell exhaustion with advancing natural history of diabetes.^7,8

Method 1: Basal Plus

The health care provider (HCP) needs to consider whether the patient is over-basalized when the HbA_lc and postprandial BG readings are still not at goal despite careful titration of basal insulin dose to > 0.5 U/kg/d.⁹ This is the time to discuss with the patient the coverage of mealtime glucose excursions. In the basal plus regimen, the prescribing provider may add 1 bolus insulin injection for the meal with the highest amount of carbohydrates or add 2 bolus injections for the most and second most meals with carbohydrates. Multiple types of bolus insulin are available in the current U.S. market (Table 1).

There are 2 ways to add bolus insulin: fixed and flexible. In the fixed regimen, the patient will take the same amount of bolus insulin regardless of premeal BG readings and carbohydrate content of the food. The authors recommend adding bolus insulin of about 4 to 6 units once or twice a day with meals, depending on the number of meals a day, carbohydrate content of the meal, current and desired degree of diabetes control, and physical activities. Another way to calculate a bolus insulin dose is to start at 0.1 U/kg if adding to the basal insulin.¹⁰ Flexible regimen allows various bolus doses based on premeal BG, carbohydrate intake, and activities. Information on this regimen, will be discussed more later.

Patient Cases

Tables 2 and 3 describe 2 patient cases. For example, patient 1 weighs 80 kg. If the prescribing HCP and patient decide to add only 1 bolus to the largest carbohydrate meal at dinnertime, then the patient may take 8 units (80 kg × 0.1 U/kg/meal = 8 units for meal). The patient’s current insulin dose, medical comorbidities, current diabetes control status, living situations, and overall cognition also should be considered.

Imagine patient 1 is taking 14 units daily of a long-acting insulin (LAI). If the patient is taking a fairly low dose of LAI, has multiple comorbidities, recent BG log/HgA_lc, and lives alone but demonstrates good cognition to follow instructions, the prescriber may consider adding the bolus insulin of 4 units for dinner; thus, the bolus dose is about one-third of total basal insulin dose. However, if the patient is on 40 units of LAI and has symptoms of hyperglycemia, 6 to 8 units for the dinner is reasonable. An important point to convey to this patient is to make sure there is carbohydrate consistency. The patient’s premeal BG was 137 mg/dL (7.6 mmol/L) on Monday, but it rose significantly to 313 mg/dL (17.4 mmol/L) after dinner. On Wednesday, the patient’s premeal BG prior to dinner was 150 mg/dL (8.3 mmol/L); it rose to 202 mg/dL (11.2 mmol/L) after dinner, which is high but not as high as on Monday.

Multiple factors may affect this variability; for example, on Monday the patient may have consumed more than the usual amount of carbohydrates for dinner, forgot to take oral medication for dinner, or missed his/her usual after-dinner walk. Or simply, the patient may have eaten a lot less than the usual amount of carbohydrates, walked the neighborhood, or vacuumed the entire house after dinner on Wednesday. Thus, it is imperative to carefully assess the patient’s lifestyle and recommend carbohydrate consistency at each meal.

Method 2: Basal-Bolus

When basal plus is insufficient to get the HbA_1c and BG readings to goal, taking bolus insulin for all main meals containing carbohydrates must be considered. This is often called basal-bolus, multiple daily injections, or intensive insulin therapy.

In order to understand the concept of basal-bolus, HCPs should consider normal physiology. The pancreas releases a constant amount of insulin, aka background insulin, to cover glucose produced by the liver to the cells between meals. In addition, a burst of insulin, aka bolus insulin, to meet the blood glucose elevation from food to maintain homeostasis. In patients with T2DM, the relative amount produced by the pancreas is insufficient to meet the demand due to pancreatic exhaustion or insulin resistance. This necessitates the need to replace background and bolus insulin.⁷

The ideal final total bolus insulin amount (the sum of all meal bolus doses) should be about half the basal dosing. Calculation of starting bolus dosing can be done as in the basal plus regimen, either 4 to 6 units per meal or 0.1 U/kg/d.¹⁰ Alternatively, if the patient is on 60 units of long-acting analog and BGs are well above goal range, the prescriber could consider about 20 units of bolus dose (60 U divided by 3 meals) if the patient eats 3 routine meals a day with at least 30 g of carbohydrates, and physical activity levels are fairly consistent. If the patient eats the most carbohydrates at lunchtime, consider more bolus at lunch (ie, 18 U of bolus for breakfast and dinner and 24 U of bolus for lunch coverage). 
Patients need to separate the time between the bolus doses, usually a minimum of 4 hours apart, to avoid insulin stacking, which is a common reason for hypoglycemia. Insulin stacking occurs when additional quick or rapid insulin is injected when the previous insulin is still in the body or when there is insulin on board.^8,11 Typically, bolus analogs stay in the body for about 4 to 6 hours, thus necessitating separation of the doses at least 4 hours apart. Patients sometimes inject more bolus insulin after high postprandial readings, which can result in insulin stacking. In some cases, the patient may misunderstand and take mealtime insulin at a scheduled time instead of at the time of the meal.

Injecting bolus insulin for every snack must be avoided to prevent a vicious cycle: Postprandial hyperglycemia –> extra bolus insulin, resulting in insulin stacking –> hypoglycemia –> overtreatment with food –> hyperglycemia –> extra bolus insulin, resulting in insulin stacking –> and so on. Whenever there are readings in the hypoglycemic and hyperglycemic range, address hypoglycemia first because hyperglycemia often is due to overtreatment of hypoglycemia.

Method 3: Premix or Split-Mix (Patient-Mix) Insulin

Postprandial BG excursions can be minimized by changing basal insulin to premix or split-mix (patient-mix) insulin that has a mixture of mealtime and intermediate action insulin (Table 4).^12-16 The use of premixed insulin is a viable option due to its ease of use and for those who have restrictions based on the complexity of the basal-bolus regimen.⁷ If a patient has routine meals and prefers not to carry around insulin for lunch, the schedule of premix insulin taken at breakfast and dinner is ideal.

Some caveats for safe prescribing should be understood. A recent summary of premixed insulin regimens noted that they seem to have a similar efficacy and safety profile compared with regimens that include basal insulin with or without mealtime insulin; however, cost and patient adherence are improved.¹⁷ It is important to monitor insulin-naïve patients for hypoglycemia and reduced efficacy when used twice daily compared with basal plus 3-times daily prandial insulin in patients needing insulin intensification.¹⁷

A randomized trial noted that hypoglycemia rates were twice as high with premixed insulin compared with basal-bolus insulin.¹⁸ This study also noted that the premixed insulin group experienced the highest dropout rate, partly due to hypoglycemia. A regimen of basal insulin with the option to add a single prandial insulin injection at the main meal was as effective in reducing HbA_1c with less hypoglycemia. The premixed insulin is convenient but does not allow a separate correction of either mealtime or intermediate-acting insulin doses. If the premixed dose needs to be adjusted due to fasting hyperglycemia > 180 mg/dL(10.0 mmol/L), the TDD can be increased by 10%.²

In contrast, a split-mix (patient-mix) insulin regimen allows for the ability to vary the amount/ratio of combinations and adjustment of bolus and intermediate insulin doses. The disadvantages of split-mix insulin include the inconvenience of manually mixing of insulin and the potential for dosing errors. The patient needs to be taught additional steps on how to mix both insulins. Ensure the correct mixing order to maintain insulin potency; regular first, then neutral protamine Hagedorn (NPH). An HCP should remember the RN acronym if the patient is combining regular insulin and NPH. If there is doubt about the patient’s insulin injection technique, HCPs should ask the patient to demonstrate how to correctly pull up a dose of normal saline and inject it during a clinic visit. The only basal insulin that can be physically mixed with quick or rapid insulin is NPH. It should never be mixed with long-acting analogs. The patient should not even use the same syringe to draw up bolus analog insulin and inject it and then use the same syringe to draw up long-acting analog insulin.

One caveat to a fixed regimen (same amount of insulin dose) is that providers often expect that the patient will eat a consistent amount of carbohydrates at each meal and premeal glucose readings are fairly stable. Oftentimes, this is not true. If a patient took a bolus dose of 8 units of rapid-acting insulin and ate a 6 oz steak, 3 oz baked potato, steamed broccoli at a dinner; and no bread, the after dinner BG might register 145 mg/dL (8.1 mmol/L). Then, the next day for dinner, if he or she took the same amount of 8 units of rapid-acting insulin and ate 1 cup of spaghetti, ½ cup of spaghetti meat sauce, and 2 slices of garlic bread, the after dinner reading might be 322 mg/dL (17.9 mmol/L). The patient’s BG was higher on the second day because of the higher carbohydrate content of the meal. If the rapid-acting insulin was increased to 12 units of bolus based on the high carbohydrate meal and the patient ate a lower carbohydrate meal, hypoglycemia could ensue. Thus, it is important to work with the patient regarding the consumption of a consistent amount of carbohydrates and refer to a registered dietitian for carbohydrate consistency.

For the flexible regimen, the prescriber may consider using an insulin to carbohydrate (IC) ratio and sensitivity factor (SF), also called sliding scale or correction factor. The IC ratio represents how much insulin is needed to cover consumed carbohydrates. For instance, if the patient uses IC ratio of 1:15, 1 unit of bolus insulin will cover 15 g of carbohydrates. If the patient eats a meal with 60 g of carbohydrates and is using IC ratio of 1:15, the patient will inject 4 units of bolus insulin. Sensitivity factor represents how much BG will be lowered in mg/dL by taking 1 unit of bolus insulin. For example, if the patient uses SF of 1:50, 1 unit of bolus insulin will lower BG by 50 mg/dL (2.8 mmol/L). When the desired (target) BG reading is 100 mg/dL (5.6 mmol/L) and the patient’s current BG is 200 mg/dL (11.1 mmol/L), the patient will divide 100 mg/dL (5.6 mmol/L) by 50 (derived from SF of 1:50). The net result is 2 units of bolus insulin are needed to lower BG by 100 mg/dL (5.6 mmol/L). If the premeal BG is 200 mg/dL (11.1 mmol/L) and 60 g of carbohydrates are eaten, then the patient will need a total of 6 units (4 U for carbohydrate and 2 U for high BG) bolus before the meal. For additional information, readers are encouraged to read the articles by Petznick and by Joslin Diabetes Center for IC and SF.^19,20

Bolus Insulin Titration

When the difference in BG readings before and 2 hours after a meal, called the Δ value, is > 50 mg/dL (2.8 mmol/L), the bolus insulin may need to be adjusted after ensuring the patient is ingesting consistent carbohydrates and performs the usual amount of activities around mealtime. For example, if the premeal reading was 130 mg/dL (7.2 mmol/L) but the 2-hour postprandial reading is > 180 mg/dL (10.0 mmol/L), the prescriber can increase the mealtime insulin by 1 unit if the mealtime insulin is < 10 units, by 2 units if < 20 units, or by 10% of the mealtime insulin dose. If the premeal BG is < 80 mg/dL (4.4 mmol/L) and the drop in BG is > Δ value of 50 mg/dL (2.8 mmol/L), the prescriber can decrease the mealtime insulin using the same calculation. Monitoring BG and titration recommendations are shown in Table 5. When adjusting the bolus insulin dose, it is best to make adjustments gradually rather than making several changes at once.

The 15/15 rule needs to be followed in cases involving hypoglycemia.²¹ When the BG is ≤ 70 mg/dL (3.9 mmol/L) and the patient is conscious and able to eat or drink, it is recommended they eat 15 g (30 g if BG is below 50) of carbohydrates then repeat BG check every 15 minutes until the BG is in the target range.^22,23 If the patient is unconscious, providers should administer glucagon (if available), place the patient in a lateral position to avoid aspiration, and call 911. If hyperkalemia is an issue in chronic kidney disease, patients should consume apple juice rather than orange juice due to its lower potassium content. If the patient is taking α glucosidase inhibitors (AGI) like acarbose or miglitol, only pure glucose like glucose tablets needs to be given to treat hypoglycemia instead of regular soda or candy, as the AGI will slow absorption of other types of carbohydrates.^24,25 After the severe hypoglycemic episode, it is imperative to assess for the cause and explore ways to prevent subsequent hypoglycemia. Providers also should advise the patient to wear medical emergency identification. 

Conclusion

Click here to read the digital edition.

Individuals with type 2 diabetes mellitus (T2DM) spend between 5 and 10 years with elevated hemoglobin A_1c (HbA_1c) before initiation of insulin.¹ Once the basal insulin is initiated, the patient can go years with only adjustment of the basal insulin, resulting in over-basalization. In general, the total daily dose (TDD) of insulin should be composed of about 50% basal “background” insulin and 50% bolus “meal” insulin. When the fasting glucose readings are on target but HbA_1c is still above the mutually set goal range, postprandial readings need to be evaluated.

This article focuses on initiating and titrating bolus insulin in nonpregnant patients with T2DM. Before initiation of bolus insulin, it is important for the patient to be actively engaged with a diabetes educator for diabetes self-management education and support (DSME/S), including the understanding of the correct use of insulin, carbohydrate counting, and increasing physical activities. Ensuring the correct technique of insulin administration and self-monitoring of blood glucose (SMBG) is critical. A knowledge deficit of carbohydrate information can lead to uncontrolled blood glucose (BG). The authors have encountered numerous times when patients were drinking sugary beverages or consuming large amounts of “healthy” food without realizing the carbohydrate content. Therefore, treatment in concert with a registered dietitian and certified diabetes educator is highly recommended.

Initiation of Bolus Insulin

There are 3 options of postprandial coverage with bolus insulin when a patient is taking basal insulin: basal plus, basal-bolus, or premix insulin. A possible fourth option for postprandial coverage is to add glucagon-like peptide-1 receptor agonist (GLP-1 RA), an injectable noninsulin antihyperglycemic agent, which has shown noninferior efficacy to adding bolus insulin and a favorable effect on weight with less risk of hypoglycemia.^2-5 Although it can be expensive, combining GLP-1 RA to basal insulin results in lowering HbA_1c of 0.66 up to 1.74% (or lowering mmol/mol of 7 up to 19) from the baseline.⁶ However, adding bolus insulin may be the only option to avoid glucotoxicity and prevent further diabetes complications when the HbA_1c level is well above the goal range. It is usually recommended to discontinue sulfonylurea when bolus insulin is added due to the β-cell exhaustion with advancing natural history of diabetes.^7,8

Method 1: Basal Plus

The health care provider (HCP) needs to consider whether the patient is over-basalized when the HbA_lc and postprandial BG readings are still not at goal despite careful titration of basal insulin dose to > 0.5 U/kg/d.⁹ This is the time to discuss with the patient the coverage of mealtime glucose excursions. In the basal plus regimen, the prescribing provider may add 1 bolus insulin injection for the meal with the highest amount of carbohydrates or add 2 bolus injections for the most and second most meals with carbohydrates. Multiple types of bolus insulin are available in the current U.S. market (Table 1).

There are 2 ways to add bolus insulin: fixed and flexible. In the fixed regimen, the patient will take the same amount of bolus insulin regardless of premeal BG readings and carbohydrate content of the food. The authors recommend adding bolus insulin of about 4 to 6 units once or twice a day with meals, depending on the number of meals a day, carbohydrate content of the meal, current and desired degree of diabetes control, and physical activities. Another way to calculate a bolus insulin dose is to start at 0.1 U/kg if adding to the basal insulin.¹⁰ Flexible regimen allows various bolus doses based on premeal BG, carbohydrate intake, and activities. Information on this regimen, will be discussed more later.

Patient Cases

Tables 2 and 3 describe 2 patient cases. For example, patient 1 weighs 80 kg. If the prescribing HCP and patient decide to add only 1 bolus to the largest carbohydrate meal at dinnertime, then the patient may take 8 units (80 kg × 0.1 U/kg/meal = 8 units for meal). The patient’s current insulin dose, medical comorbidities, current diabetes control status, living situations, and overall cognition also should be considered.

Imagine patient 1 is taking 14 units daily of a long-acting insulin (LAI). If the patient is taking a fairly low dose of LAI, has multiple comorbidities, recent BG log/HgA_lc, and lives alone but demonstrates good cognition to follow instructions, the prescriber may consider adding the bolus insulin of 4 units for dinner; thus, the bolus dose is about one-third of total basal insulin dose. However, if the patient is on 40 units of LAI and has symptoms of hyperglycemia, 6 to 8 units for the dinner is reasonable. An important point to convey to this patient is to make sure there is carbohydrate consistency. The patient’s premeal BG was 137 mg/dL (7.6 mmol/L) on Monday, but it rose significantly to 313 mg/dL (17.4 mmol/L) after dinner. On Wednesday, the patient’s premeal BG prior to dinner was 150 mg/dL (8.3 mmol/L); it rose to 202 mg/dL (11.2 mmol/L) after dinner, which is high but not as high as on Monday.

Multiple factors may affect this variability; for example, on Monday the patient may have consumed more than the usual amount of carbohydrates for dinner, forgot to take oral medication for dinner, or missed his/her usual after-dinner walk. Or simply, the patient may have eaten a lot less than the usual amount of carbohydrates, walked the neighborhood, or vacuumed the entire house after dinner on Wednesday. Thus, it is imperative to carefully assess the patient’s lifestyle and recommend carbohydrate consistency at each meal.

Method 2: Basal-Bolus

When basal plus is insufficient to get the HbA_1c and BG readings to goal, taking bolus insulin for all main meals containing carbohydrates must be considered. This is often called basal-bolus, multiple daily injections, or intensive insulin therapy.

In order to understand the concept of basal-bolus, HCPs should consider normal physiology. The pancreas releases a constant amount of insulin, aka background insulin, to cover glucose produced by the liver to the cells between meals. In addition, a burst of insulin, aka bolus insulin, to meet the blood glucose elevation from food to maintain homeostasis. In patients with T2DM, the relative amount produced by the pancreas is insufficient to meet the demand due to pancreatic exhaustion or insulin resistance. This necessitates the need to replace background and bolus insulin.⁷

The ideal final total bolus insulin amount (the sum of all meal bolus doses) should be about half the basal dosing. Calculation of starting bolus dosing can be done as in the basal plus regimen, either 4 to 6 units per meal or 0.1 U/kg/d.¹⁰ Alternatively, if the patient is on 60 units of long-acting analog and BGs are well above goal range, the prescriber could consider about 20 units of bolus dose (60 U divided by 3 meals) if the patient eats 3 routine meals a day with at least 30 g of carbohydrates, and physical activity levels are fairly consistent. If the patient eats the most carbohydrates at lunchtime, consider more bolus at lunch (ie, 18 U of bolus for breakfast and dinner and 24 U of bolus for lunch coverage). 
Patients need to separate the time between the bolus doses, usually a minimum of 4 hours apart, to avoid insulin stacking, which is a common reason for hypoglycemia. Insulin stacking occurs when additional quick or rapid insulin is injected when the previous insulin is still in the body or when there is insulin on board.^8,11 Typically, bolus analogs stay in the body for about 4 to 6 hours, thus necessitating separation of the doses at least 4 hours apart. Patients sometimes inject more bolus insulin after high postprandial readings, which can result in insulin stacking. In some cases, the patient may misunderstand and take mealtime insulin at a scheduled time instead of at the time of the meal.

Injecting bolus insulin for every snack must be avoided to prevent a vicious cycle: Postprandial hyperglycemia –> extra bolus insulin, resulting in insulin stacking –> hypoglycemia –> overtreatment with food –> hyperglycemia –> extra bolus insulin, resulting in insulin stacking –> and so on. Whenever there are readings in the hypoglycemic and hyperglycemic range, address hypoglycemia first because hyperglycemia often is due to overtreatment of hypoglycemia.

Method 3: Premix or Split-Mix (Patient-Mix) Insulin

Postprandial BG excursions can be minimized by changing basal insulin to premix or split-mix (patient-mix) insulin that has a mixture of mealtime and intermediate action insulin (Table 4).^12-16 The use of premixed insulin is a viable option due to its ease of use and for those who have restrictions based on the complexity of the basal-bolus regimen.⁷ If a patient has routine meals and prefers not to carry around insulin for lunch, the schedule of premix insulin taken at breakfast and dinner is ideal.

Some caveats for safe prescribing should be understood. A recent summary of premixed insulin regimens noted that they seem to have a similar efficacy and safety profile compared with regimens that include basal insulin with or without mealtime insulin; however, cost and patient adherence are improved.¹⁷ It is important to monitor insulin-naïve patients for hypoglycemia and reduced efficacy when used twice daily compared with basal plus 3-times daily prandial insulin in patients needing insulin intensification.¹⁷

A randomized trial noted that hypoglycemia rates were twice as high with premixed insulin compared with basal-bolus insulin.¹⁸ This study also noted that the premixed insulin group experienced the highest dropout rate, partly due to hypoglycemia. A regimen of basal insulin with the option to add a single prandial insulin injection at the main meal was as effective in reducing HbA_1c with less hypoglycemia. The premixed insulin is convenient but does not allow a separate correction of either mealtime or intermediate-acting insulin doses. If the premixed dose needs to be adjusted due to fasting hyperglycemia > 180 mg/dL(10.0 mmol/L), the TDD can be increased by 10%.²

In contrast, a split-mix (patient-mix) insulin regimen allows for the ability to vary the amount/ratio of combinations and adjustment of bolus and intermediate insulin doses. The disadvantages of split-mix insulin include the inconvenience of manually mixing of insulin and the potential for dosing errors. The patient needs to be taught additional steps on how to mix both insulins. Ensure the correct mixing order to maintain insulin potency; regular first, then neutral protamine Hagedorn (NPH). An HCP should remember the RN acronym if the patient is combining regular insulin and NPH. If there is doubt about the patient’s insulin injection technique, HCPs should ask the patient to demonstrate how to correctly pull up a dose of normal saline and inject it during a clinic visit. The only basal insulin that can be physically mixed with quick or rapid insulin is NPH. It should never be mixed with long-acting analogs. The patient should not even use the same syringe to draw up bolus analog insulin and inject it and then use the same syringe to draw up long-acting analog insulin.

One caveat to a fixed regimen (same amount of insulin dose) is that providers often expect that the patient will eat a consistent amount of carbohydrates at each meal and premeal glucose readings are fairly stable. Oftentimes, this is not true. If a patient took a bolus dose of 8 units of rapid-acting insulin and ate a 6 oz steak, 3 oz baked potato, steamed broccoli at a dinner; and no bread, the after dinner BG might register 145 mg/dL (8.1 mmol/L). Then, the next day for dinner, if he or she took the same amount of 8 units of rapid-acting insulin and ate 1 cup of spaghetti, ½ cup of spaghetti meat sauce, and 2 slices of garlic bread, the after dinner reading might be 322 mg/dL (17.9 mmol/L). The patient’s BG was higher on the second day because of the higher carbohydrate content of the meal. If the rapid-acting insulin was increased to 12 units of bolus based on the high carbohydrate meal and the patient ate a lower carbohydrate meal, hypoglycemia could ensue. Thus, it is important to work with the patient regarding the consumption of a consistent amount of carbohydrates and refer to a registered dietitian for carbohydrate consistency.

For the flexible regimen, the prescriber may consider using an insulin to carbohydrate (IC) ratio and sensitivity factor (SF), also called sliding scale or correction factor. The IC ratio represents how much insulin is needed to cover consumed carbohydrates. For instance, if the patient uses IC ratio of 1:15, 1 unit of bolus insulin will cover 15 g of carbohydrates. If the patient eats a meal with 60 g of carbohydrates and is using IC ratio of 1:15, the patient will inject 4 units of bolus insulin. Sensitivity factor represents how much BG will be lowered in mg/dL by taking 1 unit of bolus insulin. For example, if the patient uses SF of 1:50, 1 unit of bolus insulin will lower BG by 50 mg/dL (2.8 mmol/L). When the desired (target) BG reading is 100 mg/dL (5.6 mmol/L) and the patient’s current BG is 200 mg/dL (11.1 mmol/L), the patient will divide 100 mg/dL (5.6 mmol/L) by 50 (derived from SF of 1:50). The net result is 2 units of bolus insulin are needed to lower BG by 100 mg/dL (5.6 mmol/L). If the premeal BG is 200 mg/dL (11.1 mmol/L) and 60 g of carbohydrates are eaten, then the patient will need a total of 6 units (4 U for carbohydrate and 2 U for high BG) bolus before the meal. For additional information, readers are encouraged to read the articles by Petznick and by Joslin Diabetes Center for IC and SF.^19,20

Bolus Insulin Titration

When the difference in BG readings before and 2 hours after a meal, called the Δ value, is > 50 mg/dL (2.8 mmol/L), the bolus insulin may need to be adjusted after ensuring the patient is ingesting consistent carbohydrates and performs the usual amount of activities around mealtime. For example, if the premeal reading was 130 mg/dL (7.2 mmol/L) but the 2-hour postprandial reading is > 180 mg/dL (10.0 mmol/L), the prescriber can increase the mealtime insulin by 1 unit if the mealtime insulin is < 10 units, by 2 units if < 20 units, or by 10% of the mealtime insulin dose. If the premeal BG is < 80 mg/dL (4.4 mmol/L) and the drop in BG is > Δ value of 50 mg/dL (2.8 mmol/L), the prescriber can decrease the mealtime insulin using the same calculation. Monitoring BG and titration recommendations are shown in Table 5. When adjusting the bolus insulin dose, it is best to make adjustments gradually rather than making several changes at once.

The 15/15 rule needs to be followed in cases involving hypoglycemia.²¹ When the BG is ≤ 70 mg/dL (3.9 mmol/L) and the patient is conscious and able to eat or drink, it is recommended they eat 15 g (30 g if BG is below 50) of carbohydrates then repeat BG check every 15 minutes until the BG is in the target range.^22,23 If the patient is unconscious, providers should administer glucagon (if available), place the patient in a lateral position to avoid aspiration, and call 911. If hyperkalemia is an issue in chronic kidney disease, patients should consume apple juice rather than orange juice due to its lower potassium content. If the patient is taking α glucosidase inhibitors (AGI) like acarbose or miglitol, only pure glucose like glucose tablets needs to be given to treat hypoglycemia instead of regular soda or candy, as the AGI will slow absorption of other types of carbohydrates.^24,25 After the severe hypoglycemic episode, it is imperative to assess for the cause and explore ways to prevent subsequent hypoglycemia. Providers also should advise the patient to wear medical emergency identification. 

Conclusion

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