Navigating Diabetes Treatments
Introduction
There are many treatments for type 2 diabetes including 13 classes of medications. While this might be great in terms of having choices to individualize therapy, it is often overwhelming for the patient and the clinician. In truth, it is difficult to have a thorough understanding and working knowledge of all the medications available to treat diabetes. No matter what type of diabetes or the duration of the condition, therapeutic lifestyle change is central to management. For type 2 diabetes, most people will start with metformin and lifestyle change as initial therapy. The American Diabetes Association (ADA) now recommends specific type 2 diabetes treatments regardless of HbA1c in people with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD). The following cases provide examples and situations for best placement of each treatment.
Case 1. Therapeutic Lifestyle Change
“I do not want to take any medications.”
A 36-year-old Asian woman presented for her annual physical exam. She felt well and had no complaints. She denied any new diagnoses, emergency room visits, hospitalizations, or medications. It had been a challenging year for her due to the COVID-19 pandemic, related to her work as a nurse in the pediatric ICU and having to coordinate home schooling for her two children.
About 4 years ago, her blood work showed that she had prediabetes, and this really scared her. At the time she made changes to her daily routines so she could get back to a normal glucose range. She began exercising more and reduced the amount of starches in her diet. She worked hard to stay healthy because both her mother and sister were taking medicines for diabetes. She wanted to do everything she could to prevent getting it herself. However, because of the COVID-19 pandemic, she had not been able to go to the gym and had not been as careful with her diet and had gained some weight.
She had her labs completed prior to this visit.
Med HX: dyslipidemia (6 years)
Medications: none and no OTC (over-the-counter) supplements or vitamins
Allergies: none
Family Medical History: mother and sister with type 2 diabetes; dad with dyslipidemia and coronary artery disease; no personal or family history (FH) of autoimmune conditions
Social History: no tobacco, no alcohol, and no recreational drug use; lives with her spouse; walks 30 minutes every day during her lunch break at work; eats a relatively traditional northern Chinese diet
Physical Exam: Ht. 5′6″, Wt. 152 lb, BMI 24.5, T 98.2, P 78, R 12, BP 112/70 (weight up 6 lb from last year)
GEN: in no distress
HEENT: normal including thyroid exam
CV: normal
RESP: normal
Otherwise: normal exam
Labs: nonfasting (90 minutes after eating)
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CASE QUESTIONS1. Does she have diabetes?
View Answer
1. Her HbA1c is currently in the diabetes range, but her nonfasting glucose is in the prediabetes range. While there is a strong clinical indication that she does have diabetes, it would be best to repeat an HbA1c to confirm the diagnosis. We advised her to repeat one of the following, an HbA1c, a glucose tolerance test (GTT), or a fasting glucose.1 A repeat HbA1c 2 weeks later was 6.9%. This was very frustrating for her because she felt like she had taken control of her eating over the past 2 weeks.
With two HbA1c readings above 6.5%, the diagnosis of diabetes can be confirmed. Given her family history of type 2 diabetes, and her lack of autoimmune disease, type 2 diabetes is most likely. Monogenic diabetes is also a possibility given a strong family history of diabetes, but you would not expect to see diabetic dyslipidemia (high trigs, low HDL [high-density lipoprotein]) in monogenic diabetes. With all of these factors considered she most likely has type 2 diabetes.
2. Is she overweight?
View Answer
2. Evidence from the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) illustrates that metabolic abnormalities can occur in lower weight individuals in some populations. Specifically, in Asian populations (Chinese, Japanese, Filipino, Indian, etc.), metabolic abnormalities can occur with a BMI of 23 kg/m2. Consequently, the WHO has modified the BMI classification of weight in the Asian population.2
BMI ≥ 23 kg/m2 overweight
BMI ≥ 27.5 kg/m2 obese
3. Why did her hemoglobin A1c not decrease despite 2 weeks of lifestyle modification?
View Answer
3. This issue is important to clarify with the patient. The hemoglobin A1c is a good measure of glucose excursion over time. However, it is a measure of the glucose as it adheres to the hemoglobin molecule in red blood cells. While it may be reasoned from a patient standpoint that 2 weeks of lifestyle changes would lower the A1c, it is not realistic to expect changes that quickly. Her current readings of 6.8% and 6.9% are essentially the same given the specificity of the exam.
4. What is the best test to diagnose her diabetes?
View Answer
4. As mentioned in Chapter 1, there are four different ways to diagnose diabetes.1,3 It can be diagnosed based upon elevated fasting glucose, elevated hemoglobin A1c, with an abnormal GTT, or upon observation of significant hyperglycemia and typical catabolic symptoms (polyuria, polydipsia, polyphagia, and weight loss) of diabetes. With no single best way to diagnose diabetes, it is worthwhile to discuss the sensitivity and specificity of each diagnostic method4 (Table 4.1).
TABLE 4.1 Glucose Ranges for Prediabetes and Diabetes Mellitus | ||||||||||||
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Historically, the oral glucose tolerance test (OGTT) was the gold standard for diagnosing diabetes.1,3 It has been the most sensitive assay for identifying glucose abnormalities (87.2% sensitivity, 77.7% specificity), but it does not have good reproducibility and has been shown to overestimate the incidence of diabetes. Further, it is difficult to get people to complete an OGTT due to the time it takes and the symptoms it may induce. Diagnosis via fasting glucose is less sensitive (70% sensitivity, 86.7% specificity), but the presence of fasting hyperglycemia correlates well with chronic hyperglycemia.3
Diagnosis via HbA1c is both sensitive and specific (sensitivity 87.1%, specificity 85.6%) and correlates well with diabetes-related complications.3 It also does not require the patient to fast. However, HbA1c is reliant on the patient having a normal and stable hemoglobin. If a patient is anemic, has a hemoglobinopathy, or has recently lost, donated, or received blood, the HbA1c will be inaccurate for diagnosing or monitoring glucose control.3 Finally, there is some evidence that there are ethnic differences in the HbA1c levels at the same glycemic levels.5 Finally, some investigators have proposed combining the fasting glucose and HbA1c as a combined screen as this is as sensitive as the OGTT and more easily reproducible.3
While there are fewer supporting data, there is some evidence that the same tests and thresholds can be used to diagnose diabetes in children and adolescents6 (Table 4.2).
Note. Positive predictive values are highly dependent on the prevalence of the disease in the population, whereas sensitivity and specificity do not vary by prevalence of the disease in the population. This explains the lower values for the positive predictive values.
TABLE 4.2 Sensitivity and Specificity for Current Tests for Hyperglycemia | ||||||||||||||||
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5. What are the best dietary interventions for her diabetes?
View Answer
5. As mentioned earlier, there is good evidence that diabetes can be prevented with lifestyle interventions.7,8 However, the data are less conclusive on the use of lifestyle interventions for the treatment and remission of type 2 diabetes.9,10,11,12
The ADA provided updated guidelines for nutritional support in the management of diabetes in 2019.13 This document described several core components of care. It identified medical nutrition therapy (MNT) as the evidence-based therapy provided by a dietitian. It also stated that all patients with diabetes should receive nutrition therapy, defined as treatment through the modification of nutrient or whole-food intake.
MNT has been shown to reduce HbA1c by up to 2.0% in patients with type 2 diabetes and 1.9% in those with type 1 diabetes.14 In terms of nutrient recommendations, evidence suggests that there is not an ideal percentage of calories from carbohydrates, proteins, and fats for all people with or at risk for diabetes; therefore, macronutrient distribution should be based on individualized assessment of current eating patterns, preferences, and metabolic goals.13 To be effective, MNT must be also highly individualized to the patient’s cultural and family norms, work within the patient’s means and preferences, and accommodate the individual patient’s skill level in terms of diabetes self-management behaviors.13
A single nutrition therapy plan for all of diabetes may seem “too generic.” There are a number of factors that should be considered when providing nutrition therapy to help to individualize advice to the patient and their needs:
What type of diabetes does the person have?
What role do food and nutrition play in the person’s culture and religion?
What is the patient’s living situation?
What financial and food resources are available for the patient?
Who does the person eat with, and who prepares the food?
Are there other medical problems that would complicate the recommendations (for example, heart failure, ASCVD, disorder eating) for this person?
A dietary plan that may at first seem simple may become daunting when these factors are taken into consideration. The true complexity of one’s dietary practices is one of the many reasons that people with diabetes benefit from a diabetes self-management education and support (DSMES) program. This comprehensive training with the patient (and often family members as well) requires time, attention, and in-depth knowledge. Unfortunately, primary care clinicians typically lack the time and resources to adequately provide this level of support. A strong recommendation to seek the guidance of a dietitian or diabetes care and education care specialist can help the patient get the personalized help that they need to effectively manage their diabetes.
The goals of nutrition therapy are seen in Table 4.3.
TABLE 4.3 ADA 2019 Consensus Statement: Goals of Nutrition Therapy | |
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Specific fundamental MNT teaching points include the following:
Assess the patient’s cultural and family norms before advising on dietary plans. Working with a patient’s heritage diet can help manage chronic metabolic conditions more effectively.
The ideal amount of carbohydrates is unknown. The 130 g/d of carbohydrates needed for brain function can be provided from the diet, but these can also be produced from the body’s normal physiologic processes. Therefore, the previous thought that this was a minimum number of carbohydrates needed in a diet no longer applies. Lower carbohydrate diets are likely to be beneficial for most people with type 2 diabetes.
The quality of carbohydrates is important and can have a major impact on glycemic excursions. Whole-food sources should be encouraged as this will produce increased fiber content as well.
Fiber content is helpful not only for glucose control, but fiber intake has also been associated with reduced mortality. A minimum of 14 g of fiber should be consumed for every 1000 kcals ingested.
Fat should be 20% to 35% of all calories. Trans fats should be eliminated from the diet, and saturated fats should be limited.
Higher protein calories may improve weight loss but should be focused on plant sources whenever possible. Restricting protein in people with CKD is no longer recommended for most patients.
Patients with CKD will benefit from switching to a plant-based diet.
6. What resources are available to help her?
ANSWERS AND EXPLANATIONS1. Her HbA1c is currently in the diabetes range, but her nonfasting glucose is in the prediabetes range. While there is a strong clinical indication that she does have diabetes, it would be best to repeat an HbA1c to confirm the diagnosis. We advised her to repeat one of the following, an HbA1c, a glucose tolerance test (GTT), or a fasting glucose.1 A repeat HbA1c 2 weeks later was 6.9%. This was very frustrating for her because she felt like she had taken control of her eating over the past 2 weeks.
With two HbA1c readings above 6.5%, the diagnosis of diabetes can be confirmed. Given her family history of type 2 diabetes, and her lack of autoimmune disease, type 2 diabetes is most likely. Monogenic diabetes is also a possibility given a strong family history of diabetes, but you would not expect to see diabetic dyslipidemia (high trigs, low HDL [high-density lipoprotein]) in monogenic diabetes. With all of these factors considered she most likely has type 2 diabetes.
2. Evidence from the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) illustrates that metabolic abnormalities can occur in lower weight individuals in some populations. Specifically, in Asian populations (Chinese, Japanese, Filipino, Indian, etc.), metabolic abnormalities can occur with a BMI of 23 kg/m2. Consequently, the WHO has modified the BMI classification of weight in the Asian population.2
BMI ≥ 23 kg/m2 overweight
BMI ≥ 27.5 kg/m2 obese
3. This issue is important to clarify with the patient. The hemoglobin A1c is a good measure of glucose excursion over time. However, it is a measure of the glucose as it adheres to the hemoglobin molecule in red blood cells. While it may be reasoned from a patient standpoint that 2 weeks of lifestyle changes would lower the A1c, it is not realistic to expect changes that quickly. Her current readings of 6.8% and 6.9% are essentially the same given the specificity of the exam.
4. As mentioned in Chapter 1, there are four different ways to diagnose diabetes.1,3 It can be diagnosed based upon elevated fasting glucose, elevated
hemoglobin A1c, with an abnormal GTT, or upon observation of significant hyperglycemia and typical catabolic symptoms (polyuria, polydipsia, polyphagia, and weight loss) of diabetes. With no single best way to diagnose diabetes, it is worthwhile to discuss the sensitivity and specificity of each diagnostic method4 (Table 4.1).
hemoglobin A1c, with an abnormal GTT, or upon observation of significant hyperglycemia and typical catabolic symptoms (polyuria, polydipsia, polyphagia, and weight loss) of diabetes. With no single best way to diagnose diabetes, it is worthwhile to discuss the sensitivity and specificity of each diagnostic method4 (Table 4.1).
TABLE 4.1 Glucose Ranges for Prediabetes and Diabetes Mellitus | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Historically, the oral glucose tolerance test (OGTT) was the gold standard for diagnosing diabetes.1,3 It has been the most sensitive assay for identifying glucose abnormalities (87.2% sensitivity, 77.7% specificity), but it does not have good reproducibility and has been shown to overestimate the incidence of diabetes. Further, it is difficult to get people to complete an OGTT due to the time it takes and the symptoms it may induce. Diagnosis via fasting glucose is less sensitive (70% sensitivity, 86.7% specificity), but the presence of fasting hyperglycemia correlates well with chronic hyperglycemia.3
Diagnosis via HbA1c is both sensitive and specific (sensitivity 87.1%, specificity 85.6%) and correlates well with diabetes-related complications.3 It also does not require the patient to fast. However, HbA1c is reliant on the patient having a normal and stable hemoglobin. If a patient is anemic, has a hemoglobinopathy, or has recently lost, donated, or received blood, the HbA1c will be inaccurate for diagnosing or monitoring glucose control.3 Finally, there is some evidence that there are ethnic differences in the HbA1c levels at the same glycemic levels.5 Finally, some investigators have proposed combining the fasting glucose and HbA1c as a combined screen as this is as sensitive as the OGTT and more easily reproducible.3
While there are fewer supporting data, there is some evidence that the same tests and thresholds can be used to diagnose diabetes in children and adolescents6 (Table 4.2).
Note. Positive predictive values are highly dependent on the prevalence of the disease in the population, whereas sensitivity and specificity do not vary by prevalence of the disease in the population. This explains the lower values for the positive predictive values.
TABLE 4.2 Sensitivity and Specificity for Current Tests for Hyperglycemia | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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5. As mentioned earlier, there is good evidence that diabetes can be prevented with lifestyle interventions.7,8 However, the data are less conclusive on the use of lifestyle interventions for the treatment and remission of type 2 diabetes.9,10,11,12
The ADA provided updated guidelines for nutritional support in the management of diabetes in 2019.13 This document described several core components of care. It identified medical nutrition therapy (MNT) as the evidence-based therapy provided by a dietitian. It also stated that all patients with diabetes should receive nutrition therapy, defined as treatment through the modification of nutrient or whole-food intake.
MNT has been shown to reduce HbA1c by up to 2.0% in patients with type 2 diabetes and 1.9% in those with type 1 diabetes.14 In terms of nutrient recommendations, evidence suggests that there is not an ideal percentage of calories from carbohydrates, proteins, and fats for all people with or at risk for diabetes; therefore, macronutrient distribution should be based on individualized assessment of current eating patterns, preferences, and metabolic goals.13 To be effective, MNT must be also highly individualized to the patient’s cultural and family norms, work within the patient’s means and preferences, and accommodate the individual patient’s skill level in terms of diabetes self-management behaviors.13
A single nutrition therapy plan for all of diabetes may seem “too generic.” There are a number of factors that should be considered when providing nutrition therapy to help to individualize advice to the patient and their needs:
What type of diabetes does the person have?
What role do food and nutrition play in the person’s culture and religion?
What is the patient’s living situation?
What financial and food resources are available for the patient?
Who does the person eat with, and who prepares the food?
Are there other medical problems that would complicate the recommendations (for example, heart failure, ASCVD, disorder eating) for this person?
A dietary plan that may at first seem simple may become daunting when these factors are taken into consideration. The true complexity of one’s dietary practices is one of the many reasons that people with diabetes benefit from a diabetes self-management education and support (DSMES) program. This comprehensive training with the patient (and often family members as well) requires time, attention, and in-depth knowledge. Unfortunately, primary care clinicians typically
lack the time and resources to adequately provide this level of support. A strong recommendation to seek the guidance of a dietitian or diabetes care and education care specialist can help the patient get the personalized help that they need to effectively manage their diabetes.
lack the time and resources to adequately provide this level of support. A strong recommendation to seek the guidance of a dietitian or diabetes care and education care specialist can help the patient get the personalized help that they need to effectively manage their diabetes.
The goals of nutrition therapy are seen in Table 4.3.
TABLE 4.3 ADA 2019 Consensus Statement: Goals of Nutrition Therapy | |
|---|---|
|
Specific fundamental MNT teaching points include the following:
Assess the patient’s cultural and family norms before advising on dietary plans. Working with a patient’s heritage diet can help manage chronic metabolic conditions more effectively.
The ideal amount of carbohydrates is unknown. The 130 g/d of carbohydrates needed for brain function can be provided from the diet, but these can also be produced from the body’s normal physiologic processes. Therefore, the previous thought that this was a minimum number of carbohydrates needed in a diet no longer applies. Lower carbohydrate diets are likely to be beneficial for most people with type 2 diabetes.
The quality of carbohydrates is important and can have a major impact on glycemic excursions. Whole-food sources should be encouraged as this will produce increased fiber content as well.
Fiber content is helpful not only for glucose control, but fiber intake has also been associated with reduced mortality. A minimum of 14 g of fiber should be consumed for every 1000 kcals ingested.
Fat should be 20% to 35% of all calories. Trans fats should be eliminated from the diet, and saturated fats should be limited.
Higher protein calories may improve weight loss but should be focused on plant sources whenever possible. Restricting protein in people with CKD is no longer recommended for most patients.
Patients with CKD will benefit from switching to a plant-based diet.
Case Summary and Closing Points
Type 2 diabetes is a chronic metabolic condition that is largely influenced by daily activities. While most people will need medication to treat their diabetes, there is strong evidence that lifestyle activities can play a large role in diabetes prevention and management. As such, it is important for clinicians to be knowledgeable about what programs have had the most success and how to help coach the patient to engage in these programs. Most clinicians engage a team to help with education including a certified diabetes education and care specialist and a dietitian. Equally important, any lifestyle change has to be a lifelong change, so it is also key to build in methods to sustain these changes.
References
1. American Diabetes Association. Standards of Medical Care 2022. Classification and Diagnosis and of Diabetes. 2022. https://diabetesjournals.org/care/article/45/Supplement_1/S17/138925/2-Classification-and-Diagnosis-of-Diabetes
2. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363(9403):157-163. Erratum in: Lancet. 2004;363(9412):902. doi:10.1016/S0140-6736(03)15268-3
3. Barr RG, Nathan DM, Meigs JB, Singer DE. Tests of glycemia for the diagnosis of type 2 diabetes mellitus. Ann Intern Med. 2002;137(4):263-272. doi:10.7326/0003-4819-137-4-200208200-00011
4. Colagiuri S, Lee CMY, Wong TY, Balkau B, Shaw JE, Borch-Johnsen K; DETECT-2 Collaboration Writing Group. Glycemic thresholds for diabetes-specific retinopathy: implications for diagnostic criteria for diabetes. Diabetes Care. 2011;34(1):145-150.
5. Wolffenbuttel BHR, Herman WH, Gross JL, Dharmalingam M, Jiang HH, Hardin DS. Ethnic differences in glycemic markers in patients with type 2 diabetes. Diabetes Care. 2013;36(10):2931-2936. doi:10.2337/dc12-2711
6. Vijayakumar P, Nelson RG, Hanson RL, Knowler WC, Sinha M. HbA1c and the prediction of type 2 diabetes in children and adults. Diabetes Care. 2017;40(1):16-21. doi:10.2337/dc16-1358
7. The Diabetes Prevention Program (DPP) Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.
8. Eriksson J, Lindstrom J, Valle T, et al. Prevention of Type II diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study (DPS) in Finland. Study design and 1-year interim report on the feasibility of the lifestyle intervention programme. Diabetologia. 1999;42(7):793-801.
9. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care. 1997;20(4):537-544.
10. Look AHEAD Research Group; Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care. 2007;30(6):1374-1383. doi:10.2337/dc07-0048
11. Lean MEJ, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019;7(5):344-355. ISSN 2213-8587 doi:10.1016/S2213-8587(19)30068-3.
12. Evert AB, Boucher JL, Cypress M, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. 2013;36(11):3821-3842. doi:10.2337/dc13-2042_
13. Evert AB, Dennison M, Gardner CD, et al. Nutrition therapy for adults with diabetes or prediabetes: a consensus report. Diabetes Care. 2019;42(5):731-754. doi:10.2337/dci19-0014
14. Franz MJ, MacLeod J, Evert A, et al. Academy of Nutrition and Dietetics Nutrition practice guideline for type 1 and type 2 diabetes in adults: systematic review of evidence for medical nutrition therapy effectiveness and recommendations for integration into the nutrition care process. J Acad Nutr Diet. 2017;117(10):1659-1679.
Case 2. Best Practices With Metformin Therapy
“Is metformin going to hurt my kidneys?”
A 38-year-old man presents for a second opinion about his diagnosis of diabetes and recommendations for treatment if needed. He was diagnosed with prediabetes 4 years ago at an employee health fair. At the time he was given information about weight loss and the Diabetes Prevention Program. However, due to his busy schedule he was unable to make any major changes in his diet and in fact, had gained weight since then. This past year he learned that his glucose values climbed and were in the diabetes range. Subsequently, he was referred for diabetes education and given a prescription for metformin 1000 mg twice daily. He was reluctant to start the medication because he had friends who had “all kinds of problems” with this medication and his brother-in-law had to stop it because “metformin hurt his kidneys.”
His goal for today’s visit is he would like to confirm his diagnosis and wants to know if he really needs to take metformin. His HbA1c 1 year ago was 6.8%. He has not been monitoring his glucose. He has not been a diabetes educator yet.
Med HX: type 2 diabetes mellitus (1 year), hypertension (1 year), dyslipidemia (4 years)
Medications: metformin 1000 mg bid (not taking), enalapril 2.5 mg daily, pravastatin 40 mg daily (not taking)
Allergies: none
Family Medical History: obesity is present among all immediate family members; dad has high cholesterol and type 2 diabetes; mom is deceased from a stroke
Social History: no tobacco, no alcohol, and no recreational drug use; lives with his spouse and two kids, ages 3 and 5; works at the city facilities department; no regular physical activity outside of work and playing with his kids; does not follow any diet, but his wife says he is picky; eats sandwiches at most meals.
Physical Exam: Ht. 5′9″, Wt. 200 lb, BMI 29.5, T 97.7, P 78, R 12, BP 132/78
GEN: overweight adult, in no distress
HEENT: normal including thyroid exam
CV: normal
RESP: normal
Diabetes foot exam: normal pulses, no calluses, or skin breakdown, normal sensation to monofilament
Otherwise: normal exam
Fasting Labs:
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CASE QUESTIONS1. Does he have diabetes? How can this diagnosis be confirmed?
View Answer
1. Typically, the diagnosis of diabetes requires two tests separated by time in an asymptomatic person. This patient had an HbA1c 1 year ago of 6.8%. His current HbA1c is 8.8% and his current fasting glucose is 185 mg/dL. No further testing is needed to confirm that this patient has diabetes. He has had at least three tests demonstrating an abnormal glucose and the last three tests were within diabetes range values. He has type 2 diabetes that has progressed further during this past year.
2. Does he need to take metformin? If yes, how should it be prescribed to a first-time user?
View Answer
2. This patient has type 2 diabetes and at least one complication related to his diabetes. We need to initiate a treatment regimen immediately to control his blood sugars and limit future sequelae. His hypertension and hyperlipidemia place him at high risk for renal and cardiovascular disease (CVD); the presence of microalbuminuria is a predictor of worse outcomes for both disease states.1
Metformin is the most common treatment initiated for type 2 diabetes as it is typically safe, inexpensive, and weight neutral. Starting metformin, in addition to therapeutic lifestyle change, is a common and reasonable first step for treatment with patients such as this. It is likely, based on his current HbA1c and the presence of microalbuminuria, he will require additional medications; however, metformin should be part of the regimen, nonetheless.
Patients starting metformin often experience mild gastrointestinal (GI) side effects including nausea and diarrhea. These can be minimized by starting with a dose of 500 mg in the evening. Once the patient is tolerating this without side effects, the dose can be increased to 500 mg bid (breakfast and dinner). Subsequently this can be increased to 500 mg in the AM, and 1000 mg in the PM, and then 1000 mg bid. It is important to maintain each dose until the patient tolerates it without side effects. Since metformin will be a long-term medication, it makes sense to take time to work up to the target dose2 to assure tolerability and to improve compliance. Since type 2 diabetes is progressive, every attempt should be made to find a dose that this patient can tolerate so metformin can be part of his treatment plan.
An alternative approach is to use extended-release metformin. This has less side effects and can be dosed once daily. The same approach to titration is utilized when using the extended-release formulation. It is worth noting that approximately 18% of people will not tolerate a therapeutic dose of metformin and will require other treatment regimens.
3. What are the warnings with metformin? Does metformin injure the kidneys?
View Answer
3. Metformin has several warnings and precautions. Some people can develop B12 deficiency and a related peripheral neuropathy from metformin.3 Doses of metformin >1500 mg daily can reduce vitamin B12 levels 14% to 30%. For most people this does not lead to clinical B12 deficiency.4 However, it is recognized that the development of B12 deficiency is directly associated with the duration of treatment with metformin.5 While there is no consensus in terms of screening, any person on long-term metformin should have vitamin B12 levels tested on a regular basis and take supplemental B12 if they are deficient or if they have symptomatic peripheral sensory neuropathy.
The most serious warning with metformin is the risk of lactic acidosis.6 This is primarily based on the occurrence of lactic acidosis with a different biguanide, phenformin that was removed from the US market in 1976.7 Data suggesting an increased risk of lactic acidosis in metformin-treated patients with CKD are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function.8
However, the risk for lactic acidosis can be prevented in most people if metformin is avoided in patients with acute renal insufficiency, stage 4 and 5 CKD or conditions that predispose to reduced renal function, including cirrhosis, and heart failure. It is important to remember that metformin dose should be reduced if estimated glomerular filtration rate (eGFR) is less than 45 mL/min and it should be stopped if the eGFR is <30 mL/min.7 Metformin is usually also stopped before elective procedures and during hospitalizations. This is due to concern about a reduction in kidney function (from the hospital illness or procedure) that can result in metformin levels building up if they cannot be cleared by the kidney.
Patients often misinterpret the warnings regarding the use of metformin in the presence of severe renal disease, believing that metformin was the cause of renal dysfunction. It is important that patients know that metformin is not causing the problem, and there is no evidence that metformin is hazardous to the kidneys.
4. What other treatments can be recommended to this patient?
View Answer
4. There are lots of options for this patient. First, it is very important to let him know that being an active partner in his diabetes management is important. This means we will be working together to address the lifestyle factors affecting his chronic health conditions including diabetes, hypertension, dyslipidemia, and albuminuria.
Based upon his current metabolic panel and urinalysis, he has stage G1A2 CKD. This indicates normal renal function, based on his eGFR of 98 mL/min with the presence of proteinuria. Despite his normal eGFR, it is important to recognize that he is at higher risk of developing progressive CKD and cardiovascular events.10
The 2022 ADA treatment algorithm lists specific recommended treatments based upon compelling comorbidities and indications.9 The presence of albuminuria makes the use of an SGLT-2 (sodium-glucose cotransporter-2) inhibitor a good choice, independent of his HbA1c, since this class of medication has evidence for renal protective benefits. SGLT-2 inhibitors have been shown to reduce the progression of diabetic kidney disease (both decline in eGFR and increase in albuminuria), as well as lower the risk for end-stage kidney disease, death, and cardiovascular death.11,12,13
This patient could also take a GLP-1RA (glucagon-like peptide-1 receptor agonist). This will treat his hyperglycemia and reduce his cardiovascular risk. This class has many formulations including a once-daily oral agent, once- or twice-daily subcutaneous injectable agents, and once-weekly subcutaneous injectable agents.
These variations allow patients to choose medication based upon coverage and dosing preferences. Weight loss is a prominent benefit of this class of agents. A primary care-focused review outlines the additional benefits of these medications.14
Finally, there is a relatively new medication that is helpful to reduce albuminuria in diabetes-related kidney disease. Finerenone, a mineralocorticoid receptor agonist, has been shown to reduce albuminuria in these patients on top of standard of care described above.15 Further, adding finerenone to standard of care will reduce progression to CKD and cardiovascular events.16,17 This treatment has been added to the ADA and the Kidney Foundation treatment recommendations9,18 (updated guidelines in diabetes will be coming out in late 2022).
ANSWERS AND EXPLANATIONS1. Typically, the diagnosis of diabetes requires two tests separated by time in an asymptomatic person. This patient had an HbA1c 1 year ago of 6.8%. His current HbA1c is 8.8% and his current fasting glucose is 185 mg/dL. No further testing is needed to confirm that this patient has diabetes. He has had at least three tests demonstrating an abnormal glucose and the last three tests were within diabetes range values. He has type 2 diabetes that has progressed further during this past year.
2. This patient has type 2 diabetes and at least one complication related to his diabetes. We need to initiate a treatment regimen immediately to control his blood sugars and limit future sequelae. His hypertension and hyperlipidemia place him at high risk for renal and cardiovascular disease (CVD); the presence of microalbuminuria is a predictor of worse outcomes for both disease states.1
Metformin is the most common treatment initiated for type 2 diabetes as it is typically safe, inexpensive, and weight neutral. Starting metformin, in addition to therapeutic lifestyle change, is a common and reasonable first step for treatment with patients such as this. It is likely, based on his current HbA1c and the presence of microalbuminuria, he will require additional medications; however, metformin should be part of the regimen, nonetheless.
Patients starting metformin often experience mild gastrointestinal (GI) side effects including nausea and diarrhea. These can be minimized by starting with a dose of 500 mg in the evening. Once the patient is tolerating this without side effects, the dose can be increased to 500 mg bid (breakfast and dinner). Subsequently this can be increased to 500 mg in the AM, and 1000 mg in the PM, and then 1000 mg bid. It is important to maintain each dose until the patient tolerates it without side effects. Since metformin will be a long-term medication, it makes sense to take time to work up to the target dose2 to assure tolerability and to improve compliance. Since type 2 diabetes is progressive, every attempt should be made to find a dose that this patient can tolerate so metformin can be part of his treatment plan.
An alternative approach is to use extended-release metformin. This has less side effects and can be dosed once daily. The same approach to titration is utilized when using the extended-release formulation. It is worth noting that approximately 18% of people will not tolerate a therapeutic dose of metformin and will require other treatment regimens.
3. Metformin has several warnings and precautions. Some people can develop B12 deficiency and a related peripheral neuropathy from metformin.3 Doses of metformin >1500 mg daily can reduce vitamin B12 levels 14% to 30%. For most people this does not lead to clinical B12 deficiency.4 However, it is recognized that the development of B12 deficiency is directly associated with the duration of treatment with metformin.5 While there is no consensus in terms of screening, any person on long-term metformin should have vitamin B12 levels tested on a regular basis and take supplemental B12 if they are deficient or if they have symptomatic peripheral sensory neuropathy.
The most serious warning with metformin is the risk of lactic acidosis.6 This is primarily based on the occurrence of lactic acidosis with a different biguanide, phenformin that was removed from the US market in 1976.7 Data suggesting an increased risk of lactic acidosis in metformin-treated patients with CKD are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function.8
However, the risk for lactic acidosis can be prevented in most people if metformin is avoided in patients with acute renal insufficiency, stage 4 and 5 CKD or conditions that predispose to reduced renal function, including cirrhosis, and heart failure. It is important to remember that metformin dose should be reduced if estimated glomerular filtration rate (eGFR) is less than 45 mL/min and it should be stopped if the eGFR is <30 mL/min.7 Metformin is usually also stopped before elective procedures and during hospitalizations. This is due to concern about a reduction in kidney function (from the hospital illness or procedure) that can result in metformin levels building up if they cannot be cleared by the kidney.
Patients often misinterpret the warnings regarding the use of metformin in the presence of severe renal disease, believing that metformin was the cause of renal dysfunction. It is important that patients know that metformin is not causing the problem, and there is no evidence that metformin is hazardous to the kidneys.
4. There are lots of options for this patient. First, it is very important to let him know that being an active partner in his diabetes management is important. This means we will be working together to address the lifestyle factors affecting his chronic health conditions including diabetes, hypertension, dyslipidemia, and albuminuria.
Based upon his current metabolic panel and urinalysis, he has stage G1A2 CKD. This indicates normal renal function, based on his eGFR of 98 mL/min with the presence of proteinuria. Despite his normal eGFR, it is important to recognize that he is at higher risk of developing progressive CKD and cardiovascular events.10
The 2022 ADA treatment algorithm lists specific recommended treatments based upon compelling comorbidities and indications.9 The presence of albuminuria makes the use of an SGLT-2 (sodium-glucose cotransporter-2) inhibitor a good choice, independent of his HbA1c, since this class of medication has evidence for renal protective benefits. SGLT-2 inhibitors have been shown to reduce the progression of diabetic kidney disease (both decline in eGFR and increase in
albuminuria), as well as lower the risk for end-stage kidney disease, death, and cardiovascular death.11,12,13
albuminuria), as well as lower the risk for end-stage kidney disease, death, and cardiovascular death.11,12,13
This patient could also take a GLP-1RA (glucagon-like peptide-1 receptor agonist). This will treat his hyperglycemia and reduce his cardiovascular risk. This class has many formulations including a once-daily oral agent, once- or twice-daily subcutaneous injectable agents, and once-weekly subcutaneous injectable agents.
These variations allow patients to choose medication based upon coverage and dosing preferences. Weight loss is a prominent benefit of this class of agents. A primary care-focused review outlines the additional benefits of these medications.14
Finally, there is a relatively new medication that is helpful to reduce albuminuria in diabetes-related kidney disease. Finerenone, a mineralocorticoid receptor agonist, has been shown to reduce albuminuria in these patients on top of standard of care described above.15 Further, adding finerenone to standard of care will reduce progression to CKD and cardiovascular events.16,17 This treatment has been added to the ADA and the Kidney Foundation treatment recommendations9,18 (updated guidelines in diabetes will be coming out in late 2022).
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