Sulfonylureas — Sulfonylureas have been used to treat type 2 diabetes for many years. They work by increasing the amount of insulin your body makes and can lower blood sugar levels by approximately 20 percent.

However, over time they gradually stop working. They are reasonable second agents because they are inexpensive, effective, universally available, and have a long-term track record.

Most patients can take sulfonylureas even if they have an allergy to "sulfa" drugs. You should be very cautious taking a sulfonylurea if you have kidney failure. A number of short-acting sulfonylureas are available sample brand names: Glucotrol, Amaryl , and the choice between them depends mainly upon cost and availability.

If you take a sulfonylurea, you can develop low blood sugar, known as hypoglycemia. Low blood sugar symptoms can include:. Low blood sugar must be treated quickly by eating 10 to 15 grams of fast-acting carbohydrate eg, fruit juice, hard candy, glucose tablets.

It is possible to pass out if you do not treat low blood sugar quickly enough. To reduce the risk of low blood sugar when you are not eating, if you know you are going to miss a meal, you can skip the sulfonylurea tablet you would usually take before eating.

A full discussion of low blood sugar is available separately. See "Patient education: Hypoglycemia low blood glucose in people with diabetes Beyond the Basics ". DPP-4 inhibitors — This class of medicines, dipeptidyl peptidase-4 DPP-4 inhibitors, includes sitagliptin brand name: Januvia , saxagliptin brand name: Onglyza , linagliptin brand name: Tradjenta , alogliptin brand name: Nesina , and vildagliptin brand name: Galvus.

Vildagliptin is available in some countries but not in the United States. These medicines lower blood sugar levels by increasing insulin release from the pancreas in response to a meal. They can be given alone in people who cannot tolerate the first-line medicine metformin or other medicines, or they can be given together with other oral medicines if blood sugar levels are still higher than the goal.

These medicines do not cause hypoglycemia or changes in body weight. There have been rare reports of joint pain, pancreatitis, and severe skin reactions.

SGLT2 inhibitors — The sodium-glucose co-transporter 2 SGLT2 inhibitors, canagliflozin brand name: Invokana , empagliflozin brand name: Jardiance , dapagliflozin brand name: Farxiga , and ertugliflozin brand name: Steglatro , lower blood sugar by increasing the excretion of sugar in the urine.

They are variably effective, but on average, they are similar in potency to the DPP-4 inhibitors see 'DPP-4 inhibitors' above. SGLT2 inhibitors may be a good choice for people with heart failure or chronic kidney disease because they have been shown to have some cardiovascular, renal, and mortality benefits.

SGLT2 inhibitors do not cause low blood sugar. They promote modest weight loss and blood pressure reduction. Side effects include genital yeast infections in men and women, urinary tract infections, and dehydration.

Some medicines in this class have been associated with an increased risk of bone fracture or amputation. An uncommon but deadly infection of the tissue in the perineum the area between the genitals and the anus has also been reported in men and women.

SGLT2 inhibitors can increase the risk of diabetic ketoacidosis DKA ; this is a serious problem that can happen when acids called "ketones" build up in the blood. DKA can happen even when blood sugar is only mildly elevated.

GLP-1 receptor agonists — The glucagon-like peptide-1 GLP-1 receptor agonists are medications given by injection that increase insulin release in response to a meal and slow digestion. They include exenatide, dosed twice daily brand name: Byetta ; exenatide extended release, dosed weekly brand name: Bydureon ; liraglutide, dosed daily brand name: Victoza ; dulaglutide, dosed weekly brand name: Trulicity ; lixisenatide, dosed daily brand name: Adlyxin ; and semaglutide, dosed weekly as an injection brand name: Ozempic or daily as a tablet brand name: Rybelsus.

These medications are useful for people whose blood sugar is not controlled on the highest dose of one or two oral medicines.

They may be especially helpful for overweight people who are gaining weight or struggling to lose weight on other diabetes medicines. Liraglutide, dulaglutide, or semaglutide injections are recommended for people who have, or are at high risk for, cardiovascular disease, as they have been shown to have cardiovascular benefits in these groups.

GLP-1 receptor agonists do not usually cause low blood sugar when used without other medications that cause low blood sugar. They promote loss of appetite and a sense of feeling full after eating a smaller amount of food, which helps with weight loss, but can also cause bothersome side effects, including nausea, vomiting, and diarrhea.

Gastrointestinal side effects usually improve with time. Pancreatitis inflammation of the pancreas has been reported rarely in people taking GLP-1 receptor agonists, but it is not known if the medications caused the pancreatitis.

They have also been associated with gall bladder disease. You should stop taking these medications if you develop severe abdominal pain.

Exenatide and lixisenatide should not be used in people with abnormal kidney function, and liraglutide and dulaglutide should be used with caution in this situation. These drugs are generally expensive. Meglitinides — Meglitinides include repaglinide brand name: Prandin and nateglinide brand name: Starlix.

They work to lower blood sugar levels, similar to the sulfonylureas, but they act more quickly than sulfonylureas and should be taken right before a meal; they might also be recommended in people who are allergic to sulfonylureas.

They are taken in pill form. Meglitinides are not generally used as a first-line treatment, because they are more expensive than sulfonylureas.

Repaglinide can be used in patients with kidney failure. Thiazolidinediones — This class of medicines includes pioglitazone brand name: Actos and rosiglitazone brand name: Avandia , which work to lower blood sugar levels by increasing the body's sensitivity to insulin.

They are taken in pill form and usually in combination with other medicines such as metformin, a sulfonylurea, or insulin. The risk of heart failure is small but serious. An early sign of heart failure is swelling of the feet and ankles. People who take thiazolidinediones should monitor for swelling.

Alpha-glucosidase inhibitors — These medicines, which include acarbose brand name: Precose and miglitol brand name: Glyset , work by interfering with the absorption of carbohydrates in the intestine.

This helps to lower blood sugar levels but not as well as metformin or the sulfonylureas. They can be combined with other medicines if the first medicine does not lower blood sugar levels enough.

The main side effects of alpha-glucosidase inhibitors are gas flatulence , diarrhea, and abdominal pain; starting with a low dose may minimize these side effects. The medicine is usually taken three times per day with the first bite of each meal. Insulin — In the past, insulin treatment was reserved for patients with type 2 diabetes whose blood sugar was not controlled with oral medicines and lifestyle changes ie, diet and exercise.

However, there is increasing evidence that insulin treatment at earlier stages may improve overall diabetes management over time. Side effects include low blood sugar, if you take more insulin than your body needs, and weight gain.

Adjusting the dose of insulin to the body's needs can minimize the risk of these side effects. It may be necessary to readjust your dose frequently. In some situations, insulin injections shots can be used as a first-line treatment for type 2 diabetes. In other cases, insulin can be added to or substituted for oral medicines.

If you take insulin, you will need to get comfortable giving yourself the injections or have a family member or housemate learn how to do it for you. More detailed information about insulin treatment is available separately. Living with type 2 diabetes can be stressful. It is a lot of responsibility to have to monitor your blood sugar if you need to do this , watch your diet, exercise regularly, keep all your appointments, and take your medications every day.

It can also be scary to think about the potential complications of diabetes. It can help to involve your family and friends and make sure you have a solid support system in place to provide encouragement, reminders, and help as you need it. It is not uncommon for stress to lead to burnout or even depression, and this can make taking care of yourself more difficult.

Having an open and honest discussion with your doctor, nurse, or other health care provider can help you to understand your diagnosis, treatment plan, and what to do if you are overwhelmed.

Some people also benefit from talking with a counselor or social worker to help them cope with their responsibilities and worries.

Your health care provider is the best source of information for questions and concerns related to your medical problem. This article will be updated as needed on our website www. Related topics for patients, as well as selected articles written for health care professionals, are also available.

Some of the most relevant are listed below. Patient level information — UpToDate offers two types of patient education materials. The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition.

These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Treatment for type 2 diabetes The Basics Patient education: Type 2 diabetes The Basics Patient education: Using insulin The Basics Patient education: Low blood sugar in people with diabetes The Basics Patient education: Nonalcoholic fatty liver disease The Basics Patient education: Exercise and movement The Basics Patient education: Carb counting for adults with diabetes The Basics Patient education: Lowering your risk of prediabetes and type 2 diabetes The Basics Patient education: Diabetic ketoacidosis The Basics Patient education: Hyperosmolar hyperglycemic state The Basics.

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon. Patient education: Type 2 diabetes: Overview Beyond the Basics Patient education: Type 2 diabetes: Insulin treatment Beyond the Basics Patient education: Type 2 diabetes and diet Beyond the Basics Patient education: Glucose monitoring in diabetes Beyond the Basics Patient education: Hypoglycemia low blood glucose in people with diabetes Beyond the Basics Patient education: Exercise and medical care for people with type 2 diabetes Beyond the Basics Patient education: Preventing complications from diabetes Beyond the Basics.

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based.

Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading. Alpha-glucosidase inhibitors for treatment of diabetes mellitus Measurements of chronic glycemia in diabetes mellitus Glycemic control and vascular complications in type 2 diabetes mellitus Insulin therapy in type 2 diabetes mellitus Management of persistent hyperglycemia in type 2 diabetes mellitus Metformin in the treatment of adults with type 2 diabetes mellitus Overview of general medical care in nonpregnant adults with diabetes mellitus Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus Thiazolidinediones in the treatment of type 2 diabetes mellitus.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content.

Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy. Why UpToDate? Product Editorial Subscription Options Subscribe Sign in.

View Topic Loading Font Size Small Normal Large. Patient education: Type 2 diabetes: Treatment Beyond the Basics. Formulary drug information for this topic. No drug references linked in this topic.

Find in topic Formulary Print Share. Official reprint from UpToDate ® www. com © UpToDate, Inc. All Rights Reserved. Author: Deborah J Wexler, MD, MSc Section Editor: David M Nathan, MD Deputy Editor: Katya Rubinow, MD. All topics are updated as new evidence becomes available and our peer review process is complete.

We therefore hypothesized that the use of these medication classes would result in larger reductions in hemoglobin A 1c HbA 1c compared with sulfonylureas, and specifically among those with HIV infection versus those without HIV infection. To address these issues, we conducted this study among a large, national cohort of HIV-infected and uninfected veterans initiating diabetic medical therapy in routine clinical care with the goal of comparing the glycemic effectiveness of the three main classes of oral diabetic medications metformin, sulfonylureas, TZDs.

We also sought to determine the impact of HIV infection on glycemic response. This study was conducted in the Veterans Aging Cohort Study Virtual Cohort VACS-VC The VACS-VC is a longitudinal, prospective cohort study of HIV-infected veterans, and a sample of age, sex, race, and site-matched HIV-uninfected veterans receiving care at Veterans Health Administration Medical Centers.

Patients initiating oral monotherapy for type 2 diabetes between 1 January and 1 January were included from the initial source population.

The date of the first pharmacy fill for a single oral diabetic medication from one of the three main classes sulfonylureas, metformin, and TZDs was denoted as the index date.

This was a longitudinal cohort study using a new user design 16 of subjects with type 2 diabetes who initiated diabetic medical therapy.

The exposures of interest were new use of a sulfonylurea, metformin, or a TZD. The primary outcome of interest was absolute change in HbA 1c level during the first year of therapy. We chose to evaluate glycemic change during the postindex year given that the greatest achievable reduction in HbA 1c level in response to oral medical therapy typically occurs in the year after medication initiation 17 — The study was approved by the institutional review board of the University of Pennsylvania.

The VACS-VC was approved by the institutional review boards at the Yale School of Medicine and the VA Connecticut Human Subjects Subcommittee.

Baseline data were collected for all subjects at the time of diabetic medication initiation, including age, sex, BMI, and race, and ethnicity. The presence of comorbid conditions and laboratory values that may have affected the initial selection of therapy were also ascertained, including HIV infection, coronary artery disease, chronic kidney disease, congestive heart failure, and hepatitis C infection, as well as serum creatinine and liver function tests.

Major psychiatric comorbid conditions, alcohol abuse, and substance abuse were also documented 4. The VACS Index score 20 , which predicts 5-year, all-cause mortality after ART initiation and has also been shown to be predictive in uninfected patients 21 , 22 , was calculated for each patient at baseline.

HbA 1c results from 6 months prior to the first pharmacy fill date up to 12 months after the first pharmacy fill date were included. Baseline ART regimens were classified into protease inhibitor PI -based ART i. Medication switch was defined as discontinuing the index medication and initiating another medication from a different class during the postindex year.

Medication intensification was considered as the addition of another medication to the initial regimen at any time during the month postindex period. Baseline characteristics among the three groups were compared using the Student t test or Wilcoxon rank sum test for continuous variables, and the χ 2 or Fisher exact test for categorical variables.

For a more meaningful assessment of HbA 1c change, using multiple measures of HbA 1c over the 1-year period, a generalized estimating equation GEE model for the primary outcome analyses was used.

The GEE model accounts for correlation within a subject e. Follow-up time intervals for HbA 1c results were categorized at 3-month intervals for analysis, as follows: 1—3 months, 4—6 months, 7—9 months, and 10—12 months.

If more than one follow-up HbA 1c value was available for a specific time interval, the most recent value was entered into the model. Variables that could act as potential confounders of the association between index medication class and change in HbA 1c , including baseline demographics and comorbid conditions, were considered for inclusion and maintained in the final model if they were statistically significant on bivariable analysis or were considered to be clinically important Baseline HbA 1c level was retained in the model a priori, given its known influence on the initial response to therapy The above analyses were repeated using propensity scores 27 generated using multiple logistic regression to address potential confounding by indication due to choice of the initial diabetic medication class Variables evaluated for inclusion in propensity scores included all demographic and clinical variables, as described above, including comorbid conditions that may have affected the initial choice of medication e.

Secondary outcome analysis of achieving the goal HbA 1c level was performed using multiple logistic regression, with adjustment for potential confounders in the final model as noted in the primary outcome analyses All statistical calculations were performed using commercially available software SAS version 9.

A total of 2, HIV-infected patients and 8, HIV-uninfected patients met the study criteria and were included in the study. HIV-infected patients also had a significantly higher VACS Index score median 28, interquartile range [IQR] 17, 43 compared with HIV-uninfected patients median 12, IQR 10, Other baseline characteristic comparisons are shown in Table 1.

Baseline characteristics of HIV-infected and HIV-uninfected new users of diabetic medical therapy. Compared with new users of metformin, or TZD, patients who started receiving therapy with a sulfonylurea had a higher mean baseline HbA 1c , a higher median VACS Index score, and an earlier year of therapy initiation.

Other characteristics of new users of diabetic medications are shown in Table 2. Black and Hispanic patients had a poorer response to therapy compared with white patients, with a relative increase in HbA 1c of 0.

In addition, a higher BMI and higher baseline HbA 1c level were associated with a worse response to diabetic medical therapy. Other factors that were associated with a change in HbA 1c level are shown in Table 3.

Adjusted changes in HbA 1c in new users of diabetic medical therapy: multivariable analysis using a GEE model. HIV-infected new users of a sulfonylurea were more likely to be receiving treatment with a PI-based ART regimen and to have a detectable HIV viral load compared with those receiving treatment with metformin or a TZD Table 2.

Black race was associated with a worse response to initial diabetic medical therapy, with an average increase in HbA 1c level of 0.

Adjusted changes in HbA 1c among HIV-infected new users of diabetic medical therapy: multivariable analysis using a GEE model. In the final multivariable model Table 5 , there was no significant difference in the achievement of the ADA goal among the three diabetes medication groups of new users.

In this longitudinal cohort of HIV-infected and uninfected new users of oral diabetic medical therapy, we found that glycemic response was independent of the initial class of medication after controlling for potential confounders.

HIV infection similarly did not impact the initial glycemic response. Black race and Hispanic ethnicity were associated with a poorer response to diabetic medical therapy in the final multivariable model. To our knowledge, ours is the first study to date comparing the effectiveness of the three major oral diabetic medication classes specifically in an HIV-uninfected and HIV-infected patient population, and the results are further strengthened by the large, racially diverse cohort; the evaluation of several important potential confounders; and the longitudinal study design, with the capture of repeated HbA 1c measurements.

Comparative effectiveness studies in the uninfected population demonstrate a similar ability of the three major oral medication classes to lower glycemia 6 , Our ability to compare TZD use to other medication classes was limited given the small numbers of new users of TZD.

However, the results of our study demonstrated that the use of metformin compared with sulfonylureas did not result in greater reductions in HbA 1c level, including in analyses restricted to patients with HIV infection.

As such, the anti-inflammatory properties of metformin may have been less important in these patients with lower degrees of chronic inflammation.

Nevertheless, these results suggest that, as in the uninfected population, HIV-infected patients respond similarly to sulfonylureas and metformin.

The selection of first-line treatment should take into account other factors, such as the effect on lipid levels and weight, as well as those that may be particularly important in the HIV-infected population, including interactions with ART agents and the potential for increased risk of adverse events e.

Ultimately, further research is needed on the long-term safety profile of these medications in HIV-infected patients. In contrast to the results of a prior study 4 , HIV infection was not significantly associated with a response to diabetic medical therapy in the postindex year.

These conflicting findings may in part be explained by differences in the characteristics of the patient populations that were assessed e. In addition, the HIV-uninfected and HIV-infected veteran populations in the current study had similar baseline HbA 1c values.

We found that, for HIV-infected new users, receiving treatment with a non—PI-based ART regimen compared with no ART was associated with a more favorable glycemic response to diabetic medical therapy. This improved glycemic response was not seen with a PI-based ART regimen compared with no ART.

It is possible that the non—PI-based regimens demonstrated a more favorable metabolic profile compared with PI-based ART e. Traditional determinants of glycemic response to diabetic medical therapy were evident in the multivariable analysis, including higher BMI and baseline HbA 1c level.

Given the association between obesity and worse glycemic control, it will be important for health care providers to aggressively address lifestyle interventions as a component of the management of diabetes in this patient population.

In addition, black race and Hispanic ethnicity were associated with a worse glycemic response to initial diabetic medical therapy, even after adjustment for baseline HbA 1c level.

This poorer glycemic response may be due in part to genetic and biologic factors, such as drug metabolism rates. These potential determinants of glycemic response, including their interaction with HIV infection, should be explored further.

In addition, racial and ethnic disparities in diabetes care, including glycemic control, have been well described in the literature from the general population 31 , with poorer glycemic control persisting even after adjustment for health care use and quality of care.

Given the burden of type 2 diabetes and HIV in these populations, further studies are needed to identify optimal strategies to address these disparities in glycemic control, including in the HIV-infected population. This finding may be due in part to the underestimation of glycemia by HbA 1c level in HIV-infected patients Similar to a prior study 4 , a substantial proportion of HIV-infected patients approximately one-third in the current study failed to achieve the ADA HbA 1c goal.

Given the long-term cardiovascular disease risk in patients with HIV infection, intensive efforts to control hyperglycemia during the treatment of type 2 diabetes are warranted. We found that total bilirubin levels were inversely associated with changes in HbA 1c values in the cohort overall, and specifically in those with HIV infection.

This finding is consistent with previous studies 33 , 34 reporting inverse associations between total bilirubin levels and HbA 1c values, independent of other risk factors.

Bilirubin, which results from heme catabolism, has antioxidant properties, and higher levels have been associated with a decreased risk of carotid atherosclerosis, coronary artery disease, and cerebrovascular disease 35 — Our results extend this negative association to the HIV-infected population.

There are several potential limitations of the current study. As with any observational study, our results may be affected by residual confounding. However, we evaluated a number of relevant variables as potential confounders in multivariable analyses, used a new user study design that minimizes prevalent-user bias, and used a longitudinal model that allowed for the inclusion of all follow-up HbA 1c results in analyses.

We also conducted a subanalysis using propensity scores to account for confounding by indication. In addition, pharmacy refill rates were used as a proxy for medication consumption in the calculation of medication adherence. Finally, as noted earlier, we were underpowered for the analyses that focused on TZDs.

In conclusion, there was no significant difference in the effectiveness of the three main classes of oral diabetic medications for glycemic control in HIV-uninfected and HIV-infected patients starting medical therapy in routine clinical care.

Furthermore, a significant proportion of patients failed to meet the ADA-recommended HbA 1c goal despite frequent clinic follow-up and excellent medication adherence. Ultimately, given the increasing prevalence of type 2 diabetes in the aging HIV-infected population, further research is needed to elucidate the safety of diabetic medications in HIV-infected patients with type 2 diabetes, as well as the effects on long-term clinical complications and mortality.

This study was supported by the Veterans Aging Cohort Study and by National Institute on Alcohol Abuse and Alcoholism grant UAA The funder had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.

Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. contributed to the study concept and design; the analysis and interpretation of the data; drafting and critical revision of the manuscript for important intellectual content; and administrative, technical, and material support.

contributed to the study concept and design; the acquisition, analysis, and interpretation of the data; statistical analysis; critical revision of the manuscript for important intellectual content; and administrative, technical, and material support and obtained funding.

contributed to the study concept and design; the acquisition, analysis, and interpretation of data; critical revision of the manuscript for important intellectual content; administrative, technical, and material support; and study supervision and obtained funding.

contributed to the study concept and design; the analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; and administrative, technical, and material support and obtained funding.

contributed to the study concept and design; the analysis and interpretation of the data; drafting and critical revision of the manuscript for important intellectual content; administrative, technical, and material support; and study supervision.

is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Can watching sports be bad for your health? Beyond the usual suspects for healthy resolutions. About the Author. Samar Hafida, MD , Contributor Samar Hafida, MD, is an adult endocrinologist at Joslin Diabetes Center in Boston, MA. Black and Hispanic patients had a poorer response to therapy compared with white patients, with a relative increase in HbA 1c of 0.

In addition, a higher BMI and higher baseline HbA 1c level were associated with a worse response to diabetic medical therapy. Other factors that were associated with a change in HbA 1c level are shown in Table 3. Adjusted changes in HbA 1c in new users of diabetic medical therapy: multivariable analysis using a GEE model.

HIV-infected new users of a sulfonylurea were more likely to be receiving treatment with a PI-based ART regimen and to have a detectable HIV viral load compared with those receiving treatment with metformin or a TZD Table 2.

Black race was associated with a worse response to initial diabetic medical therapy, with an average increase in HbA 1c level of 0. Adjusted changes in HbA 1c among HIV-infected new users of diabetic medical therapy: multivariable analysis using a GEE model.

In the final multivariable model Table 5 , there was no significant difference in the achievement of the ADA goal among the three diabetes medication groups of new users. In this longitudinal cohort of HIV-infected and uninfected new users of oral diabetic medical therapy, we found that glycemic response was independent of the initial class of medication after controlling for potential confounders.

HIV infection similarly did not impact the initial glycemic response. Black race and Hispanic ethnicity were associated with a poorer response to diabetic medical therapy in the final multivariable model.

To our knowledge, ours is the first study to date comparing the effectiveness of the three major oral diabetic medication classes specifically in an HIV-uninfected and HIV-infected patient population, and the results are further strengthened by the large, racially diverse cohort; the evaluation of several important potential confounders; and the longitudinal study design, with the capture of repeated HbA 1c measurements.

Comparative effectiveness studies in the uninfected population demonstrate a similar ability of the three major oral medication classes to lower glycemia 6 , Our ability to compare TZD use to other medication classes was limited given the small numbers of new users of TZD.

However, the results of our study demonstrated that the use of metformin compared with sulfonylureas did not result in greater reductions in HbA 1c level, including in analyses restricted to patients with HIV infection. As such, the anti-inflammatory properties of metformin may have been less important in these patients with lower degrees of chronic inflammation.

Nevertheless, these results suggest that, as in the uninfected population, HIV-infected patients respond similarly to sulfonylureas and metformin. The selection of first-line treatment should take into account other factors, such as the effect on lipid levels and weight, as well as those that may be particularly important in the HIV-infected population, including interactions with ART agents and the potential for increased risk of adverse events e.

Ultimately, further research is needed on the long-term safety profile of these medications in HIV-infected patients. In contrast to the results of a prior study 4 , HIV infection was not significantly associated with a response to diabetic medical therapy in the postindex year.

These conflicting findings may in part be explained by differences in the characteristics of the patient populations that were assessed e. In addition, the HIV-uninfected and HIV-infected veteran populations in the current study had similar baseline HbA 1c values.

We found that, for HIV-infected new users, receiving treatment with a non—PI-based ART regimen compared with no ART was associated with a more favorable glycemic response to diabetic medical therapy.

This improved glycemic response was not seen with a PI-based ART regimen compared with no ART. It is possible that the non—PI-based regimens demonstrated a more favorable metabolic profile compared with PI-based ART e. Traditional determinants of glycemic response to diabetic medical therapy were evident in the multivariable analysis, including higher BMI and baseline HbA 1c level.

Given the association between obesity and worse glycemic control, it will be important for health care providers to aggressively address lifestyle interventions as a component of the management of diabetes in this patient population. In addition, black race and Hispanic ethnicity were associated with a worse glycemic response to initial diabetic medical therapy, even after adjustment for baseline HbA 1c level.

This poorer glycemic response may be due in part to genetic and biologic factors, such as drug metabolism rates. These potential determinants of glycemic response, including their interaction with HIV infection, should be explored further. In addition, racial and ethnic disparities in diabetes care, including glycemic control, have been well described in the literature from the general population 31 , with poorer glycemic control persisting even after adjustment for health care use and quality of care.

Given the burden of type 2 diabetes and HIV in these populations, further studies are needed to identify optimal strategies to address these disparities in glycemic control, including in the HIV-infected population. This finding may be due in part to the underestimation of glycemia by HbA 1c level in HIV-infected patients Similar to a prior study 4 , a substantial proportion of HIV-infected patients approximately one-third in the current study failed to achieve the ADA HbA 1c goal.

Given the long-term cardiovascular disease risk in patients with HIV infection, intensive efforts to control hyperglycemia during the treatment of type 2 diabetes are warranted. We found that total bilirubin levels were inversely associated with changes in HbA 1c values in the cohort overall, and specifically in those with HIV infection.

This finding is consistent with previous studies 33 , 34 reporting inverse associations between total bilirubin levels and HbA 1c values, independent of other risk factors. Bilirubin, which results from heme catabolism, has antioxidant properties, and higher levels have been associated with a decreased risk of carotid atherosclerosis, coronary artery disease, and cerebrovascular disease 35 — Our results extend this negative association to the HIV-infected population.

There are several potential limitations of the current study. As with any observational study, our results may be affected by residual confounding. However, we evaluated a number of relevant variables as potential confounders in multivariable analyses, used a new user study design that minimizes prevalent-user bias, and used a longitudinal model that allowed for the inclusion of all follow-up HbA 1c results in analyses.

We also conducted a subanalysis using propensity scores to account for confounding by indication. In addition, pharmacy refill rates were used as a proxy for medication consumption in the calculation of medication adherence.

Finally, as noted earlier, we were underpowered for the analyses that focused on TZDs. In conclusion, there was no significant difference in the effectiveness of the three main classes of oral diabetic medications for glycemic control in HIV-uninfected and HIV-infected patients starting medical therapy in routine clinical care.

Furthermore, a significant proportion of patients failed to meet the ADA-recommended HbA 1c goal despite frequent clinic follow-up and excellent medication adherence. Ultimately, given the increasing prevalence of type 2 diabetes in the aging HIV-infected population, further research is needed to elucidate the safety of diabetic medications in HIV-infected patients with type 2 diabetes, as well as the effects on long-term clinical complications and mortality.

This study was supported by the Veterans Aging Cohort Study and by National Institute on Alcohol Abuse and Alcoholism grant UAA The funder had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.

Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. contributed to the study concept and design; the analysis and interpretation of the data; drafting and critical revision of the manuscript for important intellectual content; and administrative, technical, and material support.

contributed to the study concept and design; the acquisition, analysis, and interpretation of the data; statistical analysis; critical revision of the manuscript for important intellectual content; and administrative, technical, and material support and obtained funding. contributed to the study concept and design; the acquisition, analysis, and interpretation of data; critical revision of the manuscript for important intellectual content; administrative, technical, and material support; and study supervision and obtained funding.

contributed to the study concept and design; the analysis and interpretation of the data; critical revision of the manuscript for important intellectual content; and administrative, technical, and material support and obtained funding. contributed to the study concept and design; the analysis and interpretation of the data; drafting and critical revision of the manuscript for important intellectual content; administrative, technical, and material support; and study supervision.

is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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