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How To Manage Diabetes with Medication - Yale Medicine ExplainsDiabetes medication options -
This way you have three therapies working together to manage your blood glucose levels. Start by considering your options and see what might work best for you. Diabetes is a progressive disease and medications sometimes stop working as well over time.
When this happens adjustments to your medication or combination therapy can help, which may include adding insulin to your treatment plan. This doesn't mean you're doing something wrong.
Even if diabetes other medications do bring your blood glucose levels near the normal range, you may need to take insulin if you have a severe infection or need surgery.
Other medications may not be able to keep your blood glucose levels in your target range during these stressful times that affect your blood glucose. Also, if you're not taking insulin but plan to or become pregnant, you may need insulin to manage your diabetes. The target genes of PPAR gamma include those involved in the regulation of lipid and carbohydrate metabolism and inflammation 66 , PPAR gamma is highly expressed in adipose tissue while its expression in skeletal muscle is low 66 , In the liver PPAR gamma expression is low but increases in obesity and thus in obese individuals it is possible that TZDs directly affect the liver It is likely that the primary effects of TZDs are on adipose tissue, followed by secondary benefits on other target tissues of insulin TZDs promote fatty acid uptake and storage in adipose tissue resulting in a decrease in circulating fatty acids and a decrease in fat accumulation in liver, muscle and pancreas leading to the protection of these tissues from the harmful metabolic effects of higher levels of fatty acids 16 , This decrease in fat accumulation in liver and muscle leads to an improvement in insulin action and the decrease in the pancreas may improve insulin secretion.
Additionally, PPAR gamma agonists increase the expression and circulating levels of adiponectin, an adipocyte-derived protein with insulin sensitizing activity A decrease in the gene expression of other adipokines involved in induction of insulin resistance, such as TNF-alpha, resistin, etc.
are likely to also contribute to the improvement in insulin resistance that occurs with TZDs Finally, the activation of PPAR gamma in other tissues may contribute to the beneficial effects of TZDs.
Pioglitazone and rosiglitazone decrease A1c levels to a similar degree as metformin and sulfonylurea therapy typically a 1. The decreases in fasting plasma glucose were observed as early as the second week of therapy but maximal decreases occurred after weeks 16 , This differs from other hypoglycemic drugs where the maximal effect occurs more rapidly.
TZDs lower both fasting and postprandial glucose levels TZDs are more effective in improving glycemic control in patients with marked insulin resistance TZDs are effective in combination with other hypoglycemic drugs including insulin 16 , 37 , TZDs do not cause hypoglycemia when used as monotherapy or in combination with metformin 16 , In combination with insulin or insulin secretagogues, TZDs can potentiate hypoglycemia.
If hypoglycemia occurs one needs to adjust the dose of insulin or insulin secretagogues. The durability of glycemic control with TZDs is more prolonged than with either sulfonylureas or metformin Similar results were observed when pioglitazone therapy was compared to sulfonylurea therapy After 2-years of therapy Studies have shown that TZDs improve and preserve beta cell function, which may account for their better durability 72 - A meta-analysis of 15 studies 5 with rosiglitazone and 10 with pioglitazone involving 2, patients demonstrated that TZDs decreased urinary albumin excretion in patients without albuminuria, in patients with microalbuminuria, and in patients with proteinuria TZDs modestly lower BP.
In a review of 37 studies TZDs lowered systolic BP by 4. The effect of TZDs on lipids depends on which agent is used. Rosiglitazone increases serum LDL cholesterol levels, increases HDL cholesterol levels, and only decreases serum triglycerides if the baseline triglyceride levels are high [66].
In contrast, pioglitazone has less impact on LDL cholesterol levels, but increases HDL cholesterol levels, and decreases serum triglyceride levels It should be noted that reductions in the small dense LDL subfraction and an increase in the large buoyant LDL subfraction are seen with both TZDs Treatment with pioglitazone for 12 weeks resulted in a significant increase in the ability of HDL to facilitate the efflux of cholesterol from cells In a randomized head-to-head trial, it was shown that pioglitazone decreased serum triglyceride levels and increased serum HDL cholesterol levels to a greater degree than rosiglitazone treatment 80 , Additionally, pioglitazone increased LDL cholesterol levels less than rosiglitazone.
In contrast to the differences in lipid parameters, both rosiglitazone and pioglitazone decreased A1c and C-reactive protein to a similar extent. The mechanism by which pioglitazone induces more favorable changes in lipid levels than rosiglitazone is unclear, but differential actions of ligands for nuclear hormone receptors are well described.
Studies with pioglitazone have suggested a beneficial effect on cardiovascular disease. The PROactive study was a randomized controlled trial that examined the effect of pioglitazone vs. placebo over a 3-year period in patients with T2DM and pre-existing macrovascular disease It should be noted that both leg revascularization and leg amputations are not typical primary end points in cardiovascular disease trials and these could be affected by pioglitazone induced edema.
In the pioglitazone treated group, blood pressure, A1c, triglyceride, and HDL cholesterol levels were all improved compared to the placebo group making it very likely that the mechanism by which pioglitazone decreased vascular events was multifactorial. The IRIS trial was a multicenter, double-blind trial that randomly assigned 3, patients with insulin resistance but without diabetes and a recent ischemic stroke or TIA to treatment with either pioglitazone or placebo After 4.
All components of the primary outcome were reduced in the pioglitazone treated group. Fasting glucose, fasting triglycerides, and systolic and diastolic blood pressure were lower while HDL cholesterol and LDL cholesterol levels were higher in the pioglitazone group than in the placebo group.
Although this study excluded patients with diabetes the results are consistent with and support the results of a protective effect of pioglitazone observed in the PROactive study.
In contrast to the above results, a study compared the effect of pioglitazone vs. sulfonylurea on cardiovascular disease and did not observe a reduction in events with pioglitazone treatment TOSCA.
IT The primary outcome was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularization and occurred in 6. Limitations of this study are the small number of events likely due to low-risk population studied and the relatively small number of participants.
Thus, the results of this study should be interpreted with caution. Additionally, it should be noted that when patients in this study were analyzed based on the risk of developing cardiovascular disease those at high risk had a marked reduction in events when treated with pioglitazone compared to the sulfonylurea Further support for the beneficial effects of pioglitazone on atherosclerosis is provided by studies that have examined the effect of pioglitazone on carotid intima-medial thickness.
Both the Chicago and Pioneer studies demonstrated favorable effects on carotid intima-medial thickness in patients treated with pioglitazone compared to patients treated with sulfonylureas 87 , Similarly, Periscope, a study that measured atheroma volume by intravascular ultrasonography, also demonstrated less atherosclerosis in the pioglitazone treated group compared to patients treated with sulfonylureas There are a large number of potential mechanisms by which pioglitazone might reduce cardiovascular disease Table 11 In addition to altering risk factors pioglitazone has direct anti-atherogenic effects on the arterial wall that could reduce cardiovascular disease While the data from a variety of different types of studies strongly suggests that pioglitazone is anti-atherogenic, the results with rosiglitazone are different.
Several meta-analyses of small and short-duration rosiglitazone trials suggested that rosiglitazone was associated with an increased risk of adverse cardiovascular outcomes 91 , However, the final results of the RECORD study, a randomized trial that was specifically designed to compare the effect of rosiglitazone vs.
either metformin or sulfonylurea therapy as a second oral drug in those receiving either metformin or a sulfonylurea on cardiovascular events, have been published and did not reveal a difference in cardiovascular disease death, myocardial infarctions, or stroke 93 , Similarly, an analysis of patients on rosiglitazone in the BARI 2D trial also did not suggest an increase or decrease in cardiovascular events in the patients treated with rosiglitazone Thus, while the available data indicate that pioglitazone is anti-atherogenic, the data for rosiglitazone suggests a neutral effect.
Whether these differences between pioglitazone and rosiglitazone are accounted for by their differential effects on lipid levels or other factors is unknown.
Studies have shown that pioglitazone has beneficial effects on NAFLD and NASH After 6 months of therapy liver enzymes improved and hepatic fat decreased, measured by magnetic resonance spectroscopy. However, fibrosis was unchanged.
The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Moreover, pioglitazone treatment improved the fibrosis score.
A meta-analysis of 8 randomized controlled trials 5 using pioglitazone and 3 using rosiglitazone with patients with biopsy-proven NASH reported that TZD treatment was associated with improved advanced fibrosis OR, 3.
Similar results were observed in patients with and without diabetes. Pioglitazone was more effective in improving NASH than rosiglitazone.
These studies demonstrate that pioglitazone has beneficial effects on NAFLD and NASH. Whether this will result in improved clinical outcomes will require additional studies.
TZDs are not FDA approved for the treatment of NAFLD or NASH. TZDs by improving insulin sensitivity decrease circulating androgen levels, improve ovulation rates, and improve glucose tolerance in patients with PCOS Small trials have shown some benefit of TZDs for the treatment of infertility, usually in conjunction with clomiphene Concerns regarding toxicity have limited the use of TZDs for the treatment of PCOS but if a patient has diabetes and TZDs are chosen for treating the diabetes one can anticipate beneficial effects on the PCOS.
TZDs lead to an increase in body weight of 2 to 3 kg for every 1 percent decrease in A1c levels In some studies patients gained over 4 kg during a week study Weight gain to a similar degree occurred in monotherapy studies and in studies where TZDs were added to metformin, sulfonylureas, or insulin However, in combination with an SGLT2 inhibitor or a GLP-1 receptor agonist the weight gain was blunted or prevented , In the ADOPT trial weight gain was greater with TZD therapy than with glyburide therapy 2.
The weight gain induced by TZDs is dose related and can be minimized by using low doses The TZD induced increase in body weight is due to an expansion of the subcutaneous fat depot whereas the mass of visceral fat remains unchanged or even decreases While weight increases, waist circumference typically remains stable.
Stimulation of PPAR gamma in subcutaneous adipocytes stimulates lipid accumulation Fluid retention as discussed below may also contribute to the increase in weight. Edema has been reported in 3. The increase in fluid retention is dose related.
The risk of developing edema is greatest when a TZD is used in combination with insulin The occurrence of edema is reduced when a TZD is used in combination with an SGLT2 inhibitor TZD induced edema responds poorly to treatment with thiazide and loop diuretics but responds to diuretics that effect the distal tubules such as spironolactone, triamterene, and amiloride Additionally, edema improves when TZD treatment is discontinued TZDs have been shown to decrease urine sodium excretion and to increase plasma renin and aldosterone levels In the RECORD trial, the rosiglitazone group had an increased rate of severe episodes of CHF resulting in hospital admission or death OR 2.
Patients treated with TZDs have a higher risk for CHF development if they have a history of cardiovascular disease Interestingly, TZD-associated CHF has not been linked with increased mortality 82 , Although TZDs are associated with worsening of CHF or CHF development, they are not associated with adverse effects on cardiac function or structure It is thought that the CHF is mainly due to fluid retention rather than TZDs inducing primarily cardiac dysfunction Large randomized trials have shown that TZDs increase fracture risk, particularly in women.
In the ADOPT study, which compared rosiglitazone, metformin, and glyburide, there was no difference in the incidence of fractures in men However, fractures in women at 5 years was increased in the group treated with rosiglitazone rosiglitazone The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and were seen predominantly in the lower and upper limbs In the PROactive study there was a higher rate of bone fractures in females treated with pioglitazone vs.
placebo 5. In the RECORD trial upper and distal lower limb fracture rates were increased mainly in women in the rosiglitazone treatment group Hip and femur fracture were not increased with rosiglitazone treatment In the IRIS trial an increased risk of fracture was seen in both males and females men 9.
Of note, in the ACCORD trial the risk of fractures in the women treated with rosiglitazone decreased after discontinuing rosiglitazone therapy In mice, TZDs suppress bone formation and increase bone resorption resulting in decreased bone mass Additionally, TZD administration in mice results in the massive accumulation of adipocytes in the bone marrow cavity In a meta-analysis of 14 trials with 1, participants, treatment with TZDs for 3 to 24 months decreased bone mineral density measured by DEXA at the lumbar spine difference In five studies TZD therapy was discontinued and after weeks there was no increase in bone mineral density indicating no restoration of bone mineral density with cessation of TZD treatment In an observation study each year of TZD use was associated with greater bone loss at the whole body additional loss of The effect of TZD treatment on bone turnover markers varied considerably between individual studies This reduction in bone mass induced by TZD treatment could contribute to the increase in fractures but it is possible that changes in the microarchitecture of bone also plays a role.
In preclinical studies pioglitazone administration increased bladder cancer in male rats but not in female rats or in mice, dogs, or monkeys In a number of instances, the development of bladder could not plausibly be related to treatment due to the temporal sequence of drug exposure and cancer diagnosis.
After eliminating these patients there were six patients with bladder cancer in the pioglitazone group and three patients in the placebo group After 10 years of follow-up, bladder cancer was reported in 0.
Thus, in large randomized trials the data do not definitively support that pioglitazone significantly increases the risk of bladder cancer.
The short duration of the randomized studies and infrequent occurrence of bladder cancer make interpretation of these studies difficult. Because of the preclinical data the FDA requested that the manufacturer of pioglitazone initiate a prospective study to examine the relationship between pioglitazone and bladder cancer.
This year study of , persons did not find any statistically significant association between pioglitazone treatment and bladder cancer Additionally, in a multinational cohort of 1. Similarly, no association was observed between rosiglitazone and bladder cancer in men or women In a careful review of 23 epidemiological studies Davidson concluded that there was little evidence that pioglitazone increased the risk of bladder cancer The FDA still warns about the possibility of bladder cancer with pioglitazone use and recommends that pioglitazone not be used in diabetic patients with active bladder cancer or history of bladder cancer package insert.
Macular edema has been reported in patients taking TZDs , Patients may present with blurred vision or decreased visual acuity or be diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed Some patients had improvement in their macular edema after discontinuation of the TZD As discussed above in the polycystic ovary section, treatment of premenopausal women with PCOS may induce ovulation and thereby result in unplanned pregnancies.
In premenopausal anovulatory women started on a TZD one needs to discuss the need for contraception. TZDs are contraindicated in patients with NYHA Class III or IV heart failure.
Pioglitazone should not be used in diabetic patients with active bladder cancer or history of bladder cancer. Strong CYP2C8 inhibitors e. Unfortunately, TZDs also have serious side effects, such as CHF, osteoporosis, and weight gain, that limit their use.
Clinicians need to balance the advantages and disadvantages of TZDs for the individual patient. Acarbose Precose, Glucobay , miglitol Glycet and voglibose Basen, Voglib are members of the α-glucosidase inhibitor class of oral anti-hyperglycemic compounds that were introduced in the s The recommended starting dosage of acarbose and miglitol is 25 mg given orally three times daily at the start of each meal.
The dose of acarbose and miglitol can be adjusted at 4 to 8-week intervals based on one-hour postprandial glucose or A1c levels, and on tolerance. The dosage can be increased from 25 mg tid with meals to 50 mg tid with meals. The maximum dose is mg tid with meals. Note that the dose can be varied based on the amount of carbohydrate in the meal.
In some patients one can initiate therapy once a day with the largest meal. Alpha-glucosidase inhibitors are competitive, reversible inhibitors of pancreatic α-amylase and membrane-bound intestinal α-glucosidase hydrolase enzymes 16 , Inhibiting these enzymes prevents the metabolism of disaccharides and oligosaccharides into monosaccharides delaying carbohydrate digestion and absorption 16 , Carbohydrate absorption occurs more distally in the intestine reducing the postprandial increase in glucose and lowering prandial insulin levels 16 , Acarbose and miglitol have minimal inhibitory activity against lactase and consequently will not prevent the increase in plasma glucose following the ingestion of milk or cause lactose intolerance package insert.
In addition to effecting carbohydrate absorption, alpha-glucosidase inhibitors increase postprandial GLP-1 secretion and reduce glucose-dependent insulinotropic polypeptide GIP secretion The typical decrease in A1c levels is relatively modest with alpha-glucosidase inhibitors 0.
The decrease in A1c is predominantly due to decreases in post meal glucose levels and alpha-glucosidase inhibitors have only modest effects on fasting glucose levels 16 , , Alpha-glucosidase inhibitors can be combined with other hypoglycemic drugs with additive effects and are particularly useful to lower postprandial glucose levels 37 , Alpha-glucosidase inhibitors are most effective in patients who ingest a high carbohydrate diet and for this reason have been widely used and very effective in Asian populations These drugs do not cause weight gain and hypoglycemia is uncommon 16 , 37 , If a patient experiences hypoglycemia while taking an alpha-glucosidase inhibitor in combination with insulin or sulfonylureas the patient should be instructed to use glucose gel, tablets, etc.
as alpha-glucosidase inhibitors will prevent the breakdown of sucrose and delay glucose absorption resulting in a failure to quickly correct hypoglycemia. Severe hypoglycemia may require intravenous glucose or intramuscular glucagon administration. In the STOP-NIDDM trial 1, subjects with impaired glucose tolerance were randomized to placebo vs.
acarbose and followed for 3. Among cardiovascular events, the major reduction was in the risk of myocardial infarction HR 0. In a smaller trial, patients hospitalized for the acute coronary syndrome who were newly diagnosed with IGT were randomly assigned to acarbose or placebo During a mean follow-up of 2.
Despite these favorable observations a large trial failed to demonstrate a beneficial effect of acarbose in Chinese patients with impaired glucose tolerance ACE trial In a randomized trial acarbose vs.
placebo was compared in 6, patients with coronary heart disease and impaired glucose tolerance. The primary outcome was cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure and patients were followed up for a median of 5 years.
The primary outcome was similar in the acarbose and placebo groups hazard ratio 0. No significant differences were seen for death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function.
Thus, whether acarbose favorably affects cardiovascular disease in patients at high risk for developing diabetes is uncertain. Moreover, the effect of acarbose on cardiovascular disease in patients with diabetes is unknown.
Acarbose is may result in a very small decrease in weight 0. Gastrointestinal side effects of alpha-glucosidase inhibitors include flatulence, abdominal discomfort, and diarrhea and are very commonly encountered 16 , 37 , These side effects can lead to the inability to tolerate these drugs.
A high carbohydrate diet may worsen the GI adverse effects. Over time the GI symptoms tend to decrease as the intestines adapt GI side effects are due to the mechanism of action of alpha-glucosidase inhibitors The inhibition of carbohydrate digestion in the small intestine leads to the delivery of undigested carbohydrates to the large intestine where microorganisms metabolize them into short-chain fatty acids, methane, carbon dioxide, and hydrogen, that can cause abdominal discomfort, increased flatulence, and diarrhea Acarbose, particularly at doses in excess of 50 mg tid, may give rise to elevations of serum transaminases and, in rare instances, hyperbilirubinemia.
It is recommended that serum transaminase levels be checked every 3 months during the first year of treatment with acarbose and periodically thereafter.
If elevated transaminases are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist package insert. Acarbose and miglitol are contraindicated in patients with inflammatory bowel disease, colonic ulceration, intestinal obstruction or those predisposed to intestinal obstruction, patients with chronic intestinal disease, or conditions that will be worsened by the increased gas formation in the intestine 37 package insert.
Acarbose is contraindicated in patients with cirrhosis package insert. Alpha-glucosidase inhibitors are excellent drugs for lowering postprandial glucose levels.
Unfortunately, because of their GI side effects many patients are unable to tolerate these drugs. Additionally, the need for three times a day administration makes it difficult for patients to comply with these drugs.
These drugs are very similar and there are only a few differences between these agents. The recommended starting dose of canagliflozin is mg once daily, taken before the first meal of the day. The recommended starting dose of dapagliflozin is 5 mg once daily, taken in the morning, with or without food.
In patients tolerating dapagliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily. The recommended starting dose of empagliflozin is 10 mg once daily in the morning, taken with or without food.
In patients tolerating empagliflozin, the dose may be increased to 25 mg. The recommended starting dose of ertugliflozin is 5 mg once daily, taken in the morning, with or without food.
In patients tolerating ertugliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 15 mg once daily. Before initiating SGLT2 inhibitor therapy one should assess renal function and volume status.
The dose of SGLT2 inhibitors may need to be adjusted based on renal function see below. The higher the blood glucose level the greater the quantity of glucose in the urine.
Inhibition of SGLT2 by drugs results in glycosuria and can lead to the excretion of 60—90 grams of glucose in the urine per day Figure 8 The amount of glucose excreted in the urine can vary considerably depending on renal function and the degree of hyperglycemia Decreased renal function results in a decrease in filtered glucose and less glucose in the urine while high blood glucose levels increase filtered glucose and increases the loss of glucose in the urine The ability of the inhibition of SGLT2 to lower blood glucose levels is not dependent on insulin action and hence is not affected by insulin levels or insulin resistance As will be discussed below many of the non-glucose lowering benefits and side effects of SGLT2 inhibitors can be explained by the increase in glucose excretion in the urine.
It should be recognized that glycosuria results in an osmotic diuresis. Additionally, because the SGLT2 transporters also facilitate the reabsorption of sodium from the filtrate there is also the loss of sodium in the urine. A meta-analysis of 66 randomized trials found that SGLT2 inhibitors decreased A1c levels by 0.
The A1c lowering ability of the different SGLT2 inhibitors is similar but A1c is reduced to a slightly greater extent by high-dose canagliflozin, which is probably a result of its additional action of inhibiting SGLT1 in the intestine decreasing dietary glucose absorption , , SGLT2 inhibitors when used as an add-on therapy to metformin, insulin, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas, or metformin ± DPP-4 inhibitor were similarly effective in reducing A1c levels as when used in monotherapy 16 , The efficacy of SGLT2 inhibitors is dependent on renal function and as renal function decreases the ability of these drugs to lower A1c levels diminishes 16 , SGLT2 inhibitors lower both fasting and postprandial glucose levels In monotherapy SGLT2 inhibitors have a low risk of causing hypoglycemia but in combinations with insulin or sulfonylureas may potentiate the development of hypoglycemia In patients in good glycemic control, one often decreases the insulin or sulfonylurea dose when initiating therapy with an SGLT2 inhibitor.
SGLT2 inhibitors lead to weight loss 16 , SGLT2 inhibitor-induced weight loss results primarily from a decrease in fat mass, including reductions in visceral and subcutaneous adipose tissue The weight loss is due to the loss of glucose in the urine, which represents the loss of calories , The excretion of 50 grams of glucose in the urine is equivalent to the loss of calories grams X 4.
However, the amount of glucose lost in the urine should result in a greater weight loss than is typically observed and a compensatory increase in food intake blunts the weight loss There are likely to be other homeostatic mechanisms that also play a role in limiting weight loss with SGLT2 inhibitors.
Monitoring glycemic control with 1,5-AG assay is not accurate as measurements of 1,5-AG are unreliable in patients taking SGLT2 inhibitors.
SGLT2 inhibitors decrease systolic BP by approximately mmHg and diastolic BP by approximately mmHg 16 , Patients with poorly controlled BP at baseline experience the largest reduction in BP SGLT2 inhibitors lower BP by promoting an osmotic diuresis and decreasing intravascular volume Weight loss may also contribute to the decrease in BP.
SGLT2 inhibitors cause a small increase in LDL and HDL cholesterol levels. In a meta-analysis of 48 randomized controlled trials SGLT2 inhibitors significantly increased LDL-C 3.
It is unlikely that these small changes in LDL-C, HDL-C, and triglyceride levels are of clinical significance. The mechanism for these increases in LDL and HDL cholesterol is unknown but could be due to a decrease in plasma volume.
The decrease in triglycerides might be secondary to weight loss. SGLT2 inhibitors lower blood uric acid levels This decrease is due to an increase in uric acid excretion by the kidneys. In an observational study 47, individuals receiving an SGLT2 inhibitor and , receiving a DPP4 inhibitor it was observed that the incidence of gout was There have been several large randomized studies of the effect of SGLT2 inhibitors on cardiovascular events published others are in progress.
In this study, 7, patients with established cardiovascular disease and T2DM were randomly assigned to receive 10 mg or 25 mg of empagliflozin or placebo once daily and were followed for 3.
As compared with placebo, empagliflozin treatment did not result in a significant difference in the occurrence of non-fatal myocardial infarction or strokes. However, empagliflozin resulted in a significantly lower risk of death from cardiovascular causes hazard ratio, 0.
The beneficial effects of empagliflozin were noted to occur very rapidly and the beneficial effects on heart failure appeared to be the dominant effect compared to effects on atherosclerotic events.
Decreases in cardiovascular outcomes and mortality with empagliflozin occurred across the range of cardiovascular risk Additionally, the reduction in hospitalizations for heart failure and cardiovascular death were observed both in patients with and without heart failure at baseline The effects of placebo vs.
The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke and the mean follow-up was weeks. The primary outcome was reduced in the canagliflozin group hazard ratio, 0. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease and those with preserved kidney function Death from any cause hazard ratio 0.
Similarly, canagliflozin treatment did not result in a significant difference in non-fatal strokes or non-fatal myocardial infarctions hazard ratio 0. As seen with empagliflozin, hospitalization for heart failure was markedly reduced hazard ratio 0.
In a second canagliflozin trial that focused on patients with kidney disease, a decrease in cardiovascular events was also observed In this double-blind trial 4, patients with chronic kidney disease and T2DM were randomized to canagliflozin mg per day or placebo and followed for a median of 2.
The relative benefits of canagliflozin for cardiovascular outcomes was similar in individuals across the spectrum of eGFR levels The effect of dapagliflozin on cardiovascular events has been reported The primary outcome was a composite of major adverse cardiovascular events MACE , defined as cardiovascular death, myocardial infarction, or ischemic stroke.
The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Dapagliflozin did not result in a lower rate of major adverse cardiovascular events 8. Interestingly, in the patients with a history of a previous MI dapagliflozin reduced the risk of a MACE HR 0.
Dapagliflozin reduced the risk of heart failure in patients with and without a history of heart failure but the benefit was greater in patients with a history of heart failure with heart failure HR 0. Dapagliflozin also reduced the risk of heart failure in patients without a history of atherosclerotic cardiovascular disease This trial did not demonstrate a significant difference in the primary endpoint MACE nor any components of the primary endpoint.
The primary outcome was a composite of worsening heart failure hospitalization or an urgent visit resulting in intravenous therapy for heart failure or cardiovascular death.
Treatment with dapagliflozin reduced the primary outcome HR 0. Symptoms of heart failure were also improved with dapagliflozin treatment. Additionally, dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death The benefits of dapagliflozin were similar in patients with diabetes and the non-diabetic patients This study demonstrates that an SGLT2 inhibitor is beneficial in patients with pre-existing heart failure and this occurs in both patients with and without diabetes.
The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. Treatment with empagliflozin reduced the primary outcome HR 0. The beneficial effects were observed in patients with and without diabetes.
This study is concordant with the results observed in the DAPA HF trial and demonstrates that SGLT2 inhibitors are beneficial in patients with pre-existing heart failure and this occurs in both patients with and without diabetes. The composite of death from cardiovascular causes or hospitalization for heart failure was decreased in the dapagliflozin group HR 0.
Moreover, this benefit occurred rapidly reaching statistical significance at 18 days after randomization. These results indicate that SGLT2 inhibitors are beneficial even in patients with a preserved ejection fraction. Thus, nine randomized trials of SGLT2 inhibitors demonstrated a robust decrease in heart failure table 14 with SGLT2 inhibitor therapy without a consistent strong effect on myocardial infarctions or strokes.
In a meta-analysis of eight of these trials not including Emperor Preserved with 59, patients it was observed that SGLT2 inhibitors reduced the risk of all-cause mortality HR 0. The reduction in heart failure was seen in patients with and without diabetes, patients with renal disease, and patients with and without a history of heart failure.
The Emperor Preserved trial demonstrated that patients with a preserved ejection fraction also benefit from treatment with a SGLT2 inhibitor.
Finally, the EMPULSE trial demonstrated that starting empagliflozin during the hospitalization for heart failure was beneficial For additional information see the section on drugs that inhibit both SGLT1 and 2. The mechanisms accounting for the beneficial effects of SGLT2 inhibitors on heart failure are uncertain Glycemic control was better in the SGLT2 inhibitor treated patients but it is doubtful that this modest decrease in glucose could account for the observed results additionally benefit in non-diabetics makes a glucose effect very unlikely.
SGLT2 inhibitor treatment was associated with small reductions in weight, waist circumference, uric acid level, and systolic and diastolic blood pressure, with no increase in heart rate and small increases in both LDL and HDL cholesterol.
Whether these changes played a role in reducing events remains to be determined but it is unlikely that these play a major role as other treatments that effect these factors do not markedly diminish the risk of heart failure events. It is possible that hemodynamic changes secondary to the osmotic diuresis induced by SGLT2 inhibitors contributed to the beneficial effects.
Additionally, SGLT2 inhibitors increase free fatty acid levels and glucagon secretion, which promotes the production of ketone bodies such as beta-hydroxybutyrate that are utilized by the heart for energy production It is possible that this alternative source of energy could be protective for heart function.
Finally, there may be direct effects of SGLT2 inhibition on myocardial and renal metabolism , , Further studies are required to better elucidate the mechanism of the beneficial effects of SGLT2 inhibitors on heart failure. The large randomized SGLT2 inhibitor cardiovascular outcome trials described above also examined the effect of these drugs on renal disease.
The effect of empagliflozin on renal outcomes was studied in 4, patients with T2DM who were randomized to empagliflozin 10 mg or 25 mg or placebo The prespecified outcomes were progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease and incident albuminuria.
Worsening nephropathy occurred in While empagliflozin caused an initial decrease in eGFR over the long term eGFR decreased in the placebo group at a more rapid rate than the empagliflozin group. Additionally, patients treated with empagliflozin were more likely to convert from microalbuminuria to normoalbuminuria hazard ratio [HR] 1.
Similar to the results seen with empagliflozin, canagliflozin has also been shown to decrease renal disease. Progression of albuminuria occurred less frequently in the canagliflozin group hazard ratio of 0. In addition, regression of albuminuria also occurred more frequently in the canagliflozin group hazard ratio, 1.
Annual eGFR decline was slower slope difference between groups 1. The CREDENCE Trial focused on patients with renal disease. In a double-blind trial 4, patients with T2DM and chronic kidney disease were randomized to canagliflozin or placebo and followed for a median of 2.
Benefits were seen regardless of baseline eGFR. As seen in the other SGLT2 inhibitor studies there was a decrease in the development of renal disease with the incidence of the renal outcome 4.
Excluding death from cardiovascular causes as part of the composite endpoint, the reduction in renal events was even more impressive HR 0. The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group HR 0.
There was a trend towards benefit with dapagliflozin treatment that was not statistically significant due to a small number of events HR 0.
The annual rate of decline in the eGFR was decreased in the empagliflozin group compared to the placebo group Additionally, a composite renal outcome chronic dialysis or renal transplantation or a profound, sustained reduction in the eGFR was decreased in the empagliflozin group HR 0.
All of the components of this primary outcome were decreased in the dapagliflozin group. Thus, similar to the CREDENCE trial, this trial demonstrates that dapagliflozin decreases renal disease progression in patients with pre-existing renal disease.
Moreover, this benefit is seen in patients with and without diabetes. Finally, benefit was observed in the dapagliflozin group regardless of the type of kidney disease diabetic, ischemic, hypertensive, glomerulonephritis, other, or unknown Multiple trials clearly demonstrate that SGLT2 inhibitors have beneficial effects on renal function and decrease the development and progression of renal disease Table In a meta-analysis of these 8 trials with 59, patients there was a robust decrease in the composite end points of renal disease HR 0.
The benefits are observed in patients with and without diabetes, with and without renal disease, and also in patients with heart failure. In a smaller meta-analysis this renal disease benefit was seen in patients with and without atherosclerosis These renal benefits are independent of improvement in glycemic control and occurs in patients without diabetes The mechanism accounting for this effect is unknown but a leading hypothesis is that an increase of sodium chloride in the macula densa due to SGLT2 inhibition triggers a cascade that reduces GFR through constriction of the afferent glomerular arterioles tubuloglomerular feedback , This would reduce glomerular hydrostatic pressure and initially decrease GFR, an effect that is observed with SGLT2 treatment, but in the long run this decrease in GFR protects the kidney from damage resulting in improved kidney function long-term Numerous studies have shown that treatment with SGLT-2 inhibitors decrease liver enzymes 96 , - Moreover, studies have shown a decrease in liver fat and liver stiffness 96 , , , - A study of 5 patients showed an improvement in liver histology after 24 weeks of therapy with canagliflozin Further studies are required to determine whether SGLT-2 inhibitors will result in clinical benefits in patients with NAFLD and NASH.
The decrease in all-cause mortality was seen with all of the SGLT2 inhibitors but was not statistically significant with ertugliflozin. In a meta-analysis of 51 randomized controlled trials involving 24, patients it was noted that the frequency of side effects was similar with high dose and low dose SGLT-2 inhibitors In some but not all studies an increased risk of urinary tract infections was observed with SGLT2 inhibitors 16 , In the large randomized cardiovascular outcome trials, an increase in urinary tract infections were not observed , , In a meta-analysis of 10 large outcome trials with 71, participants the relative risk of urinary tract infection was minimal RR 1.
In a large meta-analysis of 86 randomized trials with 50, patients an increase in urinary tract infections was also not observed The potential increase in the occurrence and severity of urinary tract infections is due to the glycosuria as glucose is an excellent substrate for the growth of micro-organisms.
Genital mycotic infections mainly balanitis and vulvovaginitis are increased with SGLT2 inhibitor treatment The risk of genital mycotic infections is greater in women than men.
In a meta-analysis that included over patients treated with canagliflozin mg or mg vs. In uncircumcised men the risk of genital mycotic infections is greater than in circumcised men. Genital mycotic infections are the most common side effect seen with SGLT2 inhibitors but fortunately these infections are generally mild and relatively easy to treat The increase in genital mycotic infections is due to the glycosuria as glucose is an excellent substrate for the growth of Candida.
Fournier gangrene FG is a necrotizing fasciitis of the perineum that is characterized by a rapidly progressive necrotizing infection of the external genitalia, perineum, and perianal region FG occurs most commonly in males and is a rare condition with an incidence of 3.
In a recent case series of 59 patients over a year period at a single institution, the incidence was estimated at 32 cases per , admissions Risk factors included very high A1c mean 9.
FG is a urologic emergency and requires treatment with broad-spectrum antibiotics and immediate surgical intervention A recent report described 55 FG cases in patients treated with SGLT2 inhibitors in the last 6 years since they were approved for use in the US In contrast, only 19 cases of FG were reported in 35 years among patients receiving other hypoglycemic drugs.
All of the SGLT2 inhibitors were associated with FG except ertugliflozin, which is likely explained by this drug only recently being approved for the treatment of diabetes. However, the authors were unable to assess the incidence of FG or whether SGLT2 inhibitors were causative.
A second study compared the occurrence of FG in patients treated with SGLT2 inhibitors Early recognition of FG is essential to reduce morbidity and mortality. Typical presentations include systemic symptoms, such as fatigue, fever, and malaise, and local symptoms that include tenderness, erythema, and swelling Pain out of proportion to the clinical findings is highly suggestive of necrotizing fasciitis SGLT2 inhibitors induce an osmotic diuresis This effect can result in postural dizziness, orthostatic hypotension, falls, and dehydration, particularly in elderly individuals, patients with kidney disease, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system e.
In a meta-analysis of 10 large outcome studies the risk of volume depletion was modestly increased RR 1. Volume status should be determined prior to initiating therapy with an SGLT2 inhibitor.
SGLT2 inhibitors have been reported to cause acute kidney injury It is likely that volume depletion and hypotension lead to the acute kidney injury In an analysis of two large health care utilization cohorts SGLT2 inhibitors were not associated with an increased risk of acute kidney injury Similarly, in the cardiovascular outcome studies described earlier an increase in acute kidney injury was not observed.
In fact, in a meta-analysis of 4 large studies EMPA-REG, CANVAS, CREDENCE, and DECLARE-TIMI 58 a decrease in acute kidney injury was observed Risk ratio 0.
Similarly, a meta-analysis of 10 studies with 71, participants also did not observe an increase in acute kidney injury and in fact observed a decrease RR 0. Even in patients over age 75 years of age an increase in acute kidney injury was not observed with SGLT2 treatment Before initiating SGLT2 inhibitor therapy one should consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications diuretics, ACE inhibitors, ARBs, NSAIDs.
Consider temporarily discontinuing SGLT2 inhibitors in any setting of reduced oral intake such as acute illness or fasting or fluid losses such as gastrointestinal illness or excessive heat exposure package insert.
Diabetic ketoacidosis DKA has been observed in patients with T2DM treated with SGLT2 inhibitors but is a rare side effect 16 , In some instances, the glucose levels are not very elevated despite the patient having DKA euglycemic DKA and this can result in a delay in diagnosing DKA SGLT2 inhibitors were associated with approximately twice the risk of diabetic ketoacidosis compared to treatment with DPP-4 inhibitors Additionally, in several of the large cardiovascular studies described above an increase in DKA was observed CANVAS Trial- canagliflozin 0.
placebo 0. In a meta-analysis of 10 studies with 71, participants the risk of DKA was increased RR 2. Many of the DKA events occurred in patients with T2DM treated with insulin who had reduced or stopped insulin or experienced an intercurrent illness that could precipitate DKA 16 , In some instances, the patients were thought to have T2DM but actually had latent autoimmune diabetes of adults LADA , a form of Type 1 diabetes The hyperglycemia in DKA associated with SGLT2 inhibitors is typically mild because the SGLT2 inhibitors reduce blood glucose levels SGLT2 inhibitors should be temporarily discontinued in clinical situations known to predispose to ketoacidosis e.
DKA developing during hospitalizations has been described emphasizing the need for vigilance when continuing SGLT-2 inhibitors in patients admitted to the hospital Patients should be educated regarding this potential complication and in high-risk patients for example patients on insulin therapy with a history of poor glycemic control or DKA one could provide the patient with methods to measure ketone levels at home to facilitate the early diagnosis of DKA.
A possible mechanism for the increased risk of DKA is SGLT2 inhibitors increasing plasma glucagon levels thereby increasing ketone production , In combination with the low insulin levels this could potentiate the development of DKA.
In the CANVAS cardiovascular outcome study, the rate of all fractures was higher in the canagliflozin group than in the placebo group A similar trend was observed for low-trauma fracture events canagliflozin placebo 9.
The incidence of fractures in the CANVAS study was increased with canagliflozin vs. placebo across subgroups based on sex, age, duration of Type 2 diabetes, baseline eGFR, and prior fracture history Notably, the increase in fractures associated with canagliflozin treatment began within weeks of drug initiation indicating that the increased risk occurs rapidly In contrast, both the EMPA-REG, VERTIS, and DECLARE cardiovascular outcome studies did not demonstrate an increase in fractures with empagliflozin or dapagliflozin, respectively , , Similarly, in a pooled analysis of 8 randomized canagliflozin studies with participants CANVAS trial excluded an increase in fractures was not observed Moreover, in a meta-analysis of 27 randomized controlled trials with an average duration of 64 weeks that compared the efficacy and safety of SGLT2 inhibitors to a placebo in 20, participants there was no increased risk of fractures with SGLT2 inhibitor treatment RR 1.
Similarly, a meta-analysis of 10 large outcome studies also did not observe an increase in fractures RR 1. Several studies have examined the effect of SGLT2 inhibitors on bone mineral density.
Canagliflozin was associated with a decrease in total hip bone mineral density over weeks, placebo-subtracted changesmg In a 2-year study dapagliflozin did not significantly affect bone mineral density at the lumbar spine, femoral neck, or total hip In a week study ertugliflozin also had no adverse effect on bone mineral density Thus, the evidence that SGLT2 inhibitors increase the risk of osteoporosis and fractures, with the possible exception of canagliflozin, is not very strong.
One should recognize though, that the hypovolemia and hypotension could increase the risk of falls and thereby increase the risk of fractures in susceptible individuals. In the CANVAS study described above, canagliflozin was associated with an increased risk of amputations hazard ratio, 1.
Amputation risk was strongly associated with baseline history of prior amputation and risk factors for amputation peripheral vascular disease and neuropathy. The risk of amputation was low with 6.
The basis for the increase in amputations is unknown. However, the EMPA-REG OUTCOME trial with empagliflozin, the DECLARE-TIMI 58 trial with dapagliflozin, and the VERTIS CV trial with ertuglifozin did not report an increase in amputations in the patients treated with an SGLT2 inhibitor , , , Moreover, in the CREDENCE trial, canagliflozin also did not cause an increase in amputations in the patients treated with the SLGT2 inhibitor placebo group RR 1.
Given that only one of eight large randomized trials has demonstrated an increased risk of amputations it is unlikely that SGLT2 inhibitors significantly increase the risk of amputations. Nevertheless, before initiating SGLT2 inhibitor therapy one should consider factors in the patient history that may predispose them to the need for amputations, such as a history of prior amputation, peripheral vascular disease, severe neuropathy, and diabetic foot ulcers and weigh the risks and benefits of therapy package insert.
Because of the risk of hypovolemia, hypotension, and DKA the administration of SGLT2 inhibitors should be suspended during acute illness or planned surgical procedures. SGLT2 inhibitor therapy may be resumed following recovery.
Medicatjon prescribe Dibaetes medications to treat type Diabetes medication options and type 2 diabetes and help control Fruit-based sugar substitutes blood Soothing irritated skin. Medicatioj may vary iDabetes on your Promoting sustainable eating habits, health, and other factors. In Maythe Food and Drug Administration FDA recommended that some makers of extended-release metformin remove some of their tablets from the U. This is because an unacceptable level of a probable carcinogen cancer-causing agent was found in some extended-release metformin tablets. If you currently take this drug, call a healthcare professional. They will advise whether you should continue to take your medication or if you need a new prescription.
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